WE'D LIKE TO WELCOME ALL OF
YOU BOTH IN THE ROOM AND
WATCHING US ONLY THE VIDEO CAST.
FOR THE WORKSHOP. MOST ARE HERE
TODAY FROM NINE INSTITUTESES AND
CENTERS OF THE NIH. THE FNIH
AND THE FDA. BY WAY OF SOME
BACKGROUND. IT WAS ESTABLISHED
AS PART OF THE CURE ACT. IT WAS
DESIGNED TO ACCELERATE PROGRESS
BY SUPPORTING CLINICAL WORKSHOP
ON ADULT STEM CELLS. THIS
REGENERATIVE MEDICINE IS AN
EFFORT IN COORDINATION WITH THE
FDA. THE RMIP HAS FUNDED ABOUT
20 PROJECTS AND IT'S BEEN
SUCCESSFUL AS A COORDINATED
INITIATIVE ACROSS THE NIH
INSTITUTES AND CENTERS AND OTHER
FEDERAL PARTNERS. BUT, RMIP
FUNDING IS COMPLETED AND WE'RE
ASKING THE QUESTION, OF HOW TO
SUSTAIN COLLABORATION ACROSS THE
NIH AND OTHER AGENCIES TO
FURTHER RESEARCH. WITH ABOUT
TWO THOUSAND CLINICAL TRIALS
ONGOING IN REGENERATIVE MEDICINE
WORLDWIDE EVERYONE HERE KNOWS
THAT REGENERATIVE MEDICINE HOLDS
GREAT PROMISE FOR TREATING AND
EVEN CURING A VARIETY OF
INJURIES AND DISEASES BUT WE
ALSO KNOW THAT MORE WORK REMAINS
TO BE DONE TOWARDS THE
DEVELOPMENT OF SAFE AND
EFFECTIVE REGENERATIVE MEDICINE
PRODUCTS TO REALIZE THE FULL
POTENTIAL OF THIS FIELD. THE
NIH AND OUR FEDERAL PARTNERS ARE
HOLDING WITH WORKSHOP TO LEARN
ABOUT YOUR EXPERIENCES, BOTH
YOUR SUCCESSES AND YOUR
CHALLENGES WHETHER YOU WERE
FUNDED BY RMIP OR NOT AND TO
IDENTIFY RESEARCH QUESTIONS THAT
ARE SHARED ACROSS ISSUES AND
DISEASES WHERE AN NIH-WIDE
APPROACH WOULD BE VALUABLE AND
I'M NOW GOING TO TURN THE
MEETING OVER TO BOB CARTER FOR
HIS REMARKS INVOLVING THE
WORKSHOP.
>> BOB CARTER: THANK YOU. AND
REALLY GLAD TO SEE EVERYBODY
HERE. THIS MEETING GOT PLANNED
ON A VERY FAST TIMELINE AND IT'S
WONDERFUL THAT WE MANAGED TO GET
YOU ALL HERE. AND LOOK FORWARD
TO WHAT YOU HAVE TO SAY AND I
THINK SHE CAPTURED WHAT WE'RE
TRYING TO DO BUT I WANT TO
EMPHASIZE A COUPLE POINTS.
FIRST OF ALL, LET'S HAVE THE
MEMBERS OF THE WORKING GROUP WHO
ARE HERE, STAND UP. SO THESE
-- THERE'S THE KIND OF MEDICINES
WHERE YOU GIVE PEOPLE PILLS OR
ANTIBIOTICS OR WHATEVER AND THEN
THERE'S SURGERY AND THEN THERE'S
REYEN RAHTIVE MEDICINE AND I
THINK WE CAN ALL AGREE THAT THE
BEST OUTCOME FROM ANY INJURY OR
DISEASE WOULD BE TO REGROW
HEALTHY TISSUE AND THAT'S REALLY
WHAT WE'RE ABOUT. SO WHAT ARE
THE CHALLENGES AND HOW DO WE
MEET THEM SO THAT WE CAN GET
MORE OF REGENERATIVE MEDICINE
APPROACHES TO BE USED IN THE
CLINIC. AT A SCALE THAT'S
FEASIBLE AND A COST THAT DOESN'T
PRECLUDE A LOT OF PEOPLE FROM
RECEIVING IT? THAT'S ACTUALLY A
BIG CHALLENGE. AND WE'RE
ACTUALLY STILL A GOOD WAYS FROM
THAT. IN PART BECAUSE A LOT OF
THIS IS PERSONALIZED. IN PART
BECAUSE IT'S NEW IN PART BECAUSE
IT'S CELLS WHICH IS A LOT
DIFFERENT THAN AN ANTIBODY AND
IN PART BECAUSE SOMETIMES WE
MANIPULATE THE CELLS AND WE HAVE
TO BE CAREFUL WHAT DID WE
PRODUCE IN THE TEST TUBE? SO
THE POINT TO THINK ABOUT, THE
SORT OF FRAME OF REFERENCE IS
NOT JUST WHAT IS THE NEXT
EXPERIMENT FOR MY LAB BUT WHAT'S
THE THING THAT NIH CENTERS AND
INSTITUTES CAN DO TOGETHER TO
MOVE THIS WHOLE FIELD FORWARD?
THAT'S NOT TO SAY WE DON'T WANT
TO LOOK AT INDIVIDUAL PROJECTS
BUT WE WANT TO LOOK AT
INDIVIDUAL PROJECTS IN THAT
CONTEXT. SO THERE MAY BE SOME
REYEN RAHTIVE MEDICINE APPROACH
THAT ACTUALLY HAS SOME
SIMILARITIES. BECAUSE YOU HAVE
TO MAINTAIN CELLS AND SOMETIMES
MANIPULATE THEM. WHAT CAN WE
LEARN FROM DOING THAT IN
DIFFERENT SYSTEMS? SO THE EXACT
APPROACHES, EXACTLY, WE TAKE AN
IPS CELL, HOW DO YOU REPAIR AN
ORGAN BUT HOW DO YOU ASSESS
WHETHER WHAT YOU PRODUCED IS THE
RIGHT THING, ITS QUALITY
ASSURANCE WHETHER IT'S NOT GOING
TO KILL SOMEBODY WHICH IS NOT
TRIVIAL AND THAT IT'S GOING TO
WORK FOR EVERYTHING THAT YOU
PRODUCE. IS KIND OF A SHARED
QUESTION THAT GOES ACROSS ALL OF
REGENERATIVE MEDICINE SO IT
CAN -- IN MY MIND I DO THINK OF
SPECIFIC PROJECTS THAT WE MIGHT
THINK ABOUT THAT WE MIGHT
ULTIMATELY WANT TO FUND SOZ R
SORT OF AS WE DID WITH MRP SO WE
TAKE STEM CELLS AND LOOK AT THE
JOINT OR CARDIAC TISSUE OR
RETINA. AS LONG AS THOSE
PROJECTS ARE DESIGNED SUCH THAT
THEY WOULD PRODUCE DATA THAT
WOULD ENABLE ALL THOSE DIFFERENT
APPROACHES TO MOVE FORWARD
FASTER. AND, IN FACT, AT A
RECENT NATIONAL ACADEMIES
CONFERENCE ON THEIR REGENERATIVE
MEDICINE PARTIALLY ORGANIZED BY
CHRIS ROY WHO IS ONE OF THE
ORGANIZERS OF THIS MEETING BUT
COULDN'T TRAVEL LOOKED AT
MANUFACTURING AND THE THING THAT
CAME OUT WAS HOW DO YOU DO
QUALITY ASSURANCE AT THE END
AFTER YOU PRODUCED YOUR PRODUCT
HOW DO YOU MAKE SURE THAT IT'S
FIT FOR PURPOSE? AND THAT -- HE
WAS ACTUALLY -- CAME OUT OF THAT
MEETING AS PROBABLY ONE OF THE
BIGGEST HOLDUPS BECAUSE ACTUALLY
AS A CLINICIAN YOU WANT TO BE
SURE BUT ALSO FOR REGULATORY
PURPOSES YOU HAVE TO BE SURE.
CAN WE PRODUCE DATA TO ALLOW US
TO GET A BETTER IDEA OF WHAT ARE
THE CHARACTERISTICS OF THE
THINGS THAT WE PRODUCE THAT MAKE
THEM FIT FOR PURPOSE? SO IT MAY
BE BASED ON INDIVIDUAL PROJECTS
WITH SPECIFIC CELLS AND SPECIFIC
TISSUES BUT IF IT CAN HELP US
GET THE DATA THAT WE CAN USE AND
PERHAPS WE'RE GOING TO BE HEADED
TOWARDS MACHINE LEARNING TO
UNDERSTAND WHAT THE PARAMETERS
ARE THAT ACTUALLY DETERMINE
WHETHER SOMETHING IS FIT FOR
PURPOSE, WHAT WE MIGHT BE ABLE
TO DO IS HELP GENERATE THE DATA
THAT CAN BE THEN APPLIED TO
ANSWER THOSE QUESTIONS TO SPEED
THINGS THROUGH, BOTH MOVE FROM
MANUFACTURING AND INTO THE
PATIENT AND THE REGULATORY
PROCESS. SO I HOPE I'M TRYING
TO DESCRIBE SORT OF A THOUGHT
FRAMEWORK THAT WE HAVE TO KEEP
IN MIND TODAY. SO THERE ARE TWO
DIFFERENT GOALS. THIS, THE IDEA
FOR THIS MEETING CAME OUT OF
REGENERATIVE MEDICINE INNOVATION
PROJECT AND THE IDEA WAS WE
FUNDED A LOT OF RESEARCH,
DIFFERENT STAGES OF PRECLINICAL
ALL THE WAY TO CLINICAL TRIALS.
AND SOME OF THEM ARE ONGOING NOW
RECENTLY FUNDED A YEAR AGO. BUT
WHAT CAN WE LEARN FROM THIS?
AND HOW DO WE SUSTAIN THE
MOMENTUM OF REGENERATIVE
MEDICINE INNOVATION PROJECT OF
BRINGING THE NIH INSTITUTES AND
CENTERS TOGETHER AND WHAT ARE
THE PLACES WHERE WE CAN FIND
COMMON GROUND? AND AS I'VE
DESCRIBED, A LOT OF THINGS MAY
BE ONE-OFF PROJECTS THROUGH
THERE SHOULD BE SHARED LEARNING
ACROSS THEM. THROUGH THE
EFFORTS ACTUALLY I WILL GIVE
CREDIT TO SUSANNA STEIN AND TONY
STARTED THINKING ABOUT WHAT ARE
THE OPPORTUNITY TO ACTUALLY DO
SOMETHING HERE
AND THAT RELATED TO THE
ACCELERATING MEDICINES
PARTNERSHIP RUN THROUGH FNIH AND
COURTNEY S HERE IS THE
REPRESENTATIVE AND ACTUALLY IN
CHARGE OF OF THE PARTNERSHIP AND
THEY HAD THE BESPOKE CONSORTIUM
AND WHAT THAT GROUP DID WAS
DIFFERENT FROM THE OTHER
PARTNERSHIP. IT TOOK WHAT THEY
CALLED A PLATFORM THEY TOOK A
SINGLE APPROACH AND FOCUSED ON
IT WITHOUT REALLY THINKING
BEFOREHAND WHAT IS THE DISEASE
AND CONDITION WHICH IS THE EXACT
OPPOSITE OF MOST OF THE
ACCELERATING MEDICINES PROJECT
BUT THEY DECIDED IF YOU COULD
REALLY IMPROVE AAV THERAPY THAT
WOULD BENEFIT EVERYBODY AND THEY
TOOK TWO APPROACHES ONE WAS HOW
DO YOU MAKE A BETTER AAV AND THE
OTHER IS HOW DO YOU MAKE IT IN
THE, YOU KNOW, IN -- MANUFACTURE
IT AND WITH THOSE TWO FOCUSES SO
IT'S A PLATFORM APPROACH AND
THEN THEY TAKE THOSE TWO SORT OF
GOALS FUNDED NOW A BUNCH OF
CLINICAL TRIALS IN DIFFERENT
DISEASES BY EACH WITH THAT
PURPOSE OF UNDERSTANDING THOSE
BOTH THE BASIC BIOLOGY.
OR HOW DO YOU MANUFACTURE IT TO
MAKE IT MORE UNIFORM BETTER
PROJECT? SO I THINK THAT'S
WHERE WE WANT TO DEVELOP. WE
SPOKE TO THE BESPOKE GENE
THERAPY AND SAID YOU HAVE A NICE
PLATFORM HERE FOR TESTING THIS
APPROACH. BUT THE AAV IS KIND
OF RESTRICTED TO ONE PLACE THAT
WE MAY NOT EVEN THINK IS THE
BEST ONE FOR THE FUTURE. CAN WE
BUILD ON THAT? CAN WE USE THAT
PLATFORM TO LOOK AT OTHER
APPROACHES? AND THE ANSWER WAS
THEY HAD THEIR HANDS FULL. THEY
DIDN'T WANT TO BROAD -- THE
BESPOKE GENE THERAPY CONSORTIUM
BUT THEY DID -- WERE WILLING TO
WORK WITH US AS SORT OF A
PARALLEL PROCESS TO TAKE THAT
IDEA OF A PLATFORM, TO TAKE THE
WAY THEY STRUCTURED IT, THE WAY
THEY SET UP A THEME TO FIND THE
THEME AND THEN FUNDED CLINICAL
TRIALS WITHIN THOSE THEMES SO
THAT'S WHERE WE'RE HEADED NOW
FOR THE CELL BASED THERAPIES
CONSORTIUM THE GOOD NEWS IS THAT
THE EXECUTIVE COMMITTEE FOR THE
OVERALL ACCELERATED MEDICINES
PROJECT HAS APPROVED CBTC. CELL
BASED THERAPIES CONSORTIUM AS A
CONCEPT WITHIN THE ACCELERATING
MEDICINES PARTNERSHIP WHAT THAT
MEANS IS COURTNEY'S TEAM WORKS
TO PUT TOGETHER THE DIFFERENT
STAKEHOLDERS AND SEE WHO CAN
HELP DESIGN THE PROTOCOL,
ADDRESS THE QUESTION OF WHAT'S
THIS PLATFORM GOING TO BE AND
HOW DO WE APPROACH IT?
ALTERNATIVELY THOUGH WE HAVE TO
GET A PROTOCOL THAT WILL BE OF
INTEREST TO MULTIPLE DIFFERENT
STAKEHOLDERS THAT INCLUDE NIH,
FDA BUT ALSO INDUSTRY AND IT
WILL BE A PARTNERSHIP BETWEEN
THOSE GROUPS WITH FUNDING FROM
BOTH THOSE GROUPS IF IT'S GOING
TO WORK. IN OTHER WORDS,
NOTHING'S GOING TO MOVE FORWARD
THAT IS NOT OF INTEREST ACROSS
THOSE DIFFERENT GROUPS. SO WE
HAVE TO KEEP THAT THOUGHT IN OUR
HEAD. WHAT IS THE PLATFORM THAT
WE CAN USE TO ADVANCE CELL BASED
THERAPIES THAT WILL BE BROADLY
OF INTEREST TO THOSE DIFFERENT
STAKEHOLDERS. SO WE'RE DOING
PRETTY WELL. THAT'S THE MESSAGE
I WANT TO DELIVER. IF THERE ARE
ANY QUESTIONS ABOUT WHAT I JUST
SAID? WELL, EITHER YOU ARE
REALLY CONFUSED OR -- SO WE ARE
GOING TO START WITH WHAT WAS THE
INITIAL SORT OF IMPETUS FOR THIS
MEETING. WHICH IS TO THINK
ABOUT HOW NIH INSTITUTES AND
CENTERS CAN WORK TOGETHER TO
ADVANCE REGENERATIVE MEDICINE.
AND THE -- AS WE SAID, WHAT WE
WANTED TO DO INITIALLY WAS BRING
TOGETHER THE RMIP INVESTIGATORS
TO TELL US ABOUT THEIR
EXPERIENCE OF LESSONS LEARNED,
OF WHAT HAS WORKED, WHAT HASN'T
AND THINK ABOUT COMMON
CHALLENGES GOING FORWARD.
HAVING DESIGNED THE MEETING WITH
THAT AS THE INITIAL GOAL, WE
THEN SAID, WELL, WAIT A MINUTE,
THERE ARE OTHER PEOPLE IN
REGENERATIVE MEDICINE WHO ALSO
MIGHT HELP US ANSWER THOSE
QUESTIONS AND SO WE BEGAN
INVITING A BUNCH OF OTHER
INVESTIGATOR WHO IS WERE NOT
FUNDED BY RMIP BUT COULD HELP
ABOUT SHARED INTERESTS GOING
FORWARD SO THE FIRST TWO
SESSIONS ARE ON THOSE BASIS.
AND WE HAVE TWELVE SPEAKERS IN
THE FIRST ONE, ALL FROM RMIP.
AND WE HAVE AN HOUR AND A HALF
SO THE TIME IS POSSIBLE IF
PEOPLE KEEP THEIR REMARKS TO
FIVE MINUTES WHICH IS WHAT THEY
WERE ASKED TO DO. AND MY
CO-CHAIR FAY WONG WILL HELP
POLICE THIS. IN FOUR MINUTES
SHE'LL HOLD UP A CARD AND AT
TIME ZERO WHEN FIVE MINUTES ARE
UP SHE WILL INTERFERE POLITELY
AND SHE'S VERY QUIET AND
RESERVED AND I HATE TO SAY IT
BUT THAT'S A JOKE. SO TALK
ABOUT GOOD COP BAD COP I GOT THE
GREAT BAD COP. SO WE DO WANT TO
TRY TO KEEP THAT ON TRACK.
OBVIOUSLY WHAT WE'RE GOING TO DO
IS TRANSITIONS WILL NEED TO BE
QUICK AND THANK YOU, ALL, FOR
GETTING YOUR SLIDES. WHERE IS
JANNA? IS SHE STEPPED OUT?
GOOD BECAUSE JANNA IS THE HERO
OF THIS WHOLE THING. SHE WAS AN
ANALYST AND WITHOUT HER EFFORTS
PULLING THIS THING TOGETHER IT
WOULD NOT HAVE HAPPENED SOME OF
YOU WERE BRINGING SLIDES TO HER
ONLY TEN MINUTES AGO. SOME OF
YOU MAY BE E-MAILING SLIDES TO
HER NOW SO WE HOPE THE ORDER
WORKS OUT AND WE HOPE WE GET THE
RIGHT SLIDE SET IN FACT SOME OF
THE TITLES HAVE CHANGED, SO WHAT
WE'RE GOING TO DO IS GO PRETTY
QUICKLY THROUGH THAT. IF WE
HAVE TIME AT THE END, WE CAN
START TO SAY, OKAY, WHAT WERE
THE THEMES THAT WE HEARD? WHAT
WERE THE THINGS THAT RESONATE AS
CROSS NIH PROJECTS COMING OUT OF
MEDICINE? THESE INVESTIGATORS
HAVE BEEN WORKING IN A PROGRAM
WHICH IS -- WHICH OPERATES
ACROSS NIH WHERE HAS THAT
WORKED? WE KNOW THAT THE
NEGATIVES, RMIP REQUIRED
MATCHING FRONTS FROM SOMEBODY
OUTSIDE OF NIH EITHER THE HOST
SOLUTION AND SOMETIMES ADVOCACY
ORGANIZATIONS. THAT OBVIOUSLY
WAS A PRETTY BIG IMPEDIMENT. WE
KNOW THINGS LIKE THAT SO REALLY
KEEP THE QUESTION FOCUSED ON THE
FUTURE OF HOW WE WORK TOGETHER.
THE SECOND SESSION WILL BE THE
SPEAKERS FROM OUTSIDE OF RMIP
THAT REALLY STILL FOCUSED ON
THAT INITIAL QUESTION. OF HOW
CAN NIH INSTITUTES AND CENTERS
WORK TOGETHER TO ADVANCE THIS
FIELD? AT THAT POINT WE THEN
START TO SHIFT. AND WE'LL BRING
IN SOME OTHER SPEAKERS FROM --
WHO ARE NOT INVESTIGATORS BUT IN
OTHER CASES ADVOCATE
ORGANIZATIONS, INDUSTRY
REPRESENTATIVES, SOMETIMES
ORGANIZATIONS THAT ARE FUNDED BY
INDUSTRY TO FORWARD THEIR
INTEREST. AND HEAR THEIR
PERSPECTIVES SO THAT WE KEEP
THAT IN MIND BEFORE WE START
GETTING INTO DETAILS OF WHAT WE
MIGHT DO WITHIN CELL BASED
THERAPIES CONSORTIUM AND THEN
TALK ABOUT THE FDA ABOUT THEIR
PERSPECTIVES ON WHAT THE NEEDS
ARE AND THEN GET INTO THE
SESSIONS ON TWO TOPICS THAT WE
THINK MIGHT BE RIGHT. ONE ON
TISSUE SPECIFIC STEM CELLS AND
THEN ONE ON IPSCS. THAT DOESN'T
MEAN THAT THESE ARE OUR ONLY
INTERESTS. SO WHAT WE TALKED
ABOUT IN A LOT OF OUR OTHER
OPPORTUNITIES, FOR EXAMPLE,
ORGANOIDS AND MAYBE WE WILL BE
ABLE TO ORGANIZE SOMETHING
AROUND ORGAN NOISE IN THE
FUTURE.
BUT WE WILL THEN END WITH A
GROUP DISCUSSION OF WHAT ARE THE
THINGS WE HEARD, WHAT DO WE
THINK AS A GROUP IS RIGHT FOR
CELL BASED THERAPIES CONNOISSEUR
SHIM AS A PLATFORM.
AND THEN AT -- ACTUALLY WE'RE
GOING TO CHANGE THE AGENDA TO
ONE PLACE. NIH INSTITUTES AND
CENTERS LISTEN, WANT TO LEARN
FROM YOU, BUT WE HAVE TO BE
CAREFUL THAT WE DON'T TRY TO USE
YOUR INFORMATION TO ACTUALLY
START WRITING FUNDING
OPPORTUNITY ANNOUNCEMENTS WE
CAN'T GIVE ANYBODY A HEAD START
NOW WE ARE VIDEO CAST, THIS IS
PUBLIC. BUT WE DECIDED TO MAKE
THE -- ACTUALLY WHAT HAD BEEN
THE FINAL SESSION THE CLOSE
SESSION JUST SO THAT THE NIH CAN
MEET AND TALK ABOUT WHAT THEY
HEARD AS OF THING. SO WE MIGHT
CHANGE THE AGENDA JUST A LITTLE
BIT THERE. WHEN WITH THAT, WE
CAN LAUNCH INTO SESSION ONE.
SO, AGAIN, AS I HEARD FROM YAN
-- JANNA, SOME OF THE TITLES
HAVE CHANGED.
AND I WILL READ OUT THE NAME OF
THE SPEAKER AND THE SPEAKER
AFTER THAT. HOPEFULLY THE
SPEAKER WILL COME FORWARD AND
THE ONE WHO IS ON DECK CAN COME
AND HANG OUT SO THEY'LL BE READY
TO GO AS SOON AS THE FIRST
SPEAKER'S DONE. JANNA, DO YOU
HAVE -- OKAY. JANNA DIDN'T GET
EMBARRASSED BECAUSE SHE WASN'T
IN THE ROOM WHEN I WAS SINGING
PRAISES. UNBELIEVABLE WE'VE
GOTTEN THIS FAR. SO THE FIRST
SPEAKER IS G AND AFTER THAT IS
DENNIS SO IS THERE A MICROPHONE,
DENNIS, CAN YOU GET UP ON THE
PODIUM OR ARE WE GOING TO NEED A
MICROPHONE? MAYBE JUST PULL UP
A CHAIR UP HERE? SO, YES,
THEY'RE BRINGING IT UP. OKAY.
THE FLOOR IS YOURS.
>> GOOD MORNING, I WOULD LIKE TO
THANK THE ORGANIZERS FOR
ORGANIZING THIS MEETING AND FOR
INVITING ME TO BE HERE. SO WE
WERE ASKED TO ANSWER THREE
QUESTIONS. THE FIRST ONE WAS
WHAT IS RMIP FUNDING ALLOW YOU
TO ACCOMPLISH THAT WOULD BE
DIFFICULT OTHERWISE AND WE WERE
ABLE WITH THIS FUNDING TO
ISOLATE AND DETECT WHAT WOULD BE
THE BEST CELLULAR PLATFORM TO
MODIFY WITH BIO ENGINEERED GENE
TO PROVIDE FACTOR EIGHT PROTEIN
TO TISSUES SO WE MANUFACTURED
AND TESTED THIS NEW REGENERATIVE
MEDICINE PRODUCT THAT WAS
DESIGNED TO SPECIFICALLY TREAT
HEMOPHILIA A PRIOR TO BIRTH WE
TEST THE THERAPEUTIC POTENTIAL
OF THIS PRODUCT IN A LARGE
ANIMAL MODEL AND THE PRODUCT
CONSISTED OF CELLS TRANSDUCED
WITH THE TRANSGENE A GENE THAT
PRODUCES FACTOR EIGHT AND WE
LOOKED AT THE SYSTEMIC TOXICITY
OF THIS PRODUCT AND WE FOUND
THAT THE PRODUCT WAS SAFE AND
THAT REMAIN FOR FOUR YEARS.
THAT IS A PRECLINICAL MODEL THAT
WHEN WE INJECT THE CELLS THE
SHEEP WEIGHS ONE HUNDRED GRAMS
AND BY YEAR FOUR ONE HUNDRED
KILOS SO THE CELLS REMAIN AND
PRODUCE FACTOR EIGHT LEVELS WE
ALSO ASK THE QUESTION WHAT THIS
THERAPY WOULD BE SAFE FOR THE
MOTHER. AND WE SHOW THAT
NEITHER THE CELLS OR THE PROTEIN
PASS THE PLACENTAL BARRIER AND
REACH THE MOTHER. WE WERE ABLE
TO HAVE THE CLINICAL TRIAL AFTER
WE OBTAIN IND APPROVAL. THE
SECOND QUESTION THAT WE WERE
ASKED WAS WHAT DO YOU SEE AS THE
MOST PROMINENT SHARED OR
CROSSCUTTING CHALLENGES TO
GETTING THERAPIES TO PATIENTS?
AND WORKING IN A FIELD OF FETAL
THERAPIES, AND SPECIAL CELLULAR
THERAPIES WE KNOW THERE'S A NEED
FOR AGE SPECIFIC THERAPEUTIC
PRODUCTS SUCH AS THE FETUS
DOESN'T HAVE THE SAME BIOLOGY AS
AN ADULT OR EVEN CHILD. WE ALSO
NEED TO TREAT THESE PATIENTS
EARLY IN GESTATION AND
THEREFORE, WE NEED RELIABLE AND
NON EVASIVE DIAGNOSTIC PLATFORMS
FOR EARLY DETECTION OF GENETIC
DISORDERS OR OTHER DISORDERS.
TO AND -- AND REPLACE THE
DIAGNOSTIC TOOLS BECAUSE TIME IS
OF ESSENCE AND ALSO
EXTRAPOLATING TO A BROADER FIELD
WE KNOW THAT THE TIME TO
MANUFACTURE PRODUCTS FOR
PERSONALIZED ALOE YES NAYIC IS
OF ESSENCE FOR THESE PATIENTS.
SO WE NEED A REDUCTION OF
PROCESSING AND HANDS ON TIME SO
SORT OF AUTOMATION THAT ABLE TO
GENERATE THESE PRODUCTS QUICKLY
WE NEED A CONSISTENCY OF RESULTS
INDEPENDENT OF THE SITE OF
MANUFACTURING.
AND TO ADDRESS THE PRODUCTS IN
ORDER TO TRANSLATE THESE
PROJECTS QUICKLY TO THE CLINIC
WE NEED INFRASTRUCTURES TO
MANUFACTURE THESE PRODUCTS AT
ACADEMIC INSTITUTIONS WE NEED
INFRASTRUCTURES THAT WE CAN PUSH
PRODUCTS THROUGH THE REGULATORY
APPROVAL OF NEW PRODUCTS. AND
THOSE INSTITUTIONS TO PERFORM
CLINICAL TRIALS OR AT LEAST TO
ADMINISTER THE THERAPIES. WE
ALSO NEED THE STANDARDIZED AND
VALIDATED SYSTEMS FOR CELL
ISOLATION AND WE NEED THE
RECRUITMENT WITH ACCURATE
INFORMATION AND FAIR ACCESS TO
DIAGNOSIS AND THERAPIES AND
LATELY, WHAT RESEARCH IS NEEDED
TO OVERCOME THESE CHALLENGES AND
I THOUGHT THAT DEVELOPMENT -- A
VALUELATION OF DIAGNOSTIC
TECHNOLOGIES IS APPROPRIATE FOR
ALL AGES BECAUSE WE DON'T KNOW
THE INFLUENCE OF DISEASE STAGE
ON OUTCOME OF CELL THERAPIES.
WE NEED DEVELOPMENTAL CELL
THERAPIES SPECIFIC FOR PATIENT
AGE. WE COULD USE MANUFACTURING
CELL THERAPIES PLATFORMS THAT
COULD BE USED TO TREAT BROAD
RANGES OF DISEASES.
IDENTIFICATION AND MANUFACTURE
OF ALOE YES NAYIC SOURCES AND
LABEL CELL -- LABEL FREE CELL
SYSTEMS TO GENERATE AND REACH
POPULATIONS OF CELLS WITH
MINIMAL MANIPULATION. THANK
YOU
YOU.
>> BOB CARTER: THAT WAS PRETTY
WELL PERFECT. ALAN IS ON DECK
AND DENNIS. I WILL ADVANCE THE
SLIDES FOR YOU. WE NEED TO
GET -- JANNA, HOW TO -- SO JUST
DOWN? IS THAT YOU, DENNIS?
>> DENNIS: (SPEAKER FAR FROM
MIC) OF HOW WE CAN ADDRESS THESE
CHALLENGES. NEXT SLIDE. OKAY,
SO WITH RESPECT TO CLONE TO
CLONE VARIATION AND THE CAPACITY
TO DIFFERENTIATE INTO DIFFERENT
ADULT LANGUAGES I THINK IT'S KEY
TO IDENTIFY EARLY MARKERS THAT
WOULD INDICATE THE CAPACITY OF A
GIVEN CLONE TO DIFFERENTIATE
INTO THAT ADULT LINEAGE AND
THAT, AGAIN, IS KIND OF A
COMBINED BIOINFORMATICS CELL
BIOLOGY ISSUE. WITH RESPECT TO
DIFFERENTIATING IPSC HAVE
DIFFERENT EFFICIENCIES AT LEAST
IN OUR CASE AND I THINK WE HAVE
A SPEAKER TOMORROW THE USE OF
ORGANOIDS WHERE YOU
DIFFERENTIATE IN A 3D MICRO
ENVIRONMENT WRA Y WHERE YOU HAV
CELL INTERACTION TO SOLVE THAT
PROBLEM.
WITH RESPECT TO TO USING
ORGANOIDS, AGAIN, I THINK
IT'S -- IT'LL BE CURIOUS TO SEE
HOW THE FDA RESPONDS TO USING
ORGANOIDS THAT MAY ACTUALLY --
GRAPHED IN AN HOUR PRECLINICAL
TEST FUNCTIONAL BUT WE MAY NOT
IDENTIFY ALL THE CELL TYPES TO
THE DEGREE OF CHARACTERIZATION
THAT THE FDA MAY REQUIRE WITH
RESPECT TO IDENTIFYING HEALTH
TARGET INSTEAD OF REQUIRING
SEQUENCING WHICH IS CLEARLY
GOING TO SHOW A LOT OF MUTATIONS
THAT MAY NOT HAVE ACTUALLY AN
IMPACT ON FUNCTION, MAYBE SELECT
PANEL THAT WOULD POTENTIAL
ONCOGENES TO FOCUS ON AND
FINALLY WITH REQUIRE POLY
ALLYLIC DISEASES, INSTEAD OF ONE
GUIDE PER IND CONSIDER EACH
GUIDE RNA HAS AN AGENT CHANGE
AND I THINK THIS WOULD SIMPLIFY
THIS ISSUE FOR THOSE WORKING ON
RARE DISEASES THAT ARE POLY
ALLELIC. SO THOSE ARE MY
COMMENTS.
>> THANK YOU, DENNIS, ALAN WITH
TIMOTHY CAMP ON DECK. IS
TIMOTHY HERE, YEP.
>> I GOT MY RPIP AWARD IN 2020.
THERE WAS A LOT OF WORK THAT WAS
NOT FUNDED BUT PART OF TWO
COMPANIES I'VE WORKED WITH. THE
GOAL OF OUR WORK WAS TO BRING AN
OFF THE SHELF ALOE YES NAYIC
DERIVED CELL TO THE MARKET. TO
TREAT AGE-RELATED MACULAR
DEGENERATION DISEASE THAT
AFFECTS NEARLY TWO HUNDRED
MILLION PEOPLE WORLDWIDE THE
PICTURES ARE EXAMPLES OF THAT
PRODUCT BUT THE RMIP AWARD WAS
FOR THE DEVELOPMENT OF MASTER
AND WORKING BANKS FOR USE IN
THIS ALOE YES NAYIC CELL THERAPY
AND MAYBE OTHERS. WHEN WE DID
THAT WORK, THE CELL LINE THAT WE
WERE WORKING WITH WHICH WAS A
RARE CELL LINE BUT WE HAVE FOUND
WITH RIPCSS IS IT'S 5% OF LINES
THAT WE'VE TESTED HAVE THE
CHARACTERISTICS THAT WE WERE
LOOKING FOR IN AN ALOE YES NAYIC
THERAPY WITH REGARD TO
DIFFERENTIATION AND WITH FIVE
MINUTES I CAN'T GO INTO DETAILS
OF THAT. BUT ABOUT 95% DON'T SO
THIS WAS A VERY SPECIAL CELL
LINE WE DID THE MASTER BANK WE
DID THE WORKING BANK. WE HAD
ALL OF THE DOCUMENTATION AND
REGULATORY FILINGS REVIEWED
ACTUALLY BY THREE DIFFERENT
INDEPENDENT CONSULTANTS AND
DETERMINED AFTER THAT AN
INTERACTION THAT THERE WERE A
FEW PROBLEMS WITH THAT CELL LINE
AND THESE WERE NOT IN THE AREA
OF DONOR ELIGIBILITY,
DOCUMENTATION SURROUNDING THE
PROGRAMMING VECTORS AND
UNFORTUNATELY SOME POOR
RECORDKEEPING AROUND THE FIE
FIBROBLASTS EXTENSION.
IN THE SUBSEQUENT YEARS WE MADE
SOME NEW CELL LINES OUR DONOR
ELIGIBILITY CRITERIA FOR REVISED
AND THE COMPLIANT PROCESSES THAT
COVER THE POOR RECORDKEEPING
WERE PUT INTO PLACE. AND A NEW
CELL LINE WAS GENERATED USING
GMP-LIKE PRACTICES AND I WANT TO
SAY GMP-LIKE BECAUSE WE'RE
MAKING THIS LINE ONE TIME AND
IT'S ALWAYS BEEN AN ISSUE
BECAUSE WHAT I HAVE FOUND WITH
IPCSS IS ONE IPCS DOES NOT WORK
THE SAME AS THE NEXT THE NUMBER
OF DEVIATIONS THAT YOU HAVE TO
FILE IN YOUR RECORDKEEPING IF
YOU THINK THAT EVERY IPSC
MANUFACTURE THE SAME WAY IS
GOING TO BE DONE THE SAME WAY IS
INCALCULABLE GMP-LIKE AND FROM
THIS, WE HAD ONE LINE OUT OF 23
CLONES THAT WERE ISOLATED FROM
FIBROBLASTS THAT WERE DONATED BY
FOUR SEPARATE DONORS THAT HAD
SUITABLE PROPERTIES FOR
DEVELOPMENT AND TO PUSH FORWARD
IN OUR WORK. SO WHAT ARE THE
CHALLENGES THAT WE IDENTIFIED
HERE? I LISTED TWO BECAUSE
THESE ARE THE TWO BIG ONES IN MY
OPINION THE FIRST ONE REALLY IS
THE MANUFACTURER OF IPSCS IN OUR
OPINION YOU NEED TO HAVE BETTER
THAN A 98% YIELD OF THE FINAL
DESIRED CELL TYPE AND PREFERABLY
HIGHER THAN THAT THOUGH IT'S
DIFFICULT TO ASSESS PERCENTAGES
THAT ARE GETTING INTO THAT RANGE
I KNOW IN OUR INTERACTIONS WITH
THE AGENCY THEY'VE ASKED US
EVERY SINGLE TIME TO TELL THEM
WHAT THE IMPURITIES ARE. SO
THIS IS SOMETHING THAT WE
DEFINITELY SEE AS A CHALLENGE.
ONE OF THE PROBLEMS IN
GENERATING THE IPS LINES IS THAT
THE EXPRESSION OF POTENT MARKERS
OR DIFFERENTIATION REALLY
DOESN'T CORRELATE WITH THE
UTILITY OF THE LINE AT ALL.
EVERY SINGLE ONE OF THOSE 23
CLONES THAT I MENTIONED IN THE
PREVIOUS SLIDE ALL OF THEM
EXPRESSED LARGE PERCENTAGES OF
POTENCY MARKERS, ON FLOW, ALL OF
THEM PERFORMED BEAUTIFULLY IN
TRILINEAGE ASSAYS AND THE VAST
MAJORITY OF THEM WERE ABSOLUTELY
GARBAGE FOR USE IN TERMS OF
MANUFACTURE OF A THERAPEUTIC THE
IPS LINES THAT YOU DO HAVE TO
HAVE NO SPONTANEOUS
DIFFERENTIATION. THIS IS ONE OF
THE ATTRIBUTES THAT WE LOOKED AT
AND SOMETHING THAT NEEDS TO BE
LOOKED INTO TO UNDERSTAND HOW
AND WHY WE CAN REMOVE THAT. THE
OTHER THINGS THESE ARE JUST
REGULATORY CONCERNS REALLY THAT
PURIFICATION INVOLVING REAGENTS
SO WHEN YOU'RE DIFFERENTIATING
THAT MAY BE REGULATED AS
BIOLOGICS ON THEIR OWN WHICH
REALLY MAKES THE REGULATORY
FILINGS EXTRAORDINARILY
COMPLICATED JUST A PERSONAL
EXPERIENCE CDMOS DO NOT
APPRECIATE THE CHALLENGES OF
WORKING WITH IPSCS AND REALLY
ULTIMATELY, IF YOU WANT TO BRING
AN ALOE YES NAYIC CELL TO MARKET
YOU NEED TO HAVE UNIVERSAL DONOR
CELLS THE COMPLEXITY IS SUCH TO
TAKE ONE THAT IS GOOD AND
FURTHER SUBJECT IT TO ANY SORT
OF GENE EDDIITING OR OTHER
PROCEDURES LIKE THAT MAY HAVE
TERRIBLE CONSEQUENCES FOR THE
UTILITY OF THAT CELL LINE I WILL
LEAVE IT AT THAT. THANK YOU.
>> TIM CAMP AND THEN FINN WILL
BE VIRTUAL AFTER TIM.
>> OKAY. THANK YOU VERY MUCH
FOR THE INVITATION AND IT'S MY
PLEASURE TO SHARE SOME OF THE
WORK THAT WE PERFORMED WITH MY
CO-PI WE DID A PROJECT LOOKING
AT CARDIAC CELLS IN A MYOCARDIAL
INFARCTION MODEL WE TEAMED WITH
FUJIFILM THAT MADE IPS DERIVED
CELLS. AND WE COMBINED THAT
WITH CARDIAC EXTRACELLULAR
MATRIX MADE FROM DENSE
FIBROBLASTS, CARDIAC FIBROBLASTS
CULTURES AND THEN MANUFACTURED.
THE IDEA IF WE TRANSPLANTED THE
CELLS IN A MATRIX FOLLOWING A
MODEL PRODUCED BY BALLOON
OCCLUSION AND REPERFUSION AND A
MONTH LATER DELIVER THE CELLS BY
DELIVERY USING A CATHETER BASED
SYSTEM BY THE DOCTOR AND MAPPING
TO SEE IF WE CAN REGENERATE
CARDIAC MUSCLE AND LOOK AT
THINGS LIKE ARRHYTHMIA RISK WITH
A LOOP RECORDER, CARDIAC
FUNCTION WITH MRI ANALYSIS AND
PRESSURE VOLUME LOOP ANALYSIS
AND THEN TERMINAL STUDIES
LOOKING AT THE HISTOLOGIC IMPACT
ON THE HEART TO GET CLOSER TO
CLINICAL APPLICATIONS BUT THIS
IS PRECLINICAL. AND WHAT WE
ACCOMPLISHED IN THIS STUDY WHICH
DOING A LARGE ANIMAL STUDY IN
THIS WAY WITH THESE UNIQUE
PRODUCTS, WAS UNIQUELY ENABLED
BY THE RMIP WE DID SHOW THAT THE
CCPS COULD ENGRAFT AND COULD
DIFFERENTIATE IN THE INFARCTED
HEART THIS IS IMAGES FROM TWO
WEAK HEARTS IF YOU HAVE GOOD
EYES THE LITTLE RED DOTS THERE
ARE THE HUMAN CELLS SO THEY'RE
BEGINNING TO FORM EARLY STAGE
CARDIOMYOCYTES THAT FURTHER
MATURE IN TIME AND WE SAW SOME
IMPACT ON RESERVE IN OTHER WORDS
THE HEART PERFORMED BETTER IN
RESPONSE TO BETA ADRA NEVER JUST
IN CASE STIMULATION AFTER
RECEIVING THE CELLS.
HOWEVER, OUR PRIMARY END POINT
CARDIAC MRI EJECTION FRACTION
DID NOT SHOW A SIGNIFICANT
DIFFERENCE SO WE DID RUN INTO
SOME CHALLENGES. AND I'LL
HIGHLIGHT CHALLENGES
PARTICULARLY FOCUSING ON HUMAN
POTENT STEM CELL THERAPIES AND
SOME OF THE CROSSCUTTING
CHALLENGES THAT WE SEE ARE THAT
OFF THE SHELF ALOE YES NAYIC
THERAPIES REALLY WE NEED TO
THINK ABOUT IMMUNE TOLERANCE AND
HOW BEST TO PERFORM IMMUNE
SUPPRESSION AS NEEDED AND THAT
IS I THINK A VERY MUCH SHARED
CHALLENGE ACROSS VARIOUS
APPROACHES. ALTERNATIVELY, IF
WE'RE THINKING ABOUT
PERSONALIZED OR ONTOLOGIST
THERAPIES BEING ABLE TO IN A
TIME EFFICIENT MANNER CELLS IS
CLEARLY A CHALLENGE. BUT
PERHAPS THE BIGGEST CHALLENGE WE
FACED IN OUR PROJECT WAS THAT WE
NEEDED PROFOUND
IMMUNOSUPPRESSION FOR THE ZENO
YES NAYIC PRODUCT EVALUATION IN
THE SWINE MODEL AND WE SAW
PROBLEMS WITH OPPORTUNISTIC
INFECTIONS AND ALSO WE WORRY
THAT HAD THE IMMUNOSUPPRESSION
WAS ALTERING THE PATH OF
PHYSIOLOGY BECAUSE FOLLOWING THE
INFARCTION THE IMMUNE SYSTEM
CONTINUES TO PLAY A PROMINENT
ROLE IN THE CARDIAC REMODELLING.
TO GIVE YOU AN IDEA THE IMMUNE
SUPPRESSION REQUIRED CYCLOSPORIN
AND ALSO AN IMMUNO MODULATOR
THAT BLOCKS T-CELL FUNCTION AND
THIS PROFOUND IMMUNOSUPPRESSION
CAUSED US TO HAVE A NUMBER OF
ANIMALS THAT GOT OPPORTUNISTIC
INFECTIONS INSTEAD OF -- IN
SPITE OF PROPHYLACTIC
ANTIBIOTICS. SO HOW CAN WE
OVERCOME SOME OF THESE
CHALLENGES? WELL FOR THE ISSUE
OF IMMUNE TOLERANCE OBVIOUSLY
MANY GROUPS ARE LOOKING AT GENE
EDITING APPROACHES KNOCKING OUT
A VARIETY OF MOLECULES AS WELL
AS OVEREXPRESSING SOME. I THINK
IT'S GOING TO TAKE US TIME TO
UNDERSTAND WHAT THE APPROPRIATE
HYPO IMMUNE CELLS ARE AND WE
NEED GOOD STUDIES FOR THAT. FOR
AUTOLOGOUS APPROACHES, OBVIOUSLY
QUALITY CONTROL PRACTICES AND
PROCESSES NEED TO IMPROVE BUT
THE THING AGAIN I WILL HIGHLIGHT
IS WE REALLY NEED PREDICTIVE
AFFORDABLE ANIMAL MODELS THAT
DON'T REQUIRE SUCH MARKED IMMUNO
SIP PRESENTATION FOR THESE ZENO
YES NAYIC PRODUCTS.
JUST TO GIVE YOU AN EXAMPLE OF
WHY I SAID AFFORDABLE THIS WAS
TWO THOUSAND DOLLARS PER DOSE
REQUIRING DOSES EVERY TWO WEEKS,
THE COST OF DRUGS AND THE
NECESSARY MAINTENANCE OF THIS
MODEL ARE EXTRAORDINARY SO IF WE
CAN GET HUMANIZED MODELS WE
ALREADY HAVE GOOD PROGRESS WITH
MOUSE MODELS BUT WE REALLY NEED
LARGER MAMMALS THAT WOULD BE A
MAJOR ADVANCE AND CORE
FACILITIES THAT REALLY ARE
EXPERT AT THESE UNIQUE ANIMAL
MODELS WOULD ALSO HELP. THANKS.
>> JANNA, HOW DO WE DO THIS?
>> GOOD MORNING, CAN YOU HEAR ME
OKAY?
>> AND YING IF YOU COULD BE ON
DECK, PLEASE.
>> SINCERE APOLOGIES THEY CANNOT
BE THERE IN-PERSON I'M GIVING
THE UPDATE FOR BOSTON UNIVERSITY
RMIP GROUP LED BY DARRYL AND I
WAS A CO-PI ON THESE DUD
STUDIES.
OUR GOAL IS LUNG REGENERATION.
AND OUR VISION IS THAT IN THE
RELATIVE SHORTER TERM GENETIC
DISEASES OF THE AIRWAY LIKE
CYSTIC FIBROSIS COULD IN THEORY
BE CURED BY CELL BASED THERAPY
TO THE AIRWAYS. AND I'M JUST
GOING TO SHOW YOU THIS ONE DATA
SLIDE WHICH I THINK WAS A
CRUCIAL TO US. AND ACHIEVED
THROUGH THE RMIP FUNDING AND
THIS IS THE MOST IMPORTANT DATA
SLIDE I'VE SEEN SO FAR IN MY
CAREER SO IPSC DERIVED BASAL
CELLS FROM A MOUSE THAT WERE
DELIVERED TO A TRACHEA AFTER A
DETERGENT BASED INJURY AND THIS
IS TWO YEARS LATER AND THIS IS A
WHOLE TRACHEAL. SO VERY LOW
MAGNIFICATION VIEW AND YOU CAN
SEE HIGHLY EFFICIENT GRAFTED
CELLS THAT IS CLEARLY DURABLE
BECAUSE THIS IS AFTER TWO YEARS
AND THESE CELLS -- THE DELIVERED
CELLS WERE AN AIRWAY CELL CALLED
THE BASAL CELL SO ESSENTIALLY WE
WERE ABLE TO SHOW THAT DELIVERY
OF THIS CELL WAS ABLE TO
RECONSTITUTE ALL THE AIRWAY
EPITHELIUM FOR THE LIFETIME OF
THE MOUSE AND WE WERE ABLE TO
REPEAT THIS WITH A HUMAN IPSC
DERIVED BASAL CELLS. AND WE
ALSO HAVE DATA JUST PUBLISHED IN
THE COMPARTMENT SO THESE PAPERS
JUST CAME OUT BACK-TO-BACK IN
CELL STEM CELL WE ARE REALLY
EXCITED ABOUT THIS WE THINK, FOR
EXAMPLE, YOU KNOW, CYSTIC
FIBROSIS JUST TO GIVE YOU AN
IDEA THERE'S HIGHLY EFFECTIVE
TREATMENTS. THAT'S A LIFELONG
THERAPY THAT CURRENTLY COSTS
300,000 DOLLARS PER YEAR. SO IN
THINKING ABOUT NEXT STEPS WE
THINK ABOUT THIS A LOT BECAUSE
ONE OF THE UNIQUE CHALLENGES OF
THE LUNG AND THE AIRWAYS IS IT
IS REALLY WELL-DESIGNED OVER THE
COURSE OF EVOLUTION TO ACTUALLY
EXPEL ANYTHING THAT YOU TRY TO
DELIVER TO IT. IT HAS A
PHYSICAL BARRIER OF MUCOUS AND
ALSO MUCOUS CLEARANCE AND SO
IT'S ACTUALLY A VERY UNIQUE
CHALLENGE WE THINK TO GET CELLS
SAFELY INTO THE AIRWAY SO THIS
IS A SOMEWHAT ARBITRARY SCHEMA
OF WHAT WE SEE AS A PATH TO A
CURE. AND I HAVE IDENTIFIED
WHAT OUR GROUP THINKS OF AS SOME
REALLY, REALLY KEY NEXT STEP
RESEARCH HURDLES TO TRY AND
TACKLE. ANIMAL MODELS ARE A
MAJOR NEXT STEP FOR US. AND IN
TERMS OF THIS WORKSHOP, THE
OBVIOUS ISSUES THERE ARE THE
COST AND THE EXPERTISE REQUIRED
TO DO SOME OF THESE STUDIES IN
LARGER ANIMAL MODELS, SO,
SPECIFICALLY FOR THE LUNGS, SOME
OF THE BEST ANIMAL MODELS WHERE
YOU CAN TRY TO CURE DISEASE
WOULD BE SOMETHING LIKE THE
FERRET AND THESE ARE VERY
EXPENSIVE MODELS THAT ARE NOT
EASILY FUNDED. THE OTHER POINT
I WANTED TO THEN MAKE IS
DELIVERY. DELIVERY TO THE LUNG
IS A HUGE CHALLENGE. AND SO
WE'RE MAINLY TALKING ABOUT CELL
BASED THERAPIES BUT THE GENE
THERAPY, GENE EDITING MACHINERY
WHILE WE MADE HUGE PROGRESS
WHILE IT GET TO THE POINT OF
ACHIEVING DELIVERY TO THE
AIRWAYS OR COMPARTMENTS WE HAVE
A LOT OF WORK TO DO AND SO OUR
THINKING IS THAT REALLY NOW WE
NEED TO CREATE AN ENTIRELY NEW
RESEARCH PROGRAM DIRECTION WHICH
IS HOW TO ACTUALLY DELIVER TO
THE LUNG, NEVER AS A FIELD
BEFORE HAVE WE REALLY HAD TO TRY
TO DELIBERATELY INDUCE TOLERATED
LUNG INJURY. MOST OF THE WORK
TO DATE HAS BEEN INDUCING LUNG
INJURY IN ANIMAL MODELS TO
UNDERSTAND THE BIOLOGY OF
REGENERATION BUT NOW I THINK WE
NEED A VERY CONCERTED EFFORT
FROM THE VERY MICROSCOPIC OF
UNDERSTANDING LUNG REGENERATION
TO THE MORE MACROSCOPIC
BIOENGINEERING APPROACHES TO HOW
WE EFFICIENTLY DELIVER CELL TO
SUCH A LARGE SURFACE AREA IS
WHAT IS NOW REQUIRED.
SO THIS IS JUST TO THEN
ACKNOWLEDGE THE TEAM WHO DID THE
WORK AND THANK YOU FOR YOUR
TIM
TIME
TIME. ANY .
>> THANK YOU, FINN. YING AND
THEN CHRISTOPHER BREAUXER.
>> THANK YOU. THANK YOU TO THE
ORGANIZERS FOR THE OPPORTUNITY
TO TALK ABOUT MY PROJECT AND
THAT SHARE OUR INSIGHTS ABOUT
THE -- OUR PERSPECTIVE ABOUT
REGENERATIVE MEDICINE AND MY
RMIP PROJECT IS THE ORGANOID
TREATING. LET'S START WITH THE
CLINICAL NEEDS I DON'T THINK
WITH THIS AUDIENCE I NEED TO
CONVINCE YOU THAT INFECTION IS A
PROBLEM AND THIS IS EMERGING AS
WE IMPROVE CELLS FOR TREATING.
THE TRADITIONAL WAY TO TREATING
MYOCARDIAL INFARCTION IS TO
INJECTING. THE PROBLEM IS THE
HEART IS, YOU KNOW, CONSTANTLY
PUMPING SO IT'S ALMOST INSTANTLY
PUMP OUT INTO CIRCULATION AND
THE LEADING PRETTY LOW, LIKE,
YOU KNOW, CELL RETENTION AND
SURVIVAL AND LEADING TO MODERATE
FUNCTION AND RECOVERY AND THE
HUMAN COST. BECAUSE THE CELLS,
IS THEY JUST, THEY DON'T
NECESSARILY COORDINATE WITH THE
HEARTS TO ADDRESS THIS ISSUE, WE
PROPOSING TO DEVELOP THIS ORGAN
NOWED SYSTEM AND, YOU KNOW, WE
ESSENTIALLY TRY TO HAVE OUR
IDEAS DEVELOP AN INJECTABLE
ORGANOIDS.
AND AN ASSEMBLY OF CUTTING OF
FIBROBL
FIBROBLASTS. THE ISSUES
CONTRACT AND THERE'S THE REGION
OF THE PERIPHERY OF THE
ORGANOIDS AND FORMING THIS
STRUCTURE WITHIN THE ORGANOIDS
AND THE IDEA HERE IS IF YOU MAKE
AN INSTEAD OF THE CELLS YOU HAVE
A TISSUE THIS BETTER SUSTAIN THE
SHEER FORCE OF THE CONTRACTION
AND MAKE IT A BETTER STAY IN THE
MYOCARDIUM AND MAKE IT BETTER
SURVIVE IN THE ENVIRONMENT. ON
TOP OF THAT WE WANT TO
INCORPORATE THE ANCILLARY
INTEGRATION WITH THE HOST HEART
TO IMPROVE THEIR FUNCTIONAL
PERFORMANCE AND WE ARE FORTUNATE
TO RECEIVING OUR SUPPORT TO
PURSUE THIS IDEA. AND RECENT
SUPPORT WE HAVE THE ORGANOID
THAT COMES WITH A BETTER
FUNCTIONAL RECOVERY WITH ONLY
10% OF CELLS COMPARED TO THE
CURRENT STATE OF ART. WE HAVE
THE PERFUSION MODEL BUT WITH THE
CLINICAL TRANSLATION THERE'S
RIGHT NOW WITH THE IPSA MOUSE.
WE HAVE THE CELLS THAT COME FROM
DIFFERENT DONOR LEADING TO
UNDEFINED EXPRESSIONS. ON TOP
OF THAT AS OF RIGHT NOW WE CAST
THIS IN THE RED MODEL BUT THE
FREQUENCY OF THE RED HEARTBEAT
IS BEATING TOO FAST MAKING THAT
AN IDEAL MODEL TO TEST THE
IMPLANTED ORGANOIDS. SO THE
RMIP PROJECT IS UNIQUE. IT'S A
WONDERFUL OPPORTUNITY AS A
TECHNOLOGY DEVELOPMENT TO GRANT
TO US TO FACILITATE IN THE
CLINICAL TRANSLATION OF THE --
OUR TECHNOLOGY SO IN THE RMIP
PROJECT IT WOULD BE INTERESTING
TO SAY WHETHER INSTEAD OF USING
CELLS FROM DIFFERENT DONOR WE
USE ONE SINGLE, LIKE AN IPSC
DONOR TO DERIVE THE CELLS AND TO
MAKING ORGANOIDS TO POTENTIALLY
PROVIDE ALSO THERAPY AND WE WANT
TO DERIVE THOSE CELLS AND
FABRICATE THE ORGANOID IN THE
CRITICAL CONDITIONS AND HAVE THE
EFFICACY TO TEST THEM IN LIKE A
LARGER ANIMAL OR MODEL. SO, YOU
KNOW, TO -- IN TERMS OF THE
QUESTION ABOUT THE, YOU KNOW,
THE CHALLENGES AND OPPORTUNITIES
I THINK IT'S LIKE A -- WELL
DURING -- DURING OUR OWN, LIKE,
YOU KNOW, TRANSLATION, ONE OF
THE THINGS THAT WE FEEL WERE THE
CHALLENGES IS THEY NEED A
BLUEPRINT OF SAFETY TRACK TO
MOVE INTO THE CELL THERAPY OF
CLINICAL TRIALS FIRSTLY THE CELL
MANUFACTURER. YOU HAVE THE CELL
GENERATION, THE LINE SELECTIONS,
LIKE THE ONECIDE -- ONE SIZE
FITS ALL FOR DIFFERENT DISEASE
YOU NEED DIFFERENT LINES. AND
THE FIELD IS MOVING TO DOING A
SAFETY CHECK. AND EXPANSION.
SCALE UP. IT'S ONE THING TO
MAKING A FEW CELL TO TREAT A RAT
BUT IT'S DIFFERENT IF YOU WANT
TO MAKE BILLIONS OF CELLS TO
TREATING THE, YOU KNOW, TREATING
THE PATIENT. AND THE CRYO
PRESERVATION. WE LOST A LOT OF
CELLS DURING THIS.
CAN WE IMPROVE IT? LIKE THE
TUMOR GENESISTY AND LIKE A TEAM
SAID WHERE IS THE GAP? WE NEED
TO ADDRESS THE GAP BETWEEN THE
ORIGIN MODEL AND THE PATIENT.
RIGHT NOW OUR REVIEW ABOUT THE
CELL, LIKE A CELL BASED MEDICINE
IS THE ALOE GENERALIC. THEN
RIGHT NOW WITH PEOPLE FOCUS ON,
WE HAVE A HUMANIZED BY BUT DO
WE NEED OTHER TECHNOLOGIES?
LAST BUT NOT LEAST IS A
WORKFORCE DEVELOPMENT. THANK
YOU FOR YOUR ATTENTION. THANK
YOU
YOU.
>> I UNDERSTAND THAT CHRISTOPHER
BREWER IS STILL WORKING TO GET
HERE SO WE'LL SAVE THAT AND HAVE
TO COME BACK, JEFFREY STERN IF
YOU COULD. WE HAD TO SKIP ONE
OF THE TALKS. THANK YOU. DO
HOPE THAT CHRISTOPHER SHOWS UP.
BUT -- A.
>> HOW DO YOU ADVANCE THIS GOOD
MORNING I WILL DISCUSS A
CHALLENGE WE'RE ALL FAMILIAR
WITH. HOW DO WE CHARACTERIZE A
DRUG SUBSTANCE? AND
TRADITIONALLY WE USE IDENTITY,
PURITY, AND POTENCY. I'M GOING
TO FOCUS ON IDENTITY. WHAT IS
THE DRUG SUBSTANCE? IF I CAN
WORK THIS SLIDE DECK.
TRADITIONALLY SINCE 1906 THE FDA
AS USED MOLECULAR FORMULA TO
VERY PRECISELY DESCRIBE A DRUG.
THIS DOESN'T WORK VERY WELL FOR
CELLS. AND POINTS TO THE
CHALLENGE, HOW DO WE DESCRIBE
THE IDENTITY OF A LIVING CELL
PRODUCT? I APOLOGIZE FOR TH
THIS -- I'M GOING TO USE ON
EXAMPLE OF THE RPE CELL WHICH WE
WORK ONTO TRANSPLANT TO TREAT
MACULAR DEGENERATION TO REVERSE
THESE AREAS UNDER THE RETINA AND
GROW RPE AND INJECTED UNDER THE
RETINA IN AN EFFORT TO REVERSE
THIS IN A CLINICAL TRIAL WE
IDENTIFY THE IDENTITY OF THE
CELLS WHICH ARE VERY HOMOGENOUS
AND ALL LOOK THE CELL USING
ANTIBODIES THAT STAIN FOR RMP
SPECIFIC MARKERS AND ALL OF
THESE CELLS STAIN FOR RMP
MARKERS AND THIS APPROACHES. IS
GOOD. IT WORKS. BUT I THINK
WE CAN DO BETTER THAN AND THE
PROGRAM HAS HELPED US MOVE IN
THAT DIRECTION. WE FOUND THAT
THE IDENTITY OF A CELL PRODUCT
CAN BE, LIKE, BROOKLYN'S
DEMOGRAPHIC. DIVERSE. CELLS.
DIVERSE POPULATIONS OF CELLS.
THAT CHANGE OVER TIME THAT EACH
HAVE DISTINCT FUNCTIONS AND THAT
WORK TOGETHER. WE'D LIKE TO
IDENTIFY THE SUBPOPULATION. I
HAD A POINTER. EXCUSE ME. WE'D
LIKE TO IDENTIFY WHICH OF THESE
SUBPOPULATIONS CONFERS RESCUE.
WHICH OF THESE SUBPOPULATIONS
CAUSE THE CELLS TO GRAFT AFTER
TRANSPLANTED AND WE'RE MAKING
SOME PROGRESS IN THAT DIRECTION
FUNDED BY THE RMIP. SO IT'D BE
RMIP HAS FUNDED AND SUPPORT THIS
HAD IN DEPTH CELL
CHARACTERIZATION. THAT IS
LEADING THE WAY TO THE NEXT
LEVEL OF DETERMINING A CELL
PRODUCT'S IDENTITY. FOR
SUBSEQUENT EVALUATIONS. WHAT WE
NEED NEXT, EXCUSE ME, HOW
EMBARRASSING. I AM LOST WITH
THE SLIDES. THE -- WHAT WE NEED
IS EARLY FDA COMMUNICATION
PROGRAMS LIKE THE R MAP,
INTERACTING PROGRAM IF WE CAN
EXPAND ACCESS FOR THE NIH, FOR
THE GRANTEES, SUCH AS OUR
OURSELVES TO WORK TOGETHER WITH
THE FDA TO OUTLINE THE PATH TO
CRYOPRESERVATION, THE SPEAKERS
BEFORE ME HAVE MENTIONED OTHER
STEPS. HOW DO WE DETERMINE
ENGRAFTMENT? HOW DO WE CREATE
HOMOGENEITY. HOW DO WE DEFINE
HOMO JAY NAYTY TO ACCELERATE
CELL DEVELOPMENT. THDEVELOPME
>> CHRISTOPHER, OKAY, YOU'LL BE
ON DECK. OKAY? SO WHICH ONE --
YES, YOU CAN COME IN BUT I DON'T
KNOW WHAT'S YOUR FIRST SLIDE.
>> GOOD MORNING, I'M GARY, THANK
YOU FOR THE INVITATION AND FOR
THE CHANCE TO TALK ABOUT THIS
PROJECT. SO MY LAB AT THE
UNIVERSITY, STUDY REGENERATION,
THIS FUNDING SUPPORTS THE
MANUFACTURING OF THE HUMAN CELLS
OR AND OUR GOAL IS FOR
SCARRING. SO IN MY PROJECT I
HAVE A CO-PI, I'M SORRY, YEAH.
OKAY. SO HE'S THE HEAD OF THE
FACILITIES AND TAKES CARE OF THE
MANUFACTURING AND ALSO THE
STUDIES. SO WE HAVE OVER MORE
THAN TEN YEARS WORK THAT WAS LED
BY THE FORMER PI. AND ALSO
CURRENTLY MYSELF. THAT WE'RE WE
HAVE SHOWN HUMANS FOR CELL
TREATMENT. THE FIBROSIS AND
ALSO THE SCAR TISSUE. SO HERE
THERE'S THE DIFFERENT MODELS
THAT WE HAVE IN OUR EXPERIMENTS.
SO THE TREATMENT IS SIMPLE THAT
WE PLACE IT TOPICALLY AND AFTER,
IN A DROP, IN THE GMP. SO AFTER
TWO WEEKS OR LONGER DEPENDING ON
EXPERIMENTS THOSE CONTROLS THAT
DO NOT RECEIVE THE TREATMENTS,
THEY DEVELOP OPACITIES. BUT FOR
THOSE CORNEAS, TREATED WITH STEM
CELLS THEY HAVE MUCH CLEAR
CORNEAS AND VERY SUPPRESSED
SCARRING AND OPACITIES AND ALSO
THE EXPRESSIONS OF THE VARIOUS
IMAGERY AND ALSO THE FIBROSIS
MARKERS ARE SIGNIFICANTLY
REDUCED. SO THESE RESULTS ARE
HIGHLY REPRODUCIBLES IN OUR
DIFFERENT ANIMAL EXPERIMENTS AND
WITH DIFFERENT STEM CELLS. SO
AND ALSO WE REPORTED MECHANISMS
OF THE STEM CELL TREATMENT THAT
INVOLVES THE ACTIVITIES MEANING
IT'S PART OF THE EXPRESSIONS.
AND ALSO THE STEM CELLS
DIFFERENTIATE WITH THE CELL
TYPE. SO THIS CAN HELP. THIS
CAN DEPOSIT THE ECM PROTEIN AND
ALSO THE STROMAL MODELING THAT
HAS CONFIGURATIONS AND ALSO THE
STROMAL STEM CELLS REDUCED. AND
ALSO THE ANTIFIBROSIS MICRO RNA
AS WELL AS THE XO SOMES THAT WE
ARE CURRENTLY EXPLORING IN THE
MOLECULES.
AND FOR THE LATEST DEVELOPMENT
IN THIS PROJECT THAT WE HAVE
ALREADY OPTIMIZED THE GMP SOP
FOR THE CULTURE PROPAGATIONS AND
SO ON AND ALSO SO THAT'S WHY
WITH THIS -- WITH THIS RMIP
FUNDING WE WILL START THE
MANUFACTURING OF THE CELLS AND
ALSO THESE STROMAL STEM CELLS
ARE ACE ISOLATED SO THAT'S WHY
WE ALSO ESTABLISHED A QCSH FOR
THE CELLS AND CALCULATE THE
SCARRING INDEX FOR DIFFERENT
STEM CELL BATCHES TO PROTECT THE
IN VIVO POTENCY OF THE CELLS.
AND WE HAVE FOUND THIS. AND
CURRENTLY WE ARE LOOKING ON THE
ANIMAL MODELS WITH THE STEM
CELLS TREATING THE ANIMAL MODEL
WITH THE CHRONIC OPACITIES AND
SO FAR IS PRETTY GOOD AND PRETTY
ENCOURAGING AND WE ARE WORK ON
DEFINING THE MECHANISMS OF
ACTIONS SO OUR GOAL IS TO
APPRISE THIS STEM CELL TREATMENT
WITH A NONNATIVE APPROACH OR
APPLICATIONS TO PROTECT AND THE
ALTERNATIVES FOR THE HIGHLY OR
HEAVILY RELIED ON THE DONOR
MATERIALS WHICH IS A WORLDWIDE
HEALTH CARE ISSUES. SO WITH
THIS RMIP FUNDING WE WILL START
OUR CELL MANUFACTURING FOLLOWED
BY CMC STUDIES TO LOOK AT CELL
SAFETY AND ALSO METABOLIC
PROFILING AND ALSO THE MET TAB
LYMPHS COMPARED WITH THE LAB
BASED CELLS.
AND ALSO WE WILL USE THIS UPON
THE STEM CELL, USE THESE GMP
STEM CELLS FOR THE ANIMAL
EXPERIMENT TO LOOK AT THE IN
VIVO CELL SAFETY, THE TREATMENT
SAFETY, ADVOCACY AND ALSO THE
ADME AND DO SOME DATA MINING FOR
THE NEXT PLAN SUBMISSIONS. SO
WHILE WE ARE WORKING ON
DIFFERENT THINGS THERE ARE
SEVERAL ISSUES THAT CAN BE
CONSIDERED AS CHALLENGES FOR
THIS STEM CELL TREATMENT BEFORE
WE PUT THEM TO THE
APPLICATIONS -- AT THE
APPLICATION. FIRST IS THE STEM
CELL FACE CHANGES WHETHER THEY
ARE STILL MAINTAINED THE STEM
CELL FUNCTIONS. SO THIS CAN BE
POSSIBLY ANSWERED BY SINGLE
CELL -- THE SINGLE CELL AND ALSO
THE STUDIES AND SO ON AND ALSO
HOW THIS CHANGES ESPECIALLY IN
THE DEPOSIT, THE ECM PROTEINS
PRODUCED BY THE TRANSPONDER STEM
CELLS SO THIS CAN BE STUDIED BY
THE HIGH RESOLUTION AND CAPPITUE
CAPTURING TO STUDY AS WELL AS
THE MATRIX REORDERING. SO FOR
THIS WE NEED THE EXPERT TO
COLLABORATE WITH A DIFFERENT
EXPERT AND THIS IS A CHANCE TO
STUDY SOME RESEARCH ON THIS
PROJECT. SO THIS IS KIND OF A
SHORT SUMMARY OF OUR PROJECT AND
OUR PRESENTERS. AND ALSO THE
DIFFERENT CHALLENGES AND I
WELCOME YOUR SUGGESTION AND ALSO
YOUR COMMENTS. THANK YOU VERY
MUC
MUCH.
>> CHRISTOPHER, YOU HAVE A CLANS
TO HANG YOUR COAT UP?
>> I DID.
>> I SO I THINK WE BACK UP
THAT'S YOU. OKAY. THIS ONE.
OH -- AND THEN RANDALL KIMBALL
WILL BE ON DECK.
>> GOOD MORNING, MY NAME'S CHRIS
I'M FROM COLUMBUS, OHIO AND I
HAD THE GOOD FORTUNE TO WORK
WITH THE PROGRAM ON MY PROJECT
DEVELOPING TISSUE ENGINEERED
VASCULAR GRAFT. THE TISSUE
ENGINEERED VASCULAR DWRAFT
GRAFT IS A COMBINATION PROJECT.
THE DEVICE SPOENT COMPONENT IS
BIODEGRADABLE AND THIS IS
HARVESTED ON THE SAME SCAFFOLD
THAT IT'S IMPLANTED AND THIS IS
OUR SECOND CLINICAL TRIAL
EVALUATE THING CONSTRUCT. THE
RATIONALE FOR DEVELOPING IT IS
IT'S A LIVING VAS YOU LOW GRAFT
SO IT CAN GROW WITH CHILDREN
WHEN IT'S IMPLANTED.
AND WHAT WE'RE TRYING TO DO WITH
THE RMIP PROJECT NOW IS TO
DEVELOP BETTER RELEASE CRITERIA
WE KNOW QUITE A BIT ABOUT THE
MECHANISM OF ACTION OF HOW THE
TISSUE TRANSFORMS FROM A BIO
DEGRADABLE SCAFFOLD TO A LIVING
BLOOD VESSEL AND THERE ARE THREE
IMPORTANT POINTS THE FIRST IS
THAT IT -- THE CELLS THAT ARE
SEATED ON TO THE SCAFFOLD ARE
NOT THE CELLS THAT MAKE THE
NEOTISSUE. THE NEOTISSUE IS
DERIVED FROM THE VESSEL. SECOND
THIS PROCESS IS INFLAMMATION
MEDIATED SO IT IS THE FOREIGN
BODY REACTION. AND FINALLY TOO
MUCH INFLAMMATION CAUSES
STENOSIS WHICH IS THE MOST
COMMON GRAFT RELATED
COMPLICATION AND WE'RE TRYING TO
DEVELOP BETTER ASSAYS FOR
LOOKING AT HOW HOW OUR SEATED
SCAFFOLD WILL AL FER THE
INFILTRATION WHICH IS WHAT
DRIVES THIS TISSUE FORMATION.
AND WE'RE DEVELOPING ASSAYS AND
EVALUATING PERFORMANCE AS WE
SPEAK. WE RECENTLY COMPLETED
THE SAFETY ARMOR OF OUR STUDY
AND THE GRAFT HAVE PREVENTATIVE
FORMATION OF STENOSIS AWHILE
BACK I WROTE A COMMENTARY FOR
SCIENCE TRANSLATIONAL MEDICINE
TALKING ABOUT THE PROBLEMS OF
TRANSLATION TO THE CLINIC AND
DECIDED THAT ONE OF THE DRIVING
FORCES OF WHAT I CALL THE
UNCERTAINTY PRINCIPLE THAT WE'RE
ALL INTERESTED IN DEVELOPING
CUTTING EDGE NEW BIOLOGICS AND
DEVICE TO BRING TO THE CLINIC TO
HELP OUR PATIENTS AND AS SUCH
THERE'LL ALWAYS BE A GREAT DEAL
OF UNCERTAINTY AND WE COINED THE
TERM THE BARNEY PHENOMENA AND I
THINK MANY OF THE ASSAYS THAT
ARE CURRENTLY USED PERHAPS
SUFFER FROM THIS BARNY
PHENOMENA. THEY'RE TRIED AND
TESTED AND TRUE FROM THE
PERSPECTIVE THAT PEOPLE ARE
COMFORTABLE USING THEM BUT I
WONDER IF WE NEED TO KICK IT UP
A NOTCH AND DEVELOP FOR SCIENCE
AND APPLY MORE SCIENCE AND I
THINK THIS GIVES US THE
OPPORTUNITY TO DO THIS I THINK
THE PROGRAM IS DOING VERY GOOD
SO FAR, IT'S HELPING MY PROJECT
QUITE A BIT. I'M LOOKING
FORWARD TO HEARING ABOUT OTHERS'
WORK BEYOND THE PROJECT I THINK
THERE ARE TWO THINGS I'D LIKE TO
SEE ONE, I THINK I'D LIKE TO SEE
THE FDA GIVEN THE ABILITY TO
WORK WITH INDUSTRY TO FIND
MECHANISMS FOR ENHANCING THEIR
ABILITY TO SHARE BETTER RELEASE
CRITERIA AS THEY'RE DEVELOPED
AND SECONDLY, I THINK THAT THE
NIH STTR PROGRAMS WOULD BE AN
EXCELLENT PLACE TO INTRODUCE
ADDITIONAL STUDIES FOCUSED ON
THE REGULATORY SCIENCES WHICH
ARE FREQUENTLY IGNORED. THANK
YOU FOR YOUR ATTENTION.
>> RANDALL AND THEN JOHNNY. AND
TELL ME WHEN --
>> ALL RIGHT. ON BEHALF OF MY
CO-I I AM PLEASED TO PRESENT
WHAT I THINK IS PROBABLY THE
SHORTEST FUNDED RMIP AWARD THAT
I'VE SEEN YET TODAY. WE STARTED
OUR FUNDING ABOUT TWO MONTHS AGO
SO WE'RE VERY EARLY IN THIS
PROCESS. AND WE'RE WORKING TO
DEVELOP SELF THERAPIES TO TREAT
DRY MOUTH PARTICULARLY THAT IN
THIS PROJECT INDUCED BY
RADIATION THERAPY FOR HEAD AND
NECK CANCER. SO REALLY IN TERMS
OF WHAT ARE THE RMIP FUNDINGS
WE'RE FUNDING THROUGH A CLINICAL
TRIAL PLANNING GRANT. THIS IS
ALLOWING US TO DEVELOP A PHASE
ONE STUDY TO TEST THE USE OF
AUTOLOGOUS CELLS TO PREVENT
DEVELOPMENT OF ROW DAWESED ZERO
TOME YA. THE DATABASES
NECESSARY TO RECORD DATA.
AND THE FINAL DATA NEEDED FOR
IND SUBMISSION AND THIS IS I
THINK A REALLY KEY POINT BECAUSE
SOME OF THE SORT OF VERY SIMPLE
STUDIES THAT WE NEED ARE THINGS
THAT ARE REALLY CHALLENGING FOR
US TO FIND FUNDING FOR. WE HAVE
A CURRENT PHASE ONE STUDY THAT
IS OPEN AND THAT WAS ALL FUNDED
THROUGH SORT OF START-UP FUNDS
TO THE INVESTIGATORS BUT THIS
IS, YOU KNOW, ALLOWING US TO USE
PEER-REVIEWED FUNDING TO HELP
SUPPORT THIS IND SUBMISSION THAT
ULTIMATELY WILL OCCUR SORT OF
MIDWAY THROUGH OUR FUNDING
PERIOD. FROM OUR POINT OF VIEW,
SO WE WORK WITH THE WISCONSIN
PROGRAM FOR ADVANCED CELL
THERAPY AND IN TALKING SORT OF
AMONG OUR WORKING GROUP
CHALLENGES AND GETTING THERAPIES
TO PATIENTS IS, YOU KNOW, AS I
MENTIONED ONE PRODUCING THIS
DATA TO SUPPORT THE IND
SUBMISSIONS AND THEN AS WE THINK
FORWARD WE'RE ALREADY SORT OF IN
THE INITIAL STEPS FOR OUR NON
RMIP STUDY TO THINK OF HOW WE GO
TO SCALE ONE TO THE STUDIES
THAT'S A MAJOR CHALLENGE FOR
ULTIMATELY GETTING THESE
PATIENT -- OR THESE THERAPIES TO
AS MANY PATIENTS AS COULD
BENEFIT FROM THEM. SO FUNDING
DEDICATED TO PRECLINICAL DATA
SUPPORTIVE OF THE IND, USING THE
IND AS A FINAL SUBMISSION
MILESTONE, SOMETHING ON THE
ORDER OF R 21 TYPE SIZE AWARDS I
THINK IS FOR -- AT LEAST FOR OUR
GROUP HAS PROVED TO BE
SUFFICIENT FUNDING TO SORT OF GO
FROM THE PRECLINICAL DATA TO THE
IND SUBMISSION. AND THEN
ULTIMATELY, YOU KNOW, LOOKING AT
THE LATER DEVELOPMENT NIH
FUNDING MECHANISMS TO SUPPORT
THESE EFFICACY FOCUSED STUDIES.
ARE CERTAINLY ONE POSSIBILITY AS
WAS JUST MENTIONED AND WITH THAT
I WILL TURN IT BACK TO THE NEXT
SPEAKE
SPEAKER.
>> JOHNNY AND THEN ASIA KHAN.
THERE YOU GO.
>> OKAY. SO, THE GOAL OF OUR
TRIALS THAT WAS FUNDED WAS
FUNDED IN 2000 SO WE ARE ON THE
END OF THIS. SO THE GOAL OF
THIS WAS TO IMPROVE THE BONE
MARROW FOR A PATIENT WITH
OSTEOARTHRITIS. THE TARGET
ENROLLMENT, AGAIN, WE HAVE FOR
ARM. WE HAVE BONE MARROW PLUS
LOSARTAN AND FIE SE TIN. WE
HAVE ONE HUNDRED PATIENT IN OUR
TARGET ENROLLMENT. 25 PER ARM
AND I REMEMBER, YOU KNOW, WHEN I
GOT THIS GRANT FUNDING BY THE
NIH, YOU KNOW, FAY CALLED ME AND
SAID YOU CAN RECRUIT ONE HUNDRED
PATIENTS AND I SAID, I THINK WE
CAN.
AND AGAIN I'M VERY HAPPY TO SAY,
THAT, YOU KNOW, WE HAVE ACHIEVED
OUR TARGET, YOU KNOW,
POPULATION, YOU KNOW, THREE
MONTH BEFORE THE DEADLINE
DESPITE COVID AND OMICRON SO I
THINK WE'RE VERY PROUD OF THIS.
AS YOU KNOW CLINICAL TRIAL
SOMETIMES THE BIGGEST PROBLEM IS
WE CANNOT ACHIEVE THE TARGET
POPULATION THAT WE NEED WHAT IS
THE BIGGEST PROBLEM WE FACE IS
REALLY, YOU KNOW, WHEN IT
BECOMES TO RECRUITMENT
MINORITIES WE TARGET, YOU KNOW,
DIFFERENT, YOU KNOW, GENDER MALE
AND FEMALE. WE DIDN'T HAVE ANY
PROBLEM THERE BUT WHEN IT COMES
TO RECRUIT MINORITIES WE HAD TO
PUT THE CLINICAL TRIALS ON PAUSE
TO MAKE SURE THAT WE CAN RECRUIT
THOSE PATIENT. AND AGAIN, THAT
REQUIRED, YOU KNOW, INTEGRATED
WORK WITH THE DSMB, IRB AND
HOSPITAL EXECUTIVES AND WHAT WE
HAD TO DO WAS TRANSLATE OUR
DOCUMENT
DOCUMENTS IN SPANISH AND MADE
SURE WE PUT IT IN THE NEWSPAPER.
THAT WAS A BIG, YOU KNOW,
SETBACK FOR US. WHAT IS ANOTHER
TECHNICAL CHALLENGE FOR US IS
OUR RMIP STUDY DESIGN WAS AN
UNUSUAL COMPLEX WAS COMBINING
SAFETY. BUT ALSO PATIENT
REPORTED PAIN AND FUNCTION.
WE'RE LOOKING AT EFFICACY OF
THOSE TREATMENT AND WE'RE
LOOKING AT MECHANISM WE WANTED
TO KNOW IF THE CELLS THEMSELVES,
FIBROSIS CAN PLAY A ROLE THERE
BUT I THINK WE BELIEVE THAT, YOU
KNOW, IT PROVIDE AN OPPORTUNITY
FOR INVESTIGATING THE FACTOR
ASSOCIATED WITH SUCCESSFUL
BIOLOGICAL TREATMENT FOR ALL
PATIENT SO WHAT WE NOW KNOW NOW
IS WE HAVE MORE IN THE BLOOD
THAN PATIENT WITH
OSTEOARTHRITIS.
AND WE KNOW THAT PATIENT WITH
PAIN HAS MORE CELLS THAN PATIENT
WITHOUT PAIN. WE KNOW IF WE DO
AN MRI OF THE KNEE JOINT WE CAN
SEE THAT THE PATIENT THAT HAS A
HIGH NUMBER SENESCE SENT CELLS
HAS MORE. AND NOW WE KNOW THE
SENESCE SENT CELLS CAN BE FOUND
IN BONE MARROW AS WELL AND CAN
ALSO BE FOUND IN THE JOINT
FLUID.
SO I THINK THAT WAS, YOU KNOW,
VERY IMPORTANT THING, YOU KNOW,
FOR US TO START THIS. THIS WILL
BE -- THIS WILL HAVE BEEN
IMPOSSIBLE TO DO WITH RN 1 FOR
SURE AND MOST SURPRISING THING
FOR ME IS WHEN I START THE
TRIALS WE WERE HARVESTING THE
BONE MARROW. WE DO THE BONE
HARROW -- MARROW CONCENTRATE AND
WE GET WHAT IS UP INJECTED IN
THE PATIENT AND THEN WE GET WHAT
COME TO THE LAB.
AND WHEN I START THE PROJECT I
THOUGHT WE WOULD FIND MILLIONS
OF STEM CELLS WITHIN THE BONE
MARROW OF THE PATIENT BUT IT
TURNS OUT THAT WAS NOT MILLIONS
OF STEM CELLS, IT WAS THOUSANDS
OF STEM CELLS AS YOU CAN SEE
HERE, YOU KNOW, THE IS BAR
THERE, THAT'S 40 PATIENT WHERE
WE HAVE PROBABLY 20,000 STEM
CELLS SO CLEARLY IT WAS REALLY
IMPORTANT FOR US BECAUSE WE HAVE
TO SHARE OUR SAMPLE WITH THE
CATALYST WHICH IS, YOU KNOW, THE
PEOPLE THAT LOOK AT THE STEM
CELLS IN THE ANALYSIS BUT WHILE
WE FIND VERY FEW MSCS, WHEN WE
START TO LOOK AT XO SOME WE FIND
BILLIONS.
SO WHAT WE DID IS WE SUBMITTED
AN ANCILLARY STUDIES TO START TO
LOOK AT THE XO SOME IN THOSE
PATIENTS BECAUSE WE BELIEVE THAT
THE EFFECT OF THE COMBINING
THESE IS MAYBE RELATED TO THE XO
SOME NOT REALLY THE STEM CELLS
WITHIN THE FRACTION. AND THIS
IS REALLY IMPORTANT FOR US.
BECAUSE WE HAVE TO SEND THOSE
SAMPLES AND I DON'T WANT TO SEND
IT TOO EARLY BEFORE WE ANALYZE
THE XO SOME WITHIN THIS. I AM
GOING TO CLOSE HERE. THIS IS
CLEARLY A TEAM EFFORT WE
WOULDN'T HAVE BEEN ABLE TO DO
WITH WITHOUT OUR RMIP FUNDING
THIS IS A SIX MILLION DOLLAR
CLINICAL TRIAL AND YOU CAN SEE
ALL THE PEOPLE THAT PARTICIPATE
IN THESE TRIALS HERE AND ALL THE
ACADEMIC INSTITUTIONS THAT
COLLABORATE WITH US, YOU KNOW,
IN THIS PROJECT. THANK YOU VERY
MUC
MUCH.
>> GOOD MORNING, I'M FROM THE
UNIVERSITY OF MIAMI. THANK YOU
SO MUCH, I WANT TO THANK
ORGANIZERS WHO HAVE SET IT UP
EVERYTHING SO NICELY. SO I WILL
BE PRESENTING BASICALLY THIS IS
OUR FIRST RMIP GRANT AND MY
PRINCIPLE INVESTIGATOR WITH ME.
WE ARE BOTH MULTIPLE
INVESTIGATORS IS DR. JOSHUA AND
HE BASICALLY FOR OUR -- THIS
PROJECT WHAT WE ARE DOING WE ARE
TRYING TO CONFIRM OUR HYPOTHESIS
AND PERFORMING A PRECLINICAL
STUDY TO MAKE SURE OR TO CONFIRM
THAT THE DELIVERIES OF THE
EXOSOMES ARE EXTRACELLULAR
VESICLE HELP WITH CARDIAC
INDICATION. SO THERE ARE A FEW.
WE JUST GOT TWO MONTHS THIS
GRANT AND WE'RE VERY NEW TO THIS
MECHANISM AND WE ARE RIGHT NOW
STARTING TO PRODUCE PRODUCTS SO
WE CAN DO THESE STUDIES SO
THERE'S NOT MUCH DATA FOR US TO
PROT
PRESENT BUT I CAN QUICKLY GO
OVER THE TRIAL DESIGN SO WE WANT
TO -- AT THE UNIVERSITY OF MIAMI
WE HAVE DONE QUITE A LOT OF WORK
ON STEM CELLS AND NOW WE ARE
MOVING TO APSCS, EXTRACELLULAR
VESICLES AND I'M TRYING TO SEE
IF SINGLE DOSE VERSUS REPEATED
DOSE MAKES A DIFFERENCE AND WE
HAVE THREE DIFFERENT COHORT AND
ONE HAS SINGLE DOSE WITH SINGLE
DOSE OF THREE DIFFERENT DOSES
BECAUSE WHEN WE DID OUR
PRELIMINARY STUDIES WE TESTED
ONE DOSE SO NOW WE HAVE SELECTED
ONE ABOVE AND ONE BELOW. SO AND
THEN THERE IS SECOND COHORT
WHERE WE ARE DOING THREE
INJECTIONS. EACH INJECTION IS A
WEEK APART AND THIS IS ON OUR MY
MODEL WHICH WE HAVE DEVELOPED
THROUGHOUT MANY YEARS AND THEN
THE LAST COHORT IS SIX
INJECTIONS WEEKLY. AND THAT
IS -- WE'RE DOING THE LOW DOSE,
MEDIUM DOSE, HIGH DOSE AND
PLACEBO SO IT'S PRETTY
ELABORATED STUDY AND WE'RE VERY
EXCITED TO START THAT NEXT
MONTH. WE'RE RIGHT NOW IN
PROCESS OF MAKING EXOSOMES OR
EXTRACELLULAR VESICLES SINCE WE
HAVE NOT STARTED OUR PROJECT.
SO I AM MORE LIKE, YOU KNOW, THE
CHALLENGE I CAN SEE I WILL BE
FACING IS TRANSLATING IT TO
LARGE ANIMAL BECAUSE THIS IS
SMALL ANIMAL STUDY. I HOPE
THERE'S MORE FUNDING MECHANISM
WHERE WE CAN SUPPORT THOSE LARGE
ANIMAL TRIALS AND WE ARE FOCUSED
ON THE INDICATION. WE HAVE THE
SMALL WORK ON MNRI AND THERE MAY
BE PROBLEM TRANSLATING TO OTHER
DISEASES. RIGHT NOW WE'RE
WORKING ON THE MODEL. SO I
BELIEVE AND THINK THAT I HAVE TO
GO BACK AND DO SOME SMALL ANIMAL
AND LARGE ANIMAL WORK WITH, YOU
KNOW, THIS PRODUCT. SO
HOPEFULLY WE WILL PASS THESE
CHALLENGES OR OVERCOME WHEN WE
GET THERE. IN GENERAL TERM THAT
WHAT I FEEL THAT THERE'S A
REGULATORY HURDLE HERE. I --
THE FDA FOLKS ARE HERE SO I CAN
PROBABLY, YOU KNOW, TALK ABOUT
THAT. THAT REGULATORY PATHWAY
FOR BRINGING REGENERATIVE
THERAPY TO MAKE IT IS COMPLEX
AND IT VERY SIGNIFICANTLY ACROSS
DIFFERENT REGIONS.
THESE ARE COMPLEX AND, YOU KNOW,
DURING WHEN PEOPLE ARE EDGE --
GETTING THEIR EDUCATION I FEEL
THAT THERE SHOULD BE SOME -- IN
MODIFICATION OR CHANGES IN
CURRICULUM THAT PHYSICIANS OR
PH.D.S, THEY ARE EDUCATED ON
THESE REGULATIONS. AND THEY
KNOW WHAT THEY WILL BE DEALING
WITH WHEN THEY HAVE A THERAPY
WHICH THEY WILL TAKE IT FROM,
YOU KNOW, BENCH TO BEDSIDE AND
ALSO THE STRINGENT REQUIREMENT
FOR SAFETY AND EFFICACY ARE
ESSENTIAL BUT CAN BE A BARRIER
TO INNOVATION AND TIMELY PATIENT
ACCESS. SO AND ALSO THIS IS
LIKE, YOU KNOW, NAVIGATING THE
EVOLVING AND GUIDELINES OR
REGULATIONS IS ALSO A CHALLENGE
AND ALSO THE HARMONIZATION OF
THESE REGULATORY STANDARDS WHICH
THERE'S A LOT OF EFFORTS DONE IN
THAT AREA BUT I FEEL IF WE CAN
HAVE INITIATIVE WHERE THESE
BIOMARKERS AND PREDICTIVE
TESTINGS AND PATIENT REPORTED
OUTCOMES CAN BE MORE
COMMUNICATED THAT WOULD BE
REALLY HELPFUL. I WILL QUICKLY
GO TO THE SLIDE. IT'S MORE
DISCUSSING ABOUT THE REGULATORY
SCIENCE, THERE'S THE GAP WHICH I
ALREADY MENTIONED BUT THERE IS
ONE THING I WANTED TO MENTION
WHICH IS MY MAIN AREA IS WHEN A
PRODUCT IS DEVELOPED, A THERAPY
IS DEVELOPED, MAKING THAT
PRODUCT, SCALING UP THAT
PRODUCT, CHARACTERIZING THAT
PRODUCT, MOST OF US FEEL OR
THINK THAT WHEN YOUR PRODUCT IS
DEVELOPED AND YOU ARE DOING
CLINICAL TRIAL IT STARTS THERE
AND I'M SURE THERE IS AN ONGOING
CHALLENGE OF SCALING UP. FULLY
CHARACTERIZING YOUR PRODUCT AND
CHALLENGING THOSE ONGOING THINGS
WHICH WE DON'T KNOW SOMETIMES
ESTABLISHING A POTENCY ASSAY AND
IF YOUR MODE OF MECHANISM IS NOT
WELL-DEFINED OR YOU'RE DEFINING
IT, ESTABLISHING THOSE ASSAYS IS
DIFFICULT SO WITH THE HELP OF
THESE FUNDING INITIATIVE I FEEL
THAT THERE SHOULD BE SOME FOCUS
ON PRODUCTS WHICH ARE ALREADY
DEVELOPED AND WE HAVE TO
MAINTAIN IT OR GO WITH THE
SCALING UP AND EDUCATION
DEFINITELY. WE NEED TO TRAIN
PEOPLE LIKE US AND RESEARCHERS
THAT WHAT ARE THESE STEPS THEY
HAVE TO TAKE IF THEY WANT TO
TAKE A THERAPY FROM THE BENCH TO
BED SITE -- SIDE. THIS
CONCLUDES MY COMMENTS. THANK
YOU, EVERYBODY.
>> I'M AMAZED. THANK YOU, ALL,
FOR DOING SO WELL. AND STICKING
TO THE SHORT TALK FORMAT. WE
SURE HEARD A LOT. AND I THINK,
YOU KNOW, THERE'S ABUNDANT FOOD
FOR THOUGHT HERE. WE WILL --
THIS WILL GROW IF FAY, WON'T YOU
COME ON UP. SO I THINK ONE
THING WE CAN START TO DO OVER
THE COURSE OF TODAY IS TO
IDENTIFY THEMES THAT WE HEAR.
AND I THINK THIS -- IT ISN'T
ROCKET SCIENCE. IT'S STEPPING
BACK AND LISTENING AND TRYING TO
UNDERSTAND SORT OF COMMON THEMES
THAT COME UP ACROSS THE TALKS.
AND BECAUSE WE HAVE SOME TIME I
THINK WE CAN START NOW IS THERE
ANY QUESTIONS FOR THE SPEAKERS?
I THINK JANUARY JANNA, WE'RE
GOING TO NEED A MICROPHONE.
SO JANNA WILL HAVE THE
MICROPHONE. JANNA, WE'RE GOING
NEED A MICROPHONE.
SO JANNA WILL HAVE THE
MICROPHONE. JANNA, WE'RE GOING
NEED A MICROPHONE.
SO JANNA WILL HAVE THE
MICROPHONE. SHOULD I START WITH
THE THEMES WE HEARD?
>> (SPEAKER FAR FROM MIC).
>> WE ARE BEING VIDEO CAST.
>> I HAVE A QUESTION FOR
DR. STERN, I WAS WONDERING IF HE
COULD ELABORATE ON THE EARLY FDA
OPPORTUNITIES. HE MENTIONED
SOME PROGRAMS.
>> WE'RE LOOKING TO MOVE A CR
CRYOPRESERVATION TECHNIQUE AND
THE PATHWAY TO GET FEEDBACK FROM
THE FDA EARLY ON IS LIMITED.
SO, I'M SORRY, THIS REQUIRES A
FAIRLY MATURE APPLICATION TO
REQUEST MEETINGS WITH THE FDA
AND THERE ARE TWO NEW PROGRAMS
THAT THE CAT WHICH I HAVEN'T
FIGURED OUT HOW TO ACCESS WHICH
THERE CAN BE A DISCUSSION WITH
THE FDA EARLY ON, LESS FORMAL
PATHWAYS AND REALLY BY RAISING
THOSE TO THE RMIP PROGRAM WAS
INITIALLY NIH AND FDA AND HOW DO
WE ENGAGE THE FDA MORE
EXTENSIVELY AND PERHAPS LESS
FORMALLY WOULD BE VERY
ADVANTAGEOUS TO OUR EFFORTS AT
LEAST.
>> SO I THINK WE HEARD THAT
CERTAINLY WAS A THEME THAT CAME
UP. THERE ARE TWO WAYS --
MULTIPLE WAYS TO THINK ABOUT IT.
ONE IS CONVERSATIONS WITH THE
FDA. AND LISTENING TO THIS AND
OTHER WORKSHOPS THE WAY I WOULD
FORMULATE IT IS, WHAT IS THE
DATA THAT WE NEED TO HELP THE
FDA MAKE DECISIONS? AND AS
SOMEONE ELSE -- AS YOU ACTUALLY
SAID, WE -- WITH THE CELL
CHARACTERIZATION WE'RE LEARNING
A LOT ABOUT WHAT'S IN THESE
PREPS AND IT'S SOMETIMES
SURPRISING AND SOMEONE ELSE SAID
THERE WERE CELLS IN THEIR PREP
THAT WAS IDENTIFIED. SO YOU CAN
SEE HOW THAT CAN GIVE THE FDA A
LITTLE PAUSE AS TO OKAY WHAT, IS
IT? WHAT'S THE DATA? WHAT IS
IT THAT WE COULD DO SOME
EXPERIMENTS THAT MAY HAVE
SPECIFIC GOALS BUT THAT WOULD
GENERATE DATA THAT WOULD HELP
THE FDA UNDERSTAND WHAT SAFETY
MEANS AND YOU CAN TALK ABOUT IN
THE ANIMAL MODEL STAGE, YOU CAN
TALK AT THE INITIAL, YOU KNOW,
WHAT ARE YOU GOING GIVE TO THE
HUMANS AND THEN SCALE UP AND
THEN IT GOES TO THE RELATED
QUESTION OF QUALITY CONTROL.
THAT WITH THE GENERATION OF THE
AUTOMATED SYSTEMS, FOR PRODUCING
CELLS, AND CLOSED CIRCUIT
SYSTEMS, I THINK THAT IS GOING
TO STREAMLINE A LOT OF THE
PRODUCTION PROCESS AT EACH
STAGE. BUT THERE'S STILL THE
SAME QUESTION. WHAT ARE YOU
GIVING? WHAT'S IN THE PREP? IS
IT SAFE AND IS IT EFFECTIVE? SO
HOW CAN WE GENERATE DATA USING
INDIVIDUAL PROJECTS WITH THE
SPECIFIC MISSIONS TO GENERATE
DATA AS TO WHAT IS SAFE AND
EFFECTIVE? I THINK -- THIS IS
ONE WAY -- THAT'S A THEME THAT I
THINK I HEARD TODAY. ANY
COMMENTS? TONY, I'M SORRY --
TONY AND -- TONY AND THEN DAN.
>> I WILL BE SPEAKING FOR THE
ISCT A LITTLE BIT LATER BUT I
THINK ONE OF THE COMMON THEMES
WE'VE HEARD IN ADDITION TO THE
MANUFACTURING REGULATORY IS
POTENCY. ALL RIGHT, THIS CAME
UP A COUPLE TIMES AND A COUPLE
OF THE EXAMPLES WERE THAT YOU
CAN DO TRIAL DIFFERENTIATION OR
CHARACTERIZE YOUR EMBRYONIC
MARKERS OR THINGS LIKE THAT.
IT'S POTENCY AND PATIENT
PHENOTYPE. NOT EVERY PATIENT IS
THE SAME REGARDLESS OF THE
DISEASE. I THINK WE'RE THE SAME
WHERE WE CAN BE REALLY HELPFUL
IN SUPPORTING THE TYPES OF
STUDIES THAT WOULD DEFINE
POTENCY. AND ALONG WITH POTENCY
IS MECHANISMS OF ACTION BECAUSE
THEY'RE HAND IN HAND FOR
DIFFERENT DISEASES YOU CAN HAVE
THE SAME CELL APPLIED OR THE
SAME CELL TYPE APPLIED ACROSS
THE SPECTRUM DIFFERENT
INDICATIONS AND IT'S GOING TO
WORK DIFFERENTLY. AND USE MSCS
THEY ALL CHANGE THEIR PHENOTYPE
DEPENDING ON THE INFLAMMATORY
ENVIRONMENT THEY ENCOUNTER
INVIVO YOU CAN CHARACTERIZE THEM
BUT THAT'S NOT REAL LIFE TO
SUPPORT STUDIES THAT WOULD
ADDRESS POTENCY, PATIENT
PHENOTYPE, WHAT REALLY HAPPEN TO
THE CELL OR CELLS ONCE THEY SEE,
AGAIN, THE CLINICAL ENVIRONMENT,
I THINK WOULD GO A LONG WAY AND
IT ALSO ADDRESSES IN PART THE
FACT THAT A LOT OF THINGS WORK
IN -- AND THIS CAME UP
REPEATEDLY THE MOUSE STATE YOUR
NAME FOR THE RECORD STUDIES
THAT JUST DON'T FLY IN PATIENTS.
THAT WOULD BE A GOOD USE OF OUR
THINKING AND FUNDING.
>> THAT'S EXCELLENT, TONY.
>> THANKS. HI, TONY. I JUST
WANTED TO ECHO WHAT JEFFREY AND
DAN SAID ABOUT POTENCY ASSAYS
AND ALSO DAN'S POINT ABOUT
EPIGENETICS TRAJECTORY ANALYSIS
AND SINGLE CELL ANALYSIS THAT IS
A COMMON ELLE TOOLE FOR EVERY
CELL LINEAGE THAT IS A COMMON
GRAMMAR THAT CAN BE USED TO
STUDY DIFFERENT CELL STATES.
ACROSS DIFFERENT TISSUE TYPES.
AND SO WE MIGHT THINK ABOUT THAT
AS -- IN TERMS OF IN PROCESS
MILE MARKERS, POTENCY ASSAYS
BECAUSE WE KNOW THOSE ARE
CORRELATED WITH PHENOTYPES WITH
THAT AND SAYING DIFFERENT KINDS
OF POTENCY ASSAYS AND DIFFERENT
TRAJECTORIES FOR TISSUES.
>> ANYONE ELSE? SO I -- ECHO
WHAT BOB SAID. WHAT KIND OF
DATA WE CAN, YOU KNOW, PROVIDE
FOR FDA BECAUSE -- AT LEAST IN
MY CONVERSATION WITH OUR FDA
COLLEAGUES, IF YOU LISTEN TO
ENOUGH FDA TALKS, THEY ACTUALLY
VERY OPEN FOR DISCUSSION. AND
THERE'S NO -- ONE PATHWAY. I
THINK FOR THEM, SAFETY IS VERY
CENTRIC. RIGHT? SO IF YOU
ARE -- OR YOUR COLLEAGUES ARE
THE FDA ADVISORY BOARD THESE ARE
THE PLACES YOU CAN PUT IN YOUR
IDEAS AND WHAT CAN YOU OFFER TO
ENSURE WHAT THEY ARE LOOKING
FOR? SO I AGREE WITH THE ENGAGE
WITH THE FDA EARLY BUT
OFTENTIMES, THEY DON'T GIVE
PRE-APPROVAL EVEN IF THEY ARE
ENGAGING EARLY. SOMETIMES THEY
MIGHT PUT THEM INTO CONFLICT.
SO YEAH. DAN, GO AHEAD.
>> SO ACKNOWLEDGING THAT, THE
FDA HAS COME BACK NOW REPEATEDLY
WITH RESPECT TO CLINICAL
INVESTIGATIONS FOR THE MSCS AND
WHAT THEY SPECIFICALLY ASK FOR
ARE POTENCY ASSAYS. HOW DO YOU
DEFINE YOUR POTENCY. SO I THINK
AGAIN WHAT INFORMATION CAN WE
PROVIDE IF WE CAN DESIGN A
CONSORTIUM APPROACH THAT WOULD
ADDRESS AMONGST EVERYTHING ELSE
MECHANISMS AND POTENCY. THAT'S
WHAT THE FDA WANTS.
>> YEAH. THANK YOU.
>> HI, CHRIS. I THINK A LOT OF
PEOPLE HERE ARE COMING FROM
ACADEMIA AND THIS IS REALLY
INDUSTRY. I DON'T THINK WE'RE
AT ALL FAMILIAR DEALING WITH
PROPRIETARY INFORMATION AND IT'S
NOT THE WAY WE'RE TRAINED BUT
YOU HAVE TO LEARN HOW TO DO IT
IF YOU WANT TO GET INTO THIS
FIELD. SO, YOU KNOW, I THINK A
LOT OF TIMES THE FDA SEES THAT A
COMPANY IS DOING IT WELL OR THAT
A PRODUCT IS DOING IT WELL, THEY
KNOW THERE'S A PROBLEM OUT THERE
AND YOU PLAY A LITTLE BIT OF
THIS GUESS WHAT I'M THINKING
GAME BECAUSE THEY KNOW WHAT THE
ANSWER IS OR AT LEAST THEY KNOW
WHAT THE PROBLEM IS BUT WHAT
INFORMATION THEY CAN SHARE WITH
YOU IS LIMITED AND SO YOU NEED
TO BE AWARE OF THAT GETTING INTO
THIS AND I THINK ANOTHER WAY
THAT THIS REALLY MANIFESTS
ITSELF ESPECIALLY AS WE TRY AND
TAKE DISCOVERY TO THE CLINIC,
THROUGH AN ACADEMIC ROUTE IS
THROUGH THE NOTION OF GLP AND
SAVING YOUR DATA THE RIGHT WAY
AND I THINK THE FDA'S BEEN
WONDERFUL FROM THAT POST THAT
THINGS DO NOT HAVE TO BE JLP BUT
YOU HAVE TO GIVE THEM DATA IN A
WAY THAT THEY CAN REPLICATE YOUR
EXPERIMENT AND YOU CAN DEVELOP
THAT CULTURE AND DO IT VERY
EFFECTIVELY.
>> YEP. THANK YOU.
>> THE INDIVIDUAL EXPERIMENTS
FOR INDUSTRY ARE GOING TO BE
PROPRIETARY BUT WE DO NEED TO BE
COMPETITIVE. WHAT THAT MEANS TO
ME IS THAT AS ACADEMICS WE
PRODUCE DATA THAT THEN CAN BE
USED TO ANSWER THESE QUESTIONS
MORE GLOBALLY. AND SO THAT'S MY
THINKING IS YES A LOT OF THIS IS
MOVING INTO MANUFACTURING
COMPANIES THAT DO DO THAT.
THERE ARE COMPANIES THAT ARE
DEVELOPING PRODUCTS. BUT IF WE
AS A GROUP CAN PRODUCE THE DATA
THAT CAN HELP ANSWER THE
QUESTION THAT YOU JUST RAISED OF
WHAT IS GOOD ENOUGH AND THAT
BECOMES ANSWERABLE WITH OUR
PRECOMPETITIVE DATA WITHOUT
HAVING TO GO TO THE COMPANY THAT
IS TO ME IS A VISION OF HOW WE
CAN ACTUALLY MOVE THINGS FORWARD
.
>> THANKS. ALAN, SORRY. ALAN
FIRST AND THEN JEN.
>> SO FOLLOWING UP ON THAT.
DR. CAMP MENTIONED THE NEED FOR
BETTER ANIMAL MODELS.
ESPECIALLY LARGE ANIMAL MODELS.
EVERY TIME WALK INTO AN OR WITH
A BIG IT'S A 15,000 DOLLAR
INVESTMENT AND I'M PUTTING HUMAN
CELLS IN A PIG AND THE PIGS DIE
FROM THE IMMUNOSUPPRESSION. WE
WORK WITH THE EYE SO WE USE
IMPLANTS AND SO ON BUT WE STILL
GET REJECTION REGARDLESS. AND
SO IF WE WERE ABLE TO BRING DATA
TO THE AGENCY USING PIG MODELS
AND I MEAN SAFETY MODELS IN
PARTICULAR. THAT ALLOW US TO
CONSIDER THE IMPURITIES IN OUR
SAMPLES SO DR. STERN, FOR
EXAMPLE, SHOWED US MULTIPLE
DIFFERENT CELL TYPES IN HIS
PREPARATION. THAT MAY ALL BE
RPE AT DIFFERENT STAGES FOR
EXAMPLE BUT SOME ARE GOING TO BE
MORE EFFICACIOUS THAN OTHERS THE
QUESTION IS DO THE IMPURITIES
MATTER? WE KNOW THAT THERE'S
SOME THAT MATTER BECAUSE THERE'S
POTENTIAL FOR TERRA TO MA
FORMATION FOR EXAMPLE AND THE
QUESTION OF HAVING THE LOT
RELEASE ASSAYS, FOR EXAMPLE,
COULD BE POTENTIALLY NEGATED IF
WE HAD PROPERLY ANIMAL MODELS TO
EVALUATE IF THERE'S A POSED RISK
TO SAFETY AND TO DO THIS AT
EARLY STAGES AND NOT AT THE
SAFETY STUDIES AND IN ANIMAL
MODELS THAT DON'T REQUIRE THE
LEVEL OF IMMUNOSUPPRESSION THAT
WE WORK WITH.
>> THANK YOU.
>> SO COMING BACK TO THE STEM
CELLS AND THE FDA IN OUR CASE,
WE WERE USING BONE MARROW
ASPIRATE SO CLEARLY THERE WAS
TALKING THERE THAT IS VERY
IMPORTANT. ONE THEY ARE NOT
PURE STEM CELLS AND ALL THAT.
BUT THE SECOND THING TOO IS THEY
ARE NOT EXPENDED AND THAT HAS
PAVED THE WAY FOR US TO GET
CLEARANCE WITH THE FDA AND
AGAIN, I THINK, YOU KNOW, WE
SHOULD THINK AS A GROUP THAT
I'VE BEEN WORKING FOR A LONG
TIME TO EXPEND A STEM CELL
FOREVER BEFORE I INJECT THEM. I
KNOW IN SOME CASE WE NEED
EXTENSION. I KNOW THOROUGHLY IN
SOME CASE WE NEED EXTENSION BUT
IN SOME CASE YOU DON'T NEED
EXTENSION AND IN OUR CASE THAT,
YOU KNOW, THAT WAS WHAT HAPPENED
SO CLEARLY I THINK, BUT WE
EMBODY THAT RIGHT AWAY. I HAVE
A TEAM OF PEOPLE THAT WORK WITH
THE FDA AND I WANT TO MAKE SURE
I EDUCATE THEM AND THEY HELP ME
TO GO THROUGH THAT, YOU KNOW,
PROCESS. AND THE FINAL THING
FOR US, THE BIGGEST PROBLEM WAS
MORE THE DRUG WE WERE USING. WE
ARE USING ENOUGH LABELED DRUG TO
REDUCE THIS AND THERE WE HAD TO
HAVE THE FDA APPROVAL AND I
COLLABORATE WITH THE CLINIC.
AND IF YOU HAVE SOMEONE IN THE
FIELD THAT IS DOING CLINICAL
TRIALS ON THE SAME DRUG MAYBE
YOU CAN PIGGYBACK ON WHAT THEY
DO AND THAT REALLY IS PAVE WHAT
YOU DO AS WELL.
>> THANK YOU. TONY, GO AHEAD.
>> I JUST WANTED TO -- I WANTED
TO BRING UP ONE MORE THEME THAT
WAS -- WE SAW IN THE FIRST
SESSION WHICH WAS THIS
COMPARISON BETWEEN OFF THE SHELF
ALOE PRODUCTS AND WHICH ARE
IMMUNO REACTIVE AND THEN
AUTOLOGOUS LONGER MANUFACTURING
ROUTES WITH VARIABILITY THAT ARE
RELATIVELY INERT AND THIS
BALANCE OF HOW TO OVERCOME THIS
TRANSPLANTATION BARRIER IS I
THINK A BIG ISSUE BECAUSE IT'S
LESS COST. SO EVERYONE'S
TALKING ABOUT IT BUT IT'S IN THE
ROOM WHERE YOU HAVE TO DEAL WITH
IT.
>> I THINK ALAN MENTIONED THE
UNIVERSAL DONORS AND I WAS
THINKING, WOULD IT EVEN BE
POSSIBLE? WOULD IT BE IDEAL OFF
THE SHELF AND DO WE HAVE A
DEFINITION FOR THAT? AND SO
MAYBE ALAN YOU WANT TO COMMENT
ON THAT?
>> WELL I DON'T HAVE IT. I
UNDERSTAND THAT THERE'S SOME
PRODUCED KNOCKOUTS THAT ARE
WORKING IN OTHERS' HANDS BUT THE
QUESTION BECOMES ONE OF
MANUFACTURING, FROM A REGULATORY
PERSPECTIVE, AS I'VE MOVED
THROUGH THIS PROCESS AND WE HAVE
NOT YET FILED AN IND BUT WE'VE
HAD MULTIPLE MEETINGS WITH THE
AGENCY THE PROBLEM IS YOU START
WITH A DONOR CELL MAYBE WHAT'S
COLLECTED UNDER GTPS AND THEN
MOVE TO THE PRODUCTION OF A LINE
AND THEN THE PRODUCTION OF THE
IPSC LINE TO A DIFFERENTIATION.
IT IS A SUPER COMPLICATED
PROCESS. AND THEN THERE MAY
BE'RE PARTS TO THAT. MAYBE YOU
HAVE, YOU KNOW, SURGICAL
INSTRUMENTS THAT ARE PART OF THE
PACKAGING, A SCAFFOLD THAT'S A
PART OF IT SO THIS IS A REALLY
COMPLEX THING AND THEN TO ADD
ONTO THAT THE REMOVAL, SAY, OF
MHA GENES DO AND DOING THAT BY
GENE EDITING KNEW -- NOW YOU'RE
TAKING A CELL THAT WAS PRODUCED
AND NOW YOU'RE GOING TO MESS
WITH THAT GOOD CELL LINE AND
MAYBE IT'S GOING TO TAKE ANOTHER
20 PASSAGES WHAT HAVE YOU DONE
GENETICALLY AT THAT POINT? HOW
MANY PASSAGES HAVE YOU BEEN
THROUGH? WHAT ARE THE
CONSEQUENCES OF THAT? I THINK
IT'S IMPORTANT TO GET THERE TO
GET OFF THE SHELF PRODUCTS IN
THE MARKETPLACE. BUT I THINK
THAT WE HAVE TO HAVE A MEANS OF
INTRODUCING THAT UNIVERSAL
DONORNESS FOR LACK OF A BETTER
TERM AT THE TIME OF
REPROGRAMMING SO IT DOESN'T
CAUSE ADDITIONAL CHANGES AND
ALLOWS US TO SELECT THE CELLS AT
THE EARLIEST STAGE POSSIBLE. I
DO KNOW A GROUP THAT IS WORKING
ON THAT BUT THEY HAVEN'T GOTTEN
TO THAT YET.
>> I TRIED TO FIND THE ANSWER ON
GOOGLE BUT I CAN'T QUITE
REMEMBER I THINK THE COMPANY IS
CALLED SOMETHING BUT THERE'S A
NUMBER OF PAPERS WHERE THEY MAKE
UNIVERSAL STEM CELLS AND THEY
USED A PRIMATE MODEL AND MADE
THESE UNIVERSAL STEM CELLS. YOU
CAN NOW DO IT FAIRLY
EFFICIENTLY. YOU CAN KNOCK OUT
AN HLA CLASS ONE OR TWO AND AT
THE SAME TIME AS YOU ARE
KNOCKING IT OUT YOU CAN KNOCK IN
SOMETHING USEFUL LIKE HLA OR
CD47 SO THEY'RE ACCOMPLISHING A
LOT OF THINGS WITH MAYBE A
COUPLE OF KNOCK OUT KNOCK IN
STEPS AND SO IN THAT SHORT
PERIOD OF TIME, THEY'RE ABLE TO
GENERATE A PRETTY NICE CELL.
>> (SPEAKER FAR FROM MIC).
>> IT'S NOT THAT THE
TECHNOLOGIES DON'T EXIST. THERE
HAVE BEEN A DIFFERENT GROUPS.
THE PROBLEM IS THE
MANUFACTURING. AND EACH STEP
IMPOSES RISK AND WHEN YOU'RE
TAKING AND AGAIN IN THE ALOE YES
NAYIC WORLD IS DIFFERENT FROM
THE AWETOLOGIST WORLD. I CAN
USE THIS IN ONE PATIENT. WHO
CARES FROM AN ALOE YES NAYIC
STANDPOINT I NEED A VERY
EFFICIENT PRICE IN ORDER TO KEEP
THE PRICE DOWN AND MAKE THIS
SOMETHING THAT IS UNIVERSAL FOR
EVERYBODY.
EVERYTHING I ADD TO THAT PROCESS
INCREASES THE COST OF GENERATING
THE CELL LINE AND INCREASES THE
RISK AND ADDS TO THE REGULATORY
BURDEN. AND THAT'S WHERE A LOT
OF THESE PROBLEMS REALLY
ORIGINATE FROM IT'S NOT THAT THE
TECHNOLOGY ISN'T THERE. IT'S
THE REGULATORY BURDEN COMBINED
WITH THE RISK TO PRODUCT.
>> THANK YOU. DAN.
>> SO TO FOLLOW UP ON THE
CONVERSATION I JUST WANT TO GO
BACK TO SOMETHING THAT CHRIS
SAID AND THE QUESTION IS, WHERE
SHOULD MANUFACTURING BE? AND
WHAT'S THE BEST MEANS TO AN END
POINT, RIGHT? IS IT REALLY
ACADEMIA? OR IS THIS WHERE
INDUSTRY PARTNERSHIP IS REALLY
GOING TO BE CRITICAL,
PARTICULARLY FOR IF YOU THINK
THE VOLUME OF PRODUCT THAT YOU
WANT TO EVENTUALLY PRODUCE IT
INCORPORATES ALL THE SAFETY AND
QUALITY CONTROL AND POTENCY AND
THINGS LIKE THAT BUT ON THE
OTHER HAND WE'RE ALL ADMISSIONS,
RIGHT? AND THERE HAVE BEEN
EXAMPLES IN THE PAST AND I WILL
POINT TO MARTHA HERE BECAUSE NH
HAD A PROGRAM CALLED THE PACT
PROGRAM THAT SUNSETTED, RIGHT?
BUT THE WHOLE GOAL WAS TO
PROVIDE MATERIALS FOR CLINICAL
INVESTIGATIONS SO WE'VE DONE
THAT BEFORE. IS THAT SOMETHING
WE CAN DO AGAIN? BUT BEEF IT UP
WITH THE TYPE OF FUNDING THAT
WOULD ALLOW, AGAIN, THE
RELIABILITY, REPRODUCIBILITY AND
MECHANISM, THINGS OF THAT
NATURE.
>> YEAH, THANK YOU. JENNA OVER
HERE AND THEN I WILL MOVE ONTO
ANOTHER COMMON THEME I'VE HEARD.
>> WE KNOW THAT ADULT STEM CELLS
OR TISSUE CELLS, THEY DON'T
EXPRESS EQUALLY. THEY EXPRESS
IN CLASS ONE AND THEY EXPRESS G
OR HLE. SO THEREFORE THEY DON'T
STIMULATE T-CELL RESPONSES. CAN
THEY STILL BE REJECTED?
PROBABLY. BUT IF WE START WITH
A PLATFORM THAT IS ALREADY SET
TO -- PRESENT THE CELLS, THEY
PREVENT THE FETUS FOR BEING
REJECTED TO THE MOTHER. FROM
PREVENTING BEING REJECTED. SO
IF YOU START WITH THOSE TYPE OF
PLATFORMS WE ALREADY HAVE CELLS
THAT CAN DO WHAT WE WANT TO DO
THEN IT'S JUST USING THEM TO
DELIVER SPECIFIC GENES OR
DIFFERENTIATE THEM INTO SPECIFIC
POTENTIAL. I THINK THE
POTENTIAL IS OUT THERE WE JUST
LIKE TO LOOK FOR THE CELLS THAT
ARE RIGHT FOR WHAT WE WANT TO DO
AND THAT THEY ARE NOT
IMMUNOGENIC IN NATURE TO START
WITH.
>> YEP. THANK YOU. SO ANOTHER
COMMON THING I'VE HEARD IS
ANIMAL MODELS, RIGHT? WE HAVE
INVESTIGATOR PRESENTED SUCH AS
DENNIS IN HUMANS AND WE HAVE
PEOPLE WORKING WITH PIGS AND
OTHERS THINKING TRANSLATING FROM
MOUSE MODEL TO LARGE ANIMAL
MODELS AND SO MY QUESTION IS ARE
THERE OTHER MODELS, I MEAN, WE
ACTUALLY HEARD SOMEONE MENTIONED
DIGITAL. AND IF YOU ARE AWARE
NIH ACTUALLY RIGHT NOW IS
DISCUSSING A COMMON FUND
INITIATIVE COMPLEMENTARY
ALTERNATIVE MODELS THAT YOU KNOW
FDA HAS CHANGED THEIR DRUG
APPROVAL GUIDELINE AND THEN
CHANGING ANIMAL MODELS TO MODELS
POSSIBLY IN VITRO MODELS I
WONDER WHETHER, YOU KNOW, IF YOU
HAVE COMMENTS? ANY?
>> I THINK ANY MODEL IS
IMPERFECT BUT IT DEPENDS ON THE
QUESTION YOU'RE ASKING AND I
TOOK STUFF FROM MICE TO HUMANS
BECAUSE I WAS USING A DRUG THAT
ALREADY HAD A KNOWN SAFETY
PROFILE SO WE SHOWED ITS
BIOLOGIC EFFECT WITH RELATION TO
THE MECHANISM OF ACTION OR
PRODUCT THEY ALREADY KNEW IT WAS
SAFE AND SO WE COULD TAKE THAT
LEAP OF FAITH IN OTHER
SITUATIONS WE USED LARGE ANIMAL
MODEL ONE OF THE THINGS THAT
STARTED PAY BENEFITS RECENTLY IS
DOING LARGE TERM LARGE ANIMAL
MODEL. SO MUCH OF THIS IS JUST
A TINY FRACTION OF THE ANIMAL'S
LIFE SPAN. WE HAD THE GOOD
FORTUNE OF FOLLOWING A COHORT OF
ANIMALS AND THE DATA IS SO
USEFUL IN HELPING YOU BRING YOUR
PRODUCT TO THE CLINIC AND
FINALLY WITH THE RELATIONSHIP TO
THE CLINICAL TWIN. ONE OF THE
THINGS THAT'S PAID GREAT
DIVIDENDS FOR US IS WHEN YOU
SYNTHESIZE THESE MODELS AND PUT
THEM TOGETHER AND IT'S PROVED
USEFUL AND IN THE DEVELOPMENT
PROCESS.
>> YEAH. THANK YOU. JOHNNY?
>> IN OUR CASE WE DIDN'T USE
LARGE ANIMAL MODEL WE WENT FROM
THE MOUSE THEORETICALLY TO THE
PATIENT AS THE PREVIOUS SPEAKER.
I MEAN, A LOT OF WHAT WAS USED
WAS ALREADY APPROVED. BUT ALSO
I WOULD LIKE TO STRESS IN THE
LARGE AN MOLL -- ANIMAL MODEL
IT'S VERY EXPENSIVE. WHEN YOU
DO SHEEP ANIMAL STUDIES, IT'S
VERY EXPENSIVE AND YOU CANNOT
USE AS MUCH AS YOU WANT LIKE YOU
DO IN MICE. YOU CANNOT EXTEND.
WITH A HORSE. I STRESS THAT
SOMETIMES LARGE ANIMAL MODEL
YES, THEY MIMIC MORE THE PATIENT
BUT THERE ARE MORE DIFFICULT TO
FUND AND SOMETIME, YOU KNOW, THE
NUMBER OF ANIMAL MODEL YOU NEED
YOU CANNOT DO IN LARGE ANIMAL
MODEL.
>> YEAH. GO AHEAD.
>> I THINK THE IDEA OF A DIGITAL
TWIN IS INTERESTING BUT IS
COMPLEMENTARY. NOT OF
CIRCUMVENTING LARGE AN MOLL
MODELS IN THE FUTURE.
IF YOU HAVE THERAPIES OUT THERE
THAT ARE ACQUIRING THE DELIVERY
SYSTEMS YOU NOT ONLY HAVE TO
APPROVE THAT THOSE SYSTEMS,
ROBOTIC ARMS OR WHATEVER IT IS
IS SAFE IN THAT ENVIRONMENT.
AND THEN YOU HAVE TO HAVE A
TRAINING PATHWAY TO BE ABLE TO
DISSEMINATE THAT KNOWLEDGE
ACROSS THE CENTERS THAT -- ONE
NEEDS TO ENROLL PATIENTS FOR.
>> THANK YOU. TONY?
>> AS FAR AS LARGE ANIMAL MODELS
I WANT TO MAKE SURE WE
UNDERSTAND THE DIFFERENCE
BETWEEN SMALL ANIMALS REQUIRED
FOR THOSE DRUG SUBSTANCES AND
LIVING CELL THERAPIES THAT
REQUIRE IMMUNOLOGIC TOLERANCE.
SO I THINK IF YOU MAKE A LARGE
ANIMAL MODEL IT HAS TO BE IMMUNO
COMPETENT. YOU HAVE TO IMMUNO
SUPPRESS AND FOR WOUND HEALING
IMMUNOSUPPRESSION AFFECTS WOUND
HEALING INDIRECTLY SO I JUST
WANT TO BE CLEAR THAT THIS CELL
THERAPY TYPE IS DIFFERENT THAN A
SMALL MOLECULE AND WE MAY NOT
NEED TO DO THE DISTRIBUTION THAT
ARE RELEVANT TO HUMANS BECAUSE
WE'RE LOOKING AT TISSUE
INTERACTIONS WHICH ARE MORE
IMPORTANT.
>> THANK YOU. I THINK THEN
BEHIND YOU AND THEN ROSEMARY
OVER HERE.
>> SO, THIS DISCUSSION HAS BEEN
GOING ON FOR 40 YEARS, RIGHT?
I'M NOT SURE WE'RE GOING TO GET
ANYTHING USEFUL OUT OF THE
ARGUMENT. I THINK IT'S ALL
CONTEXT SPECIFIC BUT THE WAY I
THINK ABOUT IT IS DIFFERENTLY,
RIGHT? AND IT REALLY ENDS UP
THAT THE CLINICAL INVESTIGATIONS
THAT ARE GOING TO GET THE MOST
INFORMATION I THINK ONE WAY OF
DOING IT IS -- AND IDENTIFY
ADVOCATED FAR LONG TIME IS WHEN
YOU DO THAT INITIAL PHASE ONE
AND MOVE ONTO PHASE TWO YOU
ABSOLUTELY BUILD IN AS MANY
MECKISTIC END POINTS AS YOU CAN.
NOT JUST CLINICAL BUT YOU TAKE
BLOOD, SAMPLES, YOU MEASURE
INFLAMMATORY THINGS AND YOU BASE
THAT ON THE HYPOTHESIS OF ACTION
AND YOU TRY TO INVESTIGATE THAT
AND THIS IS WHERE WE AS A GROUP
COULD PROVIDE FUNDING FOR THAT
TYPE OF THING. IT'S EXPENSIVE
ENOUGH TO DO A CLINICAL
INVESTIGATION WITH ALL THE
CLINICAL END POINTS AND
EVERYTHING ABOUT EXTRA FUNDING
OR MECHANISTIC INVESTIGATIONS I
THINK IT WOULD BE REALLY
HELPFUL.
>> THANK YOU. I THINK WAS THERE
ONE OVER HERE? YEAH. YEAH.
THEN WHEN ROSEMA ROSEMARY.
>> I ALSO WANT TO DISCUSS
PREDICTIVE BIOMARKER. THERE'S A
CHALLENGE, YOU CANNOT HAVE A
GOOD -- YOU KNOW, INFORMATION
DOING THESE STUDIES ON ANIMALS.
SOMETIME MAYBE BUT MOSTLY IN MY
EXPERIENCE, YOU KNOW, THEY
BEHAVE, THINGS BEHAVE VERY
DIFFERENT WHEN THERAPY IS
APPLIED THAN ON A HUMAN. AND
ALSO -- SO THESE BIOMARKER
STUDIES SHOULD BE DONE ON
HEALTHY VOLUNTEERS OR DISEASE
PATIENTS. SO, AND,
ACCESSIBILITY, HOW TO ACCESS
THESE SAMPLES IT'S LIKE A MAJOR
CHALLENGE. I SEE, LIKE,
DEPARTMENT OF DEFENSE AND SOME
OF THE OTHER FUNDING AGENCIES
ARE OPENING UP SOME RFAS IN THAT
RESPECT BUT WHEN YOU GO AND
APPLY BECAUSE THERE IS NOT MUCH
PRELIMINARY DATA YOU CAN
GENERATE SO YOU KNOW WHAT THE
RESPONSE IS SO JUST SOMETHING TO
THINK ABOUT MAYBE WE CAN ALSO
HAVE ONE OF THIS AREA IN THE
FUNDING. AND I WANT TO COMMENT
ON PACT ACTUALLY. WE -- OUR
FACILITY WAS PART OF PACT FOR
FIVE YEARS. I CLOSELY WORKED
WITH MARTHA. I FELT THAT THIS
WAS REALLY A VERY GOOD
INITIATIVE TAKEN BY NIH AND WHAT
WE HAVE DONE DURING THAT TIME,
YOU KNOW, IT'S -- A BIG
DIFFERENCE BETWEEN GMP FACILITY
AND ACADEMIA VERSUS A COMPANY.
BUT THESE FIVE -- I MEAN, WE
WERE PART OF THE LAST RENEWAL
BUT THESE FIVE-SIX YEARS OUR
FACILITY, WE WERE ABLE TO DO SO
MUCH MORE BECAUSE OF THIS
PLATFORM AVAILABLE AND THEY WERE
LIKE OUR OWN FUNDING GRANTS AND
A LOT OF OTHER INVESTIGATORS.
THAT'S SOMETHING ALSO TO THINK
ABOUT IT, MAYBE BRINGING
SOMETHING BACK LIKE THAT IT WILL
BE GREAT BECAUSE AS I SAID IN MY
TALK TOO THAT DEVELOPING IN AN
ONGOING MAINTENANCE AND ON
ONGOING DEVELOPMENT AND MAKING
SURE SCALING UP CHARACTERIZATION
LEARNING ABOUT YOUR PRODUCT IS
EXTREMELY IMPORTANT. THANK YOU.
>> THANK YOU. BIOMARKERS
CERTAINLY EXTREMELY, EXTREMELY
IMPORTANT. ROSEMARY.
>> SO ROSEMARY, ARMY, VIS-A-VIS
ON MODELS I LOVE THE IDEA. THE
CONCEPT. THAT NO MODEL IS
PERFECT. OF COURSE. BUT WE CAN
MAYBE THINK ABOUT COMBINING
MODELS TO GET US CLOSER TO
ANSWER BY TAKING THE DATA THAT
COMES OUT OF THOSE AND COMBINING
THEM WITH AI FACILITATED TOOLS
TO GET CLOSER TO ANSWERS THAT
MIGHT GET US TO THE CLINIC
FASTER AND SPECIFICALLY ON
THINKING THAT THE ADVANCEMENTS
IN TISSUE CHIPS OVER THE LAST
TEN YEARS HAVE BEEN PRETTY
DRAMATIC AND ONE OF THE THINGS
THAT I ALWAYS THOUGHT WAS A
TREMENDOUS POTENTIAL ADVANTAGE
ABOUT USING TISSUE CHIPS WAS TO
DO PATIENT MODELING AND SO, FOR
EXAMPLE, ONE OF THE THINGS
THAT'S VERY, VERY DIFFICULT TO
CHARACTERIZE IS WHAT IS THE
PATIENT ENVIRONMENT THAT YOU'RE
TAKING THESE INNOVATIONS INTO?
AND ONE SIZE WILL ABSOLUTELY NOT
FIT ALL SO WE HAVE TO BE ABLE TO
TWEAK WHAT WE HAVE GOT AND GET
ALL OF THE PARTS OF THE SYSTEM
COMFORTABLE AND W THE IDEA THAT
WE'RE GOING TO BE LOOKING AT
RAKES.
NOT NECESSARILY THESE SINGLE
WELL, WELL, WELL CHARACTERIZED
PRODUCTS AND ONE OF THE WAYS TO
GET AT THAT IS IF WE CAN MODEL
THE PATIENT ENVIRONMENT BETTER
AND A TISSUE CHIP MODEL THAT'S
CAREFULLY DESIGNED CAN DO THINGS
LIKE TITRATE THE AMOUNT OF
FIBROSIS THAT'S IN THERE.
TITRATE SOME OTHER THINGS SO IN
COMBINATION WITH SOME OF THESE
ANIMAL MODELS I THINK THEY COULD
BE BETTER USED THAN IT'S BEING
RIGHT NOW SO GO OUT THERE AND
COLLABORATE.
>> YEP. I TOTALLY AGREE. SO
BASICALLY WHAT ROSEMARY
MENTIONED IS THE CATS TISSUE
CHIP PROGRAM IF YOU GOOGLE --
YOU WILL SEE MULTIPLE. IT'S
OVER TEN YEARS OF FUNDING AND
THEN ONE OF THE OUTCOME WHERE
THE CONSEQUENCE OF THAT IS THE
COMPLEMENTARY VISION WHICH,
RIGHT, IT'S CORRECT, IT'S NOT
GOING TO REPLACE ANIMAL MODEL
WHICH IS THE REASON I ACTUALLY
USE COMPLEMENTARY. I THINK YOU
HAVE A COMMENT? YEAH AND THEN
WE ARE, YEAH, LAST ONE. WE ARE
GOING TO WRAP UP GOING TO
BREAKS.
>> ONE OF THE COMMENTS THAT WERE
MADE EARLIER THAT THESE LARGE
ANIMAL STUDIES INVOLVE A LOT OF
MONEY. 15,000 DOLLARS PER
ANIMAL, SOMETIMES MORE. WHILE
CLINICAL PATIENTS ARE TRIPLE
THAT OR QUADRUPLE THAT. THERE
MIGHT BE AN OPPORTUNITY IN A
ROLLING WAY FOR THE NIH TO
IMPART THEMSELVES AND APPROACH
THESE COMPANIES OF WHEN YOU'RE
STARTING YOUR PHASE ONE, PHASE
TWO CAN WE GET TO SOME OF THE
ANSWERS OF THE MORE BASIC
SCIENTIFIC QUESTIONS. BECAUSE
THESE COMPANIES THERE ARE
BEHOLDEN TO THEIR INVESTORS AND
SHARE HOLDERS AND THEY DON'T
HAVE UNLIMITED FUNDING TO BE
ABLE TO DO THE KIND OF SCIENCE
THAT WE'D LIKE.
AND I GUESS THE QUID PRO QUO
THERE WOULD BE THAT THAT DATA IS
NOW AVAILABLE TO OTHER INVAES
-- INVESTIGATORS.
THESE TRIALS WHEN THEY START
THEY WANT TO GO. YOU KNOW. I
THINK YOU HAVE TO HAVE IT KIND
OF A ROLLING OR SOMETHING THAT
IS AVAILABLE TO THEM QUICKLY.
>> THANK YOU. SO WE ARE GOING
TO GO INTO A FIFTEEN MINUTES
BREAK. THANK YOU VERY MUCH FOR
THE SPEAKERS AND THE
PARTICIPANTS. LET'S GIVE US A
ROUND OF APPLAUSE. THANK YOU.
THANK YOU.
SO WE'RE GOING TO FOLLOW THE
SAME FORMAT AS THE FIRST
SESSION. MY CO-MODERATOR IS
SITTING RIGHT IN THE FRONT.
MARTHA WILL BE HOLDING UP THE
ONE MINUTE TO GO SIGN SO IF
YOU'RE RUNNING A LITTLE BIT OVER
SHE WILL BE LETTING YOU KNOW. I
THROUGH THE FIRST ACT WAS GREAT.
THERE'S THE CHALLENGE TO STICK
TO YOUR TIME AS BEST YOU CAN.
FIRST UP WE CONSTANCE SHEW AND
ON DECK.
THANK YOU, MAY I HAVE MY
SLIDES, PLEASE?
THANK YOU FOR THIS
OPPORTUNITY TO TALK ABOUT SOME
OF THE WORK THAT WAS ACTUALLY
FUNDED WITH THE AMERICAN
RECOVERY ACT THE ARA FUNDS AND
SO IF WE COULD HAVE THE NEXT
SLIDE, PLEASE? SO AS AN
ORTHOPEDIC SURGEON I TREAT
ARTICULAR CARTILAGE DEFECTS AND
ARTICULAR CARTILAGE IS ONE OF
THE TISSUES THAT DOESN'T HEAL
WELL OR REGENERATE ITSELF.
THERE'S NOT A POINTER THAT I CAN
SEE BUT ON THE LEFT-HAND SIDE
BACK TO THE LAST SLIDE, PLEASE.
AND SO THROUGH THIS FUNDING WE
DID TWO RANDOMIZED CONTROL
TRIALS IN HORSES. AND SO IN
THIS INSTANCE, IF YOU LOOK ON
THE LEFT-HAND SIDE, THAT IS A
CARTILAGE DEFECT. SO IT'S A
POTHOLE IN THE JOINT CARTILAGE,
THESE PATIENTS DON'T HAVE
OSTEOARTHRITIS BUT IF THESE
POTHOLES AREN'T FILLED THEN
EVENTUALLY THE PATIENT DOES
DEVELOP OSTEOARTHRITIS SO YOU
CAN SEE THE HUMAN PATIENT ON THE
LEFT AND THEN YOU CAN SEE
HORSES. SO USING A GREAT ANIMAL
MODEL FOR THIS, WE USED BONE
MARROW CONCENTRATE TO TREAT ONE
OF THE DEFECTS AND SO YOU
ALREADY HEARD ABOUT BONE HARROW
ASPIRATE CONCENTRATE FROM JOHNNY
AND BY THE TIME WE DID THIS
STUDY THIS WAS CONSIDERED THE
CLINICAL STANDARD BY WHICH THE
THERAPIES NEEDED TO BE COMPARED
TO. SOME OF THE CHALLENGES WITH
MICRO FRACTURE INVOLVED DAMAGE
TO THE SUB CON JULY BONE SO
WE'RE MAKING TINY HOLES IN THE
BONES SO THAT THE BONE MARROW
CAN COME UP AND FILL THAT
CARTILAGE DEFECT AND ESSENTIALLY
HEAL AND SO OUR STRATEGY WAS TO
DIRECTLIES A PLACE THE BONE
MARROW CELLS FROM THE BONE
MARROW.
CONCENTRATE THEM AND PUT THEM
INTO THE DEFECT WITHOUT
PERFORMING A MICRO FRACTURE SO
WITHOUT DAMAGING THE SUB CON
DROLL BONE AND WE DID SHOW THAT
THESE BONE CONCENTRATE REPAIRS
HAD BETTER BONE CHARACTERISTICS
AND BETTER CARTILAGE TEXTURAL
FEATURES THAN MICRO FRACTURE SO
THIS WAS A POSITIVE IN THIS
RANDOMIZED CONTROL TRIAL FOR THE
CELL THERAPY.
AND NOW QUICKLY MOVE ONTO THE
NEXT STUDY. THE FIRST ONE WAS
DONE WITH LISA IN CORNELL AND
THE NEXT AT CSU AND HERE WE
COMPARED CULTURE EXPANDED BONE
HARROW CELL SEEDED FIBRIN
SCAFFOLD WITH THE CELL FREE
CONTROLLED SCAFFOLD AND THIS
SHOWED THAT THE CELL FREE
SCAFFOLD PERFORMED BETTER, HAD
MORE CONSISTENT REPAIRS, THE
QUANTITATIVE IMAGING WAS
PROIMPROVED AND WE DIDN'T HAVE
ATOPIC BONE FORMATION WHICH WE
DID SEE IN THE FOUR CELL SEEDED
REPAIRS AND SO LET'S MOVE ONTO
THE NEXT SLIDE AND SO
ESSENTIALLY OUR ACADEMIC
FINDINGS WITH RNA FINDING WAS WE
HAD SINGLE STEP PROCEDURES.
THAT IN THE FIRST INSTANCE IN
DIRECT COMPARISON WITH MICRO
FRACTURE THE REPAIRS WERE
SUPERIOR AND IN THE SECOND
INSTANCE WE HAD A CELL FREE
SCOFF FOLD THAT IF WE COMPARED
THE HISTOLOGY AND THE
QUANTITATIVE MR SO WE USED THE
SAME QUANTITATIVE MR THAT I USE
IN MY HUMAN PATIENTS I THINK THE
APF EF REPAIR WAS SIMILARLY
GOOD, POSSIBLY A LITTLE BIT
BETTER. AND SO WHAT HAPPENED?
WHY DID THESE NOT PROGRESS.
WELL I TERM THEM ORPHAN BECAUSE
IN THIS SAME TIME PERIOD, THERE
WERE TRIALS GOING ON FOR
NEOCART. THE MACY WAS COMING
INTO FRUITION FROM MULTICENTERED
TRIALS AND THESE SIMPLY WEREN'T
CONSIDERED INNOVATIVE CELL
THERAP
THERAPIES. THERE WAS ALSO
THE -- WE COULD NOT GET INDUSTRY
INTERESTED. THE PEOPLE WHO DID
THE BONE MARROW CONCENTRATES
BECAUSE THE COMMENT WAS, WELL,
YOU CAN JUST DO THIS WITHOUT
FURTHER RESEARCH. AND IN MIND
WHAT I THOUGHT WAS THIS NEEDED
AT LEAST A RANDOMIZED CONTROL
TRIAL IN HUMAN PATIENTS TO DO A
WELL CONDUCTED STUDY. GET OUR
QUANTITATIVE ASSESSMENTS AND
REALLY SEE WHERE THIS STANDS IN
HUMANS. AND IT SIMPLY HAD -- WE
FELL INTO THIS GAP. THERE WAS
NOT INDUSTRY INTEREST. FROM A
REVIEW PANEL STANDPOINT. IT WAS
CONSIDERED MAYBE NOT THAT
INTERESTING AND ALSO AMONG MY
COLLEAGUES. SO THESE CON DROLL
DEFECTS ARE NOT SO COMMON THAT
YOU CAN DO A GOOD RANDOMIZED
CONTROL TRIAL IN A SINGLE
CENTER.
YOU NEED TO HAVE MULTICENTER
STUDIES AND OTHERS WERE ALREADY
INVOLVED IN NEOCART OR SOME
OTHER STUDIES. AND SO THE
THINKING THAT I HAVE IS THAT IF
THERE'S AN NIH FUNDED STUDY.
THERE PROBABLY SHOULD BE A
REVIEW AND IT SHOULD BE A --
WITH THE FDA AND OTHER FEDERAL
AGENCIES. WHAT'S THE NEXT STEP
FOR THIS? IS THIS ONE -- GOOD
ENOUGH? IS THIS ANIMAL DATA
LARGE ANIMAL STUDY GOOD ENOUGH
FOR CLINICAL IMPLEMENTATION?
LIKE I WAS BEING TOLD BY
INDUSTRY OR DOES IT NEED ANOTHER
STUDY AND IF SO, WHAT DOES IT
NEED? ALSO, IT'S ALREADY BEEN
MENTIONED FDA PARTNERSHIP AND
DEVELOPING CLINICAL TRIAL
STANDARDS EARLY ON. CLINICAL
OUTCOMES EVALUATION AND THIS IS
A CONTINUOUS PROCESS. SO EVERY
RANDOMIZED CONTROL TRIAL DONE IN
EACH OF OUR DISEASE STATES, WE
LEARN FROM IT. VALUABLE
INFORMATION THAT'S USEFUL FOR
THE NEXT STEP. AND MANY TIMES
IT'S LOST BECAUSE ONE IS
CONDUCTED BY ONE COMPANY THAT
COMPANY GOES OUT OF BUSINESS OR
THERE ARE TRADE SECRETS, THINGS
THAT AREN'T SHARED AND SO MY
RADICAL IDEA IS THAT THIS MAY
NOT BE -- NEXT -- CLICK ON THE
THIS MAY NOT BE THE DIRECT
VERSION IS PERHAPS THESE EARLY
STAGE CLINICAL TRIALS COULD BE
DONE AT THE NIH CLINICAL CENTER
OR IN COLLABORATION MAYBE WITH
THE BETHESDA MILITARY MEDICAL
CENTER AND YOU'RE GOING TO LEARN
WHAT'S IMPORTANT IN THIS SPACE.
FOR THAT CLINICAL TRIAL. WHAT
ARE SOME OF THE PITFALLS AND
YOU'LL ALSO HAVE SOME
INSTITUTIONAL KNOWLEDGE. SO ONE
OF THE STUDIES I MENTIONED IN
NEOCART ACTUALLY WAS STOPPED
EARLY. BECAUSE THE MICRO
FRACTURE THAT I MENTIONED THAT
OUR BONE MARROW CONCENTRATE
WAS -- WAS IMPROVED OVER THE
MICRO FRACTURE OUTPERFORMS SO
THEY DIDN'T SHOW SUFFICIENT
IMPROVEMENT AT ONE YEAR ABOVE
MICRO FRACTURE.
BUT THEN ALL THOSE PATIENTS HAVE
BEEN LOST. SO NOW WE'RE GETTING
FIVE TO TEN YEARS FROM WHEN
THOSE PATIENTS WERE FIRST
IMPLANTED IN THE PHASE TWO TRIAL
AND IT WOULD BE EXTREMELY
VALUABLE IF THOSE PATIENTS COULD
ACTUALLY BE BROUGHT BACK. FOR A
LONGER TERM FOLLOW-UP SO THANK
YOU FOR YOUR PATIENCE. .
>> THANK YOU FOR HAVING ME.
THIS IS A GREAT FORUM. TIM CAMP
EMBARKED ON THIS RMIP PROJECT
AND TIM HIGHLIGHTED IT QUITE
NICELY ALREADY. I ALSO CONSULT
FOR A NUMBER OF COMPANIES
ACTIVELY AND I'VE BEEN INVOLVED
WITH OVER A DOZEN CLINICAL
TRIALS AND IN THE CARDIOVASCULAR
SPACE OVER THE LAST TWENTY YEARS
OR SO RELATED TO CELL BASED
THERAPY SO WHAT I'M GOING TO SAY
IS PART OF THAT. THERE WE GO.
ALL RIGHT. SO IN TERMS OF
CHALLENGES THAT WE FACE IN THE
FIELDS OF CARDIOVASCULAR THERAPY
AND I AM TRYING TO THINK ABOUT
IT IN HOLISTIC TERMS IN HOW WE
CAN AFFECT MULTIPLE DIFFERENT
SPECIALTIES AND SO FORTH. I
THINK ONE OF THE THINGS THAT --
AND IT'S DIFFICULT TO PRIORITIZE
WHAT'S MORE IMPORTANT THAN
OTHERS. I HAD A DIFFERENT TIME
WITH THAT BUT I WANTED TO
EMPHASIZE CELL DELIVERY. I
THINK IT'S OFTEN OVERLOOKED.
YES, WE DO NEED IMPORTANT
ADVANCES IN CLINICAL GRADE
MANUFACTURING TO MAKE IT
ACCESSIBLE TO SMALL START-UP
COMPANIES OR ACADEMIC
INSTITUTIONS. WE NEED A
CLINICAL TRIALS INFRASTRUCTURE,
YES, WE NEED THAT AS WELL. I
THINK ONE OF THE THINGS I
OBSERVED IS I WAS JUST TALKING
EARLIER IN THE BREAK, YOU KNOW,
A LOT OF ACADEMIC INSTITUTIONS
DEVELOP A CELL THERAPY PRODUCT,
GETS IT THROUGH THINKING ABOUT
ALL THE POTENCY DISCUSSION AND
THEN ALL OF A SUDDEN OKAY NOW
IT'S TIME TO DELIVER IT IN A
PATIENT AND WE'RE AT A ROADBLOCK
BECAUSE WE DON'T HAVE THE TOOLS
NECESSARY TO DELIVER THAT IN A
PATIENT YET. CROSSCUTTING, YOU
KNOW, OPPORTUNITIES TO TRY TO
ADDRESS THESE CHALLENGES I
THINK, YOU KNOW, IF WE COULD --
GET INVESTMENT INTO THINKING
ABOUT, OKAY, HOW CAN WE DELIVER
THESE CELLS TO THEIR TARGET
ORGANS? HOW DO WE DO THIS
MINIMALLY INVEINOVATVEIASIVE AN
ABOUT MAXIMUM LOCAL CELL
RETENTION AND HOW IT'S IMPORTANT
AND THEN OF COURSE THE GRAFTING.
HOW DO WE GET THE CELLS TO STAY
THERE AND THAT WAS PART OF OUR
RMIP INITIATIVE. THE LAST --
THE BOTTOM FOUR FIGURES THERE
WERE NOT COVERED BY THE RMIP BUT
DO HIGHLIGHT WHAT I'M KIND OF
GETTING AT. ON THE LEFT SIDE IS
A RAT HEART WHERE WE INJECTED
STEM CELLS. ALONGSIDE THE
RETENTION MATRIX THAT WE WERE
INVESTIGATING. IN ADDITION, THE
BLUE IT IS A BIT DIFFICULT TO
SEE THERE ARE THE CELLS INJECTED
WITHOUT THE MATRIX IN THE RAT
HEART WITH THE NEEDLE INJECTION,
THE CELLS THAT HAD THE MATRIX
RETAINED IN A LINEAR FASHION
WITH A NEEDLE INJECTION WAS THE
BLUE CELLS THAT ARE NOW BEING
DISPERSED THROUGHOUT THE
LYMPHATICS ALL THROUGHOUT BUT
OPEN CHEST IN A RAT IS NOT
REALLY APPEALING CLINICALLY.
HOW DO WE ACHIEVE THAT GOAL OF
INTRAMY OWE YARD CALENDAR
DELIVERY?
ALLOWING THE LINE OF TWO OR
THREE DIFFERENT CATHETER
COMPANIES HAVE DEVELOPED MINIMAL
STEERABLE CATHETERS THAT WE CAN
FEED IN AND INTRODUCE IN THE
HEART BUT THESE ARE ALL IDE TYPE
DEVICES. THERE'S NOTHING LIKE
THAT OUT CURRENTLY. AND, YOU
KNOW, WHEN I WAS INVOLVED WITH
CLINICAL TRIALS, YOU KNOW, YOU
ENROLLED TWO OR THREE PATIENTS
AND THEN ALL OF A SUDDEN YOU
BECAME A PROBLCTOR AND YOU GO
AROUND TEACHING PEOPLE THESE
DEVICES. THERE'S QUITE A STEEP
LEARNING CURVE NOT ONLY IN THE
PREPARATION OF THE CELLS BUT
ALSO IN THE DELIVERY ASPECT.
LOCALLY WE'RE ALSO LOOKING AT
WAYS OF DELIVERING THE CELLS IN
A TARGETED FASHION BY
MULTIMODALITY INFUSION IMAGING
WHERE WE CAN SEE THE MRI VISION
OF THE HEART. SO TO FINISH,
WHAT ARE THE OPPORTUNITIES THAT
WE -- I THINK THAT THE -- THIS
GROUP COULD POTENTIALLY DELIVER
HERE ON THIS? I THINK
INVESTMENTS IN FIGURING OUT
BETTER WAYS OF CELL TRACKING SO
WE CAN DO MORE LONGITUDINAL
STUDIES, DEVELOPING NEWER, LESS
INNOVATIVE DELIVERY TOOLS TO
REALLY EMBARK UPON THAT HOLY
GRAIL OF BEST CELL RETENTION AND
ENGRAFTMENT AND THEN TRANSLATING
THAT IN CLINICALLY TRANSLATABLE
MODELS LIKE IN THE PIG, FOR
EXAMPLE, AND OUR INSTITUTION HAS
MADE SOME INVESTMENTS IN THAT,
SOME SEED MONEY HAS GONE TOWARD
A CENTER FOR BIOMEDICAL SWINE
RESEARCH FOR EXAMPLE. AND THEN
ALONG THE WAYS DEVELOPING THE
CLINICAL TRIAL NETWORK SO WE CAN
CONSOLIDATE THE EXPERTISE AND
THEN IN A LOW TAG MODEL SEND
THAT EXPERTISE OUT AND
PROCTORING OTHER PEOPLE TO DO
THESE PROCEDURES. THAT'S IT.
THANK YOU.
>> THANK YOU FOR INVITING ME TO
SPEAK HERE TODAY. IT'S A REALLY
WONDERFUL MEETING AND I HOPE TO
LEARN A LOT AND MAYBE CONTRIBUTE
A BIT TO YOURS AS WELL. WHAT MY
LAB IS INTERESTED IN IS THE
TRANSPORTATION. IT'S A LARGE
NEURON THAT SIT IN THE BACK OF
THE EYE IN THE RETINA AND THEIR
ACCESS SENDS THE PROJECTIONS AND
ALL THE INFORMATION TO THE
BRAIN. AND WHAT IS VERY
DIFFERENT ABOUT THE RETINA OF
THE EYE, THE OPTIC NERVE IN AND
OTHER MAMMALS IS IT DOES NOT
REGENERATE AFTER THE DEVELOPMENT
IS COMPLETE. WHETHER WE EMBARK
ON DEVELOPING THE MEDICINE
THERAPIES WE HAVE TO COME UP
WITH SOME SOLUTIONS THAT EITHER
COME UP AS WHOLE TISSUE
APPROACH, SOUNDS LIKE RP
TRANSPORTATION IF YOU HEARD FROM
AARON AND JEFFREY OR DO
SOMETHING LIKE RETICKULATION OF
THE DEVELOPMENT. THIS IS WHAT
WE TRIED TO DO WITH THE GANGLION
CELL IMPLEMENTATION AND BACK TO
THE LIST OF QUESTIONS THAT WE
GOT. WITH THIS INVITATION SO I
WOULD SAY, I WILL GO BACK.
LET'S TRY THIS ONE. OH, THANK
YOU. I THINK THIS IS THE FIRST
CHALLENGE. SO THAT'S HOW THE
STANDARD CELL LOOK LIKE. YOU
CAN REPLACE THE RETINAL GANGLION
CELL WHICH IS HERE. LASER
POINTER? NO? I THINK REPLACE
RETINAL GANGLION CELL WITH ANY
OTHER CELL TYPE OF INTEREST BUT
THIS IS THE MAIN CHALLENGE. WE
HAVE TO DO EVERYTHING ALL OF
THESE STEPS THAT DO TO CELL
THERAPY WITHIN ONE LAB. SO
THAT'S WHAT I THINK THE SOLUTION
IS. YOU REALLY ADVANCE AND
MAUVE MOVE ON TO BE ABLE TO
DELIVER THE FINAL PRODUCT. THE
ACTUAL CELL THERAPY TO REGAIN
THEIR VISION.
AND THE SECOND CHALLENGE, THAT
GOES INTO THIS AND MAKE THESE
THINGS CONNECTED IS I LIKE TO
THINK ABOUT IS A NUMBERS GAME.
SO AT EACH STEP WE NEED TO HAVE
SOME DELIVERABLE. COULD YOU
ADVANCE THE SLIDE? AND WITH
RETINAL, COULD YOU ADVANCE THE
SLIDE, PLEASE? ALL RIGHT.
THANKS. AND WITH RETINAL
IMPLEMENTATION IF WE INJECT WE
NEED ABOUT FIVE THOUSAND CELLS.
THAT'S THE MINIMAL NUMBER THAT
IS NEEDED TO REGAIN FUNCTIONAL
VISION AND AT EACH STEP YOU
THINK OF ALL STEPS THAT CELL HAS
TO DO THROUGH AFTER
TRANSPLANTATION HAS SUSTAINED.
AT THE SITE OF INJECTION HAS TO
MIGRATE TO THE RETINAL GANGLION
CELL LAYER, AND TO CONNECT WITH
THE ADJACENT NEURONS AND UNDERGO
FUNCTIONAL MOLECULAR METABOLIC
AND AT THE END YOU HAVE THIS.
SO AT EACH STEP SOME CELLS ARE
LOST AND IDEALLY, AND SOME, FOR
EXAMPLE, IF WE INJECT ONE ONLY
FIVE THOUSAND CELLS WILL MAKE IT
AFTER TWO WEEKS SO YOU KNOW THAT
YOU GET TO THE FINAL NUMBER WE
NEED TO GO WITH TRILLIONS BUT
OBVIOUSLY THIS IS NOT POSSIBLE
SO THIS IS WHERE WE HAVE TO
IMPROVE AND THAT'S WHERE SHARING
INFORMATION, SHARING THE DATA,
COMING UP WITH QUANTIFIABLE
METRICS FOR EACH OF THESE STEPS
THAT CELLS HAS TO GO THROUGH
WOULD REALLY HELP TO ADVANCE THE
FIELD. AND THIS JUST AN EXAMPLE
OF HOW WE DO IT IN THE LAB. SO
WE FOCUS ON THE CELLULAR
FUNCTION TRYING TO LEARN FROM
THE DEVELOPMENT USING SINGLE LAR
CELL APPROACHES, HOW TO MODIFY
THE RETINAL MICRO ENVIRONMENT IN
ORDER TO SUPPORT DONOR CELLS
AFTER TRANSPLANTATION TO CONTROL
DONOR CELLS AFTER
TRANSPLANTATION AND WE TALK
TODAY A LOT ABOUT POLYMERS AND
DELIVERY STRATEGIES BUT ANOTHER
STEP IS WHAT ARE WE DOING WITH
THE HOST NICHE, WITH THE HOST
TISSUE, IN ORDER TO MAKE IT MORE
PERMISSIBLE FOR DONOR CELLS TO
INTEGRATE AND REALLY DO WHAT WE
WANT THEM TO DO? BECAUSE
SURVIVAL IS OBVIOUSLY NOT THE
PRIMARY INVOLVED AND YOU SEE
THOSE NEURONS THAT SURVIVE THEY
DON'T NECESSARILY THE ONES THAT
WITHDRAW NEW RIGHTS OR THE ONES
THAT WOULD FORM A LOT OF
SYNAPSES SO THAT IS WHERE WE
HAVE TO PRIORITIZE FUNCTION AS A
RESULT FOR TRANSPLANTATION AND
ALSO MODIFYING THE ENVIRONMENT.
THANK YOU.
>> KIMBERLEY IS NEXT. AND ON
DECK IS DEMETRI SHANE.
>> MY NAME IS KIM AND I'M A
NEUROOPHTHALMO
NEUROOPHTHALMOLOGIST. THE NICE
THING ABOUT GOING AFTER PETER IS
WE TRY TO REGENERATE THE OPTIC
NERVE THAT WORKS WITH THE EYE TO
THE BRAIN. MAY I HAVE MY SLIDE?
OH, PERFECT. SO THIS IS A
DIFFICULT QUESTION OR CHALLENGE
FOR A NUMBER OF REASONS AND SO
ONE IF I WOULD SAY THE WINS THAT
WE HAVE IN THIS FIELD IS THAT WE
DO HAVE A SOURCE OF RETINAL
GANGLION CELLS. THEY DON'T
NECESSARILY FUNCTION PERFECTLY
BUT THE BIG CHALLENGE IS
INTEGRATION AND IT HAS TO OCCUR
AT TWO LEVELS. RIGHT? AND SO
CAN YOU CLICK NEXT, PLEASE? AND
SO ONE, WE'RE TRYING TO
TRANSBREAST IMPLANT A NEURON
INTO A TISSUE THAT'S HIGHLY
STRUCTURED AND LAYERED.
WE NEED TO HAVE THE NEURON IN
THE CORRECT ORIENTATION AND THEN
ONCE IT ACTUALLY FINDS ITSELF IN
THE RIGHT PLACE IT'S GOT TO
CONNECT WITH THE NEIGHBORING
CELLS IN THE RETINA AND THEN
IT'S GOT TO GROW AN AX ON INTO
THE BRAIN AND THEN RECONNECT
WITH THE BRAIN.
AND SO WHAT WE'RE SEEING IS THIS
IS A DEVELOPMENTAL PROCESS
UNLIKE A SITUATION WHERE YOU CAN
HAVE A MATURE CELL THAT YOU
IMPLANT INTO YOUR TISSUE YOU'VE
GOT TO IMPLANT A CELL THAT HAS
TO DO MULTIPLE FUNCTIONS AND
CONTINUE TO DEVELOP TO
INTEGRATE. AND SO I KIND OF
EQUATE THIS AS TOO BAD WE TRIED
BUT YOU CAN'T TAKE A CHIP AND
THROW IT ONTO A MOTHERBOARD AND
SAY I HOPE IT WORKS AND CONNECTS
AND THAT'S WHAT MAKES THIS
CHALLENGE REALLY DIFFICULT AND
THE STRATEGIES THAT PEOPLE IN
OUR FIELD TEND TO USE TO
OVERCOME THIS CHALLENGE IS TO
REACTIVATE SIGNALLING PATHWAYS
IN DEVELOPMENT THAT DROVE AXON
GROWTH BUT THE PROBLEM IS THAT
THESE PATHWAYS WERE TURNED OFF
FOR A REASON. IF YOU TURN ON
THESE PATHWAYS LIKE ENTOR AND
NOT REGULATE THEM YOU'RE GOING
TO CAUSE OTHER PROBLEMS LIKE
CANCER AND WHATNOT SO WHATEVER
STRATEGY WE DO WITH THIS IS WE
HAVE TO BE ABLE TO CONTROL. WE
HAVE TO TURN THINGS ON AND ALSO
TURN THINGS OFF WHEN WE NEED
THEM AND ARZ AS FAR AS TO SEE DO
WE NEED A KILL SWITCH.
DO WE NEED SOME TYPE OF DRUG
INDUCED GENE EXPRESSION AND
ANOTHER THAT WILL TURN OFF THESE
CELLS IF THEY START TO DO
SOMETHING AVENUE RANT THAT WE
DON'T WANT? CAN YOU CLICK NEXT,
PLEASE? OKAY, NEXT AGAIN. NEXT
AGAIN. AND THE OTHER THING THAT
WE DON'T TALK ABOUT IS THERE ARE
OVER 30 DIFFERENT SUBTYPES OF
RETINAL GANGLION CELLS IN THE
EYE. THEY PORP DIFFERENT THINGS
AND WE'RE VISUAL ANIMALS VISUAL
IS A COMPLEX PROCESS AND THESE
AXONS TARGET DIFFERENT PARTS OF
THE BRAIN. IF YOU'RE TRYING TO
ACTUALLY PUT REPLACEMENT
BEGANING LEON CELLS ARE YOU
GOING TO GET THE RIGHT ONES TO
GO INTO THE RIGHT PLACE? NEXT
SLIDE, PLEASE.
AND ONE OF THE BIG CHALLENGES WE
NEED TO ADDRESS IS WHAT MODEL
SYSTEM ARE WE GOING TO USE?
THERE ARE A LOT OF DIFFERENT
OPTIC NERVE DISEASES BUT THEY
CAUSE DISEASES AT DIFFERENT
RATES DO WE WANT TO DO A
STROKE-LIKE OPTIC DISEASE WHERE
YOU GET SIMULTANEOUS DAMAGE TO
NEURONS ALL AT ONCE SO THEY'RE
ALL SYNCHRONIZED, PROBABLY DIE
AT A SYNCHRONOUS RATE OR DO
SOMETHING LIKE GLAUCOMA WHICH IS
A SLOW COMPRESSIVE DISEASE WHERE
YOU HAVE A COUPLE HUNDRED OR
THOUSAND CELLS THAT ARE DYING AT
A TIME BUT THEY'RE ALL DYING AT
DIFFERENT RATES AND HOW ARE YOU
GOING TO GET THEM TO FILL IN TO
THE PARTICULAR SPOTS THAT ARE
NEEDED? SO THIS IS A BIG
CHALLENGE FOR US IN THE FIELD.
NEXT SLIDE, PLEASE. THIS IS A
DEVELOPING PROCESS AND CELL
SURVIVAL ACTS ON GROWTH, SYNAPSE
FORMATION, MYELINATION, THESE
ARE ALL INDEPENDENTLY REGULATED
PROCESSES AND THEY OCCUR
SEQUEN
SEQUENTIALLY. AND I THINK
THAT'S A REALLY BIG PROBLEM.
YOU KNOW, LIKE, SO OUR LAB WORKS
ON ELECTRIC FIELDS AND USING
THAT TO GUIDE AXON GROWTH BUT WE
DON'T HAVE THE EXPERTISE IN
THINGS LIKE FLUOROAL SURVIVAL SO
WE NEED TO CROSS TRAIN OR WORK
TOGETHER.
I TRIED TO WORK WITH PEOPLE LIKE
A DOCTOR IN L.A. AND I'M IN
BOSTON DO I SHIP MY RATS OVER
AND YOU INJECT SOME CELLS AND
SHIP THE RATS BACK AND THEN
WE'RE GOING TO STIMULATE THEM?
HOW ARE WE GOING TO ACTUALLY DO
THAT? AND SO I FEEL LIKE WE
HAVE SOME SILOED EXPERTISE. I
ALSO, YOU KNOW, I WAS TRAINED AS
A MOLECULAR BIOLOGIST BUT I ALSO
THINK IN GENERAL THERE'S A BIG
BIAS AGAINST NON MOLECULAR
TECHNOLOGIES AND I FEEL THIS
WHEN I APPLY FOR GRANTS AND WE
NEED TO THINK OUTSIDE THE BOX
ASKING THE BIG QUESTIONS AND
COLLABORATING WITH PEOPLE IN
ENGINEERING AND WHATNOT.
IN ORDER TO HAVE SYNERGISTIC
APPROACHES. STEM CELLS ARE
DEFINED BY THEIR ENVIRONMENT AND
WE DO ALL OF THESE THINGS TO
MODULATE THE CELL BUT WHAT ABOUT
THE EXTRINSIC BARRIERS. WE NEED
TO INVOLVE THE CLINICIAN AND I
KNOW THIS IS SELF-SERVING THE
CLINICIAN IS GOING TO HELP
INFORM US AS TO WHAT IS ACTUALLY
POSSIBLE. I CAN'T TELL YOU THE
NUMBER OF TIMES MY EVENING
NEARING CL -- ENGINEERING
COLLABORATORS HAVE TOLD US TO DO
THIS. THEY'RE GOING TO TELL YOU
WHAT POSSIBLE AND MOST
IMPORTANTLY WILL TELL YOU WHAT
IS A RELEVANT OUTCOME? HOW ARE
WE GOING TO MEASURE THIS? I USE
RATS. THEY AREN'T EVEN VISUAL
ANIMAL TO THE TOPICS THAT WERE
DISCUSSED EARLIER I HAVE --
BEHAVIORAL ASSAYS WHEN USING AN
ANIMAL THAT DOESN'T USE ITS EYES
TO SURVIVE IN THE ENVIRONMENT I
THINK INVOLVING THE CLINICIAN AT
THE EARLY STAGE TO SEE AND ASK
WHAT IS ACTUALLY IMPORTANT WHAT
ARE WE AIMING TO ACHIEVE IS
REALLY IMPORTANT? THANK YOU SO
MUC
MUCH.
>> THANK YOU FOR INVITING ME
AND FEW OTHER INVESTIGATORS TO
SHARE. I THINK I WAS MORE
RELIGIOUS AT ADHERING TO THE
POLICEMEN AT A TIME. --
TEMPLATE.
NEXT SLIDE, PLEASE.
I CAME HERE TO ADVOCATE FOR IPS
DERIVED THERAPIES. SEEMS I'M
PREACHING TO THE CHOIR. WE HAVE
SOME PROTOCOLS THAT WE WORK ON
IN THE LAB AND PUSH THE CELLS IN
DIFFERENT DIRECTIONS AND MOSTLY
FOCUSED ON THE CELLS AND WE WORK
WITH DIFFERENT CELLS NOW AND
ITEN KNOW SITES, MACROPHAGES AND
KNOW SIS CEPTORS FOR DISEASE
MODEL PURPOSES. NEXT. SO WHAT
I THOUGHT ARE THAT THE
OPPORTUNITY THAT WE HAVE NOW.
WITH THESE THERAPIES? SO FIRST
OF ALL, IPSCS ARE AMAZING AND
CAN DO A LOT OF THINGS HAVE
UNLIMITED CELL SOURCE FOR CELL
THERAPIES BUT ALSO -- WE CAN
ALSO SHARE SOME IPS LINES AND WE
DON'T REALLY HAVE TO WORK
THROUGH 23 LINES THAT DON'T WORK
TO FIND ONE THAT DOES WORK. AND
ANOTHER THING I THOUGHT IS
IMPORTANT TO MENTION IS THIS --
ALL THE SINGLE CELL TECHNOLOGIES
THAT WE HAVE IN WHAT'S COMING
UP. REALLY GIVES US THE
OPPORTUNITY TO KNOW THE
LANDSCAPE OF THE TISSUE, TISSUE
IS COMPLEX, IT'S NOT ONE CELL
TYPE EVEN WITHIN ONE CELL TIME
THERE'S ANDROTIME
THERE'S ANDRO AND WE DID THAT --
WE YAUDZ IPSCS.
AND SINGLE CELL TRAN SCRIP
TOPICS TO LEARN ABOUT THE
PROCESS OF DIFFERENTIATION.
AND IMPROVE THAT PROCESS DOWN
THE LINE. NEXT. SO IN TERMS OF
CHALLENGES, I LISTED FOUR. WE
TALKED ABOUT REPRODUCIBILITY OF
THE DIFFERENTIATION PROTOCOLS.
I THINK THAT'S THE MAIN
CHALLENGE IN IPS WORK BECAUSE
EVERY LINE IS DIFFERENT. WE
MENTIONED ANIMAL MODELS AND THE
THING IS SPECIFICALLY, RELEVANT
FOR THE CONDITIONED SO WE'RE
GOOD AT INJURING ANIMALS BUT CAN
WE REGENERATE THE HUMAN
CONDITION AND CELL THERAPIES
USUALLY REQUIRE A CARRIER SO
THAT COMPLICATES THINGS AND WE
NEED TO DESIGN NOT ONLY THE CELL
BUT THE CARRIER AND ANOTHER
CHALLENGE I THINK THAT WE DID
MENTION HERE IS CELL TRACKING
HOW DO WE ENSURE WHERE THESE
CELLS END UP, WHAT'S THE FATE IN
THE END IN THE ANIMAL. IT'S --
ALL THE STUDIES ARE DESIGNED FOR
DRUGS, NOT FOR CELL THERAPIES.
NEXT. AND HOW I THOUGHT THAT WE
CAN ADDRESS THESE CHALLENGES SO
STANDARDIZING PROTOCOLS I THINK
PROGRAMS LIKE THAT HAVE A LOT OF
POWER TO FORCE INVESTIGATORS TO
STANDARDIZE AND SHARE RESOURCES
AND PROTOCOLS. RECENTLY WE HAVE
A PAPER IN SPECIAL MEDICINE
WHERE WE USED ANIMAL MODEL AND
ORGAN ON CHIP SYSTEM SO YOU CAN
USE THE INVIVO ANIMAL MODEL BUT
ALSO COMBINE IT WITH ORGAN AND
CHIP SYSTEMS THAT HAVE THE
ADVANTAGE OF USING THE ACTUAL
HUMAN CELLS. NEXT. AND WE ALSO
DEVELOPING SOME OFF THE SHELF
CELL DELIVERY SYSTEMS.
SCAFFOLDS ARE A BIG FIELD. THIS
IS OUR HEAL INITIATIVE STUDY IN
DEVELOPING THE MICRO INJECTION.
NEXT AND NEXT. NEXT. AND LAST
POINT I WANT TO MAKE IS I THINK
THERE IS A LOT OF OPPORTUNITY TO
DEVELOP IMAGING AND CELL
TRACKING TECHNIQUES. HERE WE
PUBLISHED A MULTIPLE LABEL
EXISTING FOR CELLS IN THE LARGE
ANIMAL MODEL TO TRACK IN THE
KNEE IN THE PIG BUT I THINK
THERE'S A LOT OF THINGS WE CAN
DO BETTER IN TERMS OF TRACKING
CELLS AND DEVELOPING THESE
TECHNOLOGIES. THANK YOU.
>> DAN FOLLOWED BY TONY.
>> THANK YOU VERY MUCH. I HOPE
THAT THE CLICKER DOES WORK. MY
NAME IS DAN. I'M AN ORTHOPEDIC
SURGEON. I HAD MY FIRST PART OF
MY CLINIC IN EUROPE AND NOW
HERE. THESE ARE MY DISCLOE
SURES. WHEN YOU TALK TO
SURGEONS ABOUT STEM CELL
THERAPIES THERE'S A LOT OF
CONFUSION ABOUT WHAT IS ALLOWED,
WHAT IS NOT ALLOWED, WHAT IS
REGULATED, HOW IT'S REGULATED.
WHAT IS AVAILABLE AND WHAT IS
STILL IN STUDIES AND I THINK
THAT'S ONE OF THE THINGS WHERE
NIH AND FDA AND ACADEMIC
SOCIETIES HAVE A BIG ROLE IN
EDUCATING WHAT IS ABOVE BOARD
AND WHAT'S NOT AND HIGH HOW TO
TAKE THE FIELD TO MORE LIGHTS.
THERE ARE A FEW NOT SO GOOD
TECHNOLOGIES THAT ARE OUT THERE
WITHOUT BEING REGULAR LATESED
PROPERLY SO IT'S REALLY
IMPORTANT TO COME UP WITH
SOLUTIONS THAT HELP THE FIELD AS
A CLINICIAN FURTHER.
AND THAT'S DIFFICULT. YOU HAVE
TO MAKE SURE THAT IT DOESN'T
BECOME SO DIFFICULT THAT YOU END
UP HAVING ALL YOUR CLINICIANS
FRUSTRATED BY THE CHALLENGES
THAT WE HAVE. AND THEREFORE,
SORT OF LEADING THE
TRANSLATIONAL FIELD BUT YOU ALSO
HAVE TO MAKE SURE YOU DON'T
OVERPROMISE WHAT YOU CAN BRING
TO THE CLINICAL FIELD BECAUSE OF
THE BASIC SCIENCE AND ALL THE
OPPORTUNITY THAT WORKS IN THE
LAB AND I KNOW THIS IS SOMETHING
THAT YOU GUYS ARE ALL FAMILIAR
WITH BUT NOT ALL OF MY CLINICAL
COLLEAGUES SHARE THAT SAME
PERCEPTION AND NOT ALL OF OUR
BASIC SCIENTISTS UNDERSTAND.
AND THAT'S SOMETHING WHERE SOME
OF US CLINICIANS HAVE BEEN
FORTUNATE TO BE ABLE TO BE PART
OF THESE. I AM JUST WANTING TO
SHARE PART OF THE STORY THAT'S
THERE AND COME BACK TO THE
PREVIOUS SLIDE, I'M SORRY. SO
THE RECLAIM TECHNOLOGY IS
SOMETHING WE CAME UP WITH
BECAUSE WE DID THESE TRIALS IN
EUROPE UNDER THE EMA GUIDANCE
AND THE MACY PRODUCT WHICH IS
THE CELL THERAPY UNDER FDA
GUIDANCE AND THOSE WERE DONE IN
LARGER TRIALS BECAUSE IT'S
DIFFICULT TO DO IN ONE CENTER.
IT ALSO TAUGHT ME THAT DOING TWO
SURGERIES TO FILL A POTHOLE IS
PROBABLY NOT THE WAY FORWARD.
WE WANT TO DO THIS IN
INJECTABLE. WE WANT TO BE ABLE
TO DO THIS IN ONE TECHNIQUE AND
CARTILAGE IS A RELATIVELY SIMPLE
TISSUE. THE CELLS STILL KNOW
WHAT IT'S LIKE TO MAKE CARTILAGE
BUT THE TISSUE FUNCTIONALLY
DOESN'T DO SO ANYMORE WHEN IT'S
DAMAGED SO THE HYPOTHESIS WAS AS
YOU CLEAN THE DEFECT TO MAKE
SURE IT'S NICE AND STABLE CAN'T
WE JUST RECYCLE THOSE AND
PROVIDE THEM WITH SIGNALS TO
GROW CARTILAGE AGAIN AND TO
PROVIDE A BETTER ENVIRONMENT FOR
THE CELLS TO DO SO WHICH WAS
MENTIONED BY OTHERS AS WELL WE
THOUGHT THIS COULD BE A ROLE FOR
ALOE YES NAYIC. SO THAT'S WHY
WE SAID LET'S COME ONE A
TECHNIQUE TO SURGICALLY WORK
WITH THE TISSUE AND CHEMICALLY
DIGEST IT TO THE LEVEL OF THE
CON DRON AND PUT THEM BACK INTO
N THE JOINT IN ONE PROCEDURE.
AND WE'VE DONE SO NOW IN TWO
TRIALS. IN EUROPE WE COMPLETED
THE TWO TRIALS. AND ONE IN
MINNESOTA AND TRANSFORMED THE
PRACTICE. AND AFTER, SEVEN
YEARS, FOLLOW UP IN EUROPE AND
NOW TWO YEARS FOLLOW UP OF THE
SECONDARY COHORT IN THE UNITED
STATES I CAN SAY THIS IS A
REDUCIBLE -- REPRODUCIBLE
CLINICALLY EFFICACIOUS
TECHNOLOGY THAT ALLOWS PATIENT
LESS PAIN, BETTER QUALITY OF
LIFE, FUNCTIONAL OUTCOME SCORES
THAT IS NOT ONLY STATISTICALLY
SIGNIFICANT AND CLINICALLY
SIGNIFICANT AND REPRODUCIBLE
BETWEEN CENTERS, BETWEEN
CONTINENTS AND SCIENTIFICALLY IN
EUROPE WE USE BONE MARROW
DERIVED ALOE YES NAYIC MSCS.
HERE WE USE DIFFERENT. AND THE
CLINICAL OUTCOMES ARE THE SAME.
WHICH IS INTERESTING FROM A
MANUFACTURING PERSPECTIVE. SO
WHAT DO WE KNOW ABOUT THE
PRODUCT? NOT MUCH EXCEPT THAT
WE HAVEN'T HAD ANY SAFETY ISSUES
AND IN THE EUROPEAN PATIENTS IN
33/35 PATIENTS WE WERE ABLE TO
GO BACK FOR A SECOND LOOK TO
LOOK AT THE TISSUE AND DO VIDEO
ANALYSIS TO LOOK AT THE QUALITY
OF THE REPAIR AND THE CONDITION
OF THE GROWTH AND TO DO BIOPSIES
AND TO DO DNA TYPING SO WE WERE
ABLE TO ANALYZE THE D DNA FROM
THE NEWLY GROWN TISSUE.
AND WE ONLY FOUND PATIENT'S OWN
DNA WHERE WE STARTED WITH 99%
ALOE YES NAYIC CELLS AND THAT'S
AN INTERESTING FINDING. SO WHAT
DO I THINK THE CHALLENGES ARE.
I HAVE DONE FIFTEEN YEARS OF
TRIALS AND IT SOUNDS STRANGE BUT
TRUE BY I'VE BEEN REGISTERED IN
BOTH.
HAVE LEARNED FROM THE TRIALS AND
EACH TRIAL TEACHES YOU SOMETHING
YOU WILL DO DIFFERENTLY. I HAVE
SEEN GOOD PRODUCTS NOT MAKE IT
THROUGH BECAUSE THEY DESIGNED
THE TRIAL THAT WAS TOO STRENUOUS
AND DIFFICULT TO MEET THE BAR
EVEN THOUGH THE BAR WOULD HAVE
BEEN TYPE A LITTLE TTLE BIT -- A
LITTLE BIT LOWER.
AND THE COMPARATORS ARE
WRONG.AND THE REGULATORY
AGENCIES SHOULD ALLOWS US TO
COME UP WITH BETTER
METHODOLOGIES. I HAVE ALSO SEEN
WITH INCREASING TECHNOLOGY AND
WITH INCREASE IN TIME, CLICK,
PLEASE. THE RESULTS ARE BETTER.
THIS IS AN IMPROVEMENT. SO IT
WAS THE POTENCY ASSAYS THAT
IMPROVED. IT WAS THE DNA
TECHNOLOGY THAT IMPROVED. IT
WAS THE MATRIX BASED SURGICAL
TECHNIQUE THAT IMPROVED THE MACI
OUTCOMES AND IT'S THE ONE STAGE
TECHNOLOGIES THAT ALLOW IMMUNE
MODULATION AS WELL AS CARTILAGE
REGENERATION SO THESE ARE ALL
REITERATIONS AND IMPROVEMENTS
THAT COME THROUGH TIME. WHERE
ARE THE LIMITATIONS? AND WHERE
ARE THE CHALLENGES I TRY TO SUM
THOSE UP. WE NEED TO PUT OUR
HANDS TOGETHER TO MAKE SURE THAT
MORE GOOD TECHNOLOGIES MAKE IT
THROUGH AND DON'T STAY BEHIND
THE BAR. AND I THINK THAT THE
ASPECTS TO CONSIDER MANY OF THEM
HAVE BEEN MENTIONED IS UNIFORM
CHARACTERIZATION OF CELLULAR
PRODUCTS, DESCRIPTION, TEAM
ORGANIZATION AND CENTRALIZED
MAYBE EVEN TOPDOWN INITIATIVES
SO WE DON'T HAVE TO DO TOO MANY
THINGS THE SAME WAY OR DIFFERENT
WAYS IN DIFFERENT LABS AT
DIFFERENT TIMES WITHOUT
COMMUNICATING THAT. I THINK WE
SHOULD FIND THE REALLY
INNOVATIVE PROJECT AND THE ONE
WITH CLINICAL RELEVANCE AND IT'S
ALWAYS DIFFICULT TO DO THAT AS A
CLINICIAN BECAUSE YOU'RE TOTALLY
BIASED TOWARD THE JOINT OR THE
ORGAN OR THE DISEASE THAT YOU
WANT TO CONQUER I DO THINK THAT
THE AGENCY AND NIH BOTH HAVE A
ROLE IN PROVIDING US WITH
GUIDANCE MORE THAN WITH JUDGMENT
AND PARTNERING MORE THAN SAYING
YES OR NO ONLY. AND I THINK
IT'S BEEN SAID BEFORE BUT I --
FOR US IT'S BEEN REALLY
IMPORTANT IF YOU HAVE TIME WITH
THE FDA IT'S USUALLY REALLY GOOD
QUALITY TIME SO WE WANT MORE OF
IT EARLIER ON BECAUSE THAT JUST
ACCELERATES THE PROCESS AND HAS
BEEN A VERY, VERY PLEASANT
EXPERIENCE FOR US THOSE ARE THE
THOUGHTS WE HAVE FOR THIS
PROJECT AND I LOOK FORWARD TO
DISCUSSING IT IN THE UPCOMING
DAYS, THANK YOU VERY MUCH.
>> FINAL SPEAKER FOR TODAY'S
SESSION TWO IS TONY ORO.
>> THANK YOU SO MUCH AGAIN FOR
THE INVITATION, I'M THE
CODIRECTOR FOR THE DEFINITIVE
CURATIVE MEDICINE. AND SO I'M
GOING TO TALK ABOUT A PROJECT
WHICH WAS INITIALLY FUNDED WITH
DENNIS AND SUBSEQUENTLY FUNDED
BY SERM AND THE DEVELOPMENT OF
DEFENSE WITH OTHERS. IT REALLY
IS A -- IT'S DESIGNED TO TREAT
NON HEALING WOUNDS IN PATIENTS
WITH A -- IT HAS SKIN, DERMIS.
AND IT'S -- SO BASICALLY WHAT
WE'VE DONE IS WE HAVE DEVELOPED
AN AWE TOLL LOW GUS IPS
CORRECTION.
MAKING THE BANK FOR EACH PATIENT
TARGETED TO ONE GUIDE AND ONE
MUTATION.
AND THEN USE THE SKILLS TO
DEVELOP THREE DIFFERENT
LINEAGES. ACTIVE DERM WHICH
EACH OF THESE INTERACT. WE USE
SINGLE CELL ANALYSIS TO DEFINE
THE PRODUCT. GIVE US BIOMARKERS
TO THEN BASICALLY DO DELIVER --
IN TERMS OF TISSUE ORGANOIDS
ONTO THE SKIN WHICH IS A LOT
EASIER TO DO THAN BASICALLY THE
HEART OR THE BRAIN BECAUSE IT'S
RIGHT HERE IN THE PATIENTS AND
THE WOUNDS ARE THERE AS WELL SO
WE'VE BEEN ABLE TO DO THIS BY
THREE MANUFACTURING. WITH ONE
MUTATION AND ONE GUIDE FOR --
AND THEN ALSO FOR A SEPARATE
GUIDE IN RNA MUTATION WE
DEVELOPED POTENCY MARKERS FOR
GRAFTABILITY AND EFFICACY AND
HAVE DONE THREE TO SIX MONTH
TOXICOLOGY STUDIES ON OUR
ORGANOIDS.
SO WITH THE POTENCY AND
SKILLABILITY IS THERE. WE CAN
MAKE ENOUGH TO COVER THE BODY
THREE TIMES OVER FOR EACH
PATIENT AND WE HAVE A MEETING
WITH THE FDA NEXT WEEK AND WE
LOOK FORWARD TO THE DISCUSSION
WITH THEM ON THE PROJECT. SO
WHAT HAVE WE LEARNED? WE LEARNED
BASICALLY THAT AS THE SAME
THEMES THAT YOU HEARD ABOUT
OTHER OVER THE MORNING THAT IT'S
THE COST OF MANUFACTURING.
THE BESPOKE IPS BANKS FOR EACH
PATIENT AND THE LINE TO LINE
VARIABILITY WHICH THEN INCREASE
THE COST, TIME OF MANUFACTURING.
WE HAVE GONE A LONG WAY IN
UNDERSTANDING HOW IPS CELL
DIFFERENTIATES INTO THREE
LINEAGES AND THEN BASICALLY INTO
THE INTERACTION BETWEEN THE
DIFFERENT LINEAGE TO MAKE
DIFFERENT SKIN ORGAN NOISE.
HOWEVER, IT STILL NEEDS TO BE
BETTER.
ALSO, IN TERMS OF THE DENNIS
TALKED ABOUT THIS MORNING ABOUT
THE ONE ID POLICY. AGAIN, THE
FDAS WANTS US TO PROVIDE THE
POLICY.
BY PROVIDING TWO DIFFERENT
GUIDES FOR TWO DIFFERENT
MUTATIONS AND THE IPS
INTERMEDIATE WE CAN PROVIDE THE
GUIDANCE THEY NEED TO ALLOW THEM
TO SOFTEN THE ONE GUIDE ONE RND
POLICY. I THINK THE NEXT THING
IS -- WE'RE MAKING IT AUTOLOGOUS
BECAUSE WE WANT IT TO BE INERT
BUT FOR THE BANKS WHICH HAVE --
A DECREASED COST OF GOODS, THE
ISSUE IS IMMUNOLOGIC ACTIVITY.
SO FOR THE NEXT SLIDE, SO WHAT
DO WE NEED IN TERMS OF RESEARCH?
IN TERMS OF COST AND SCALE OF
MANUFACTURING WE NEED TO
AUTOMATE THE MANUFACTURING
PROCEDURES FOR THESE PATIENTS.
WE NEED TO BASICALLY UNDERSTAND
USING AS WE TALKED ABOUT IPS
WHAT I CALL MAPS OF THE LYNN
YAMS SO WE KNOW HOW THE LINEAGE
INTERACT IN THE ORGANOIDS.
WE KNOW HOW TO PREDICT WHAT
THEY'LL DO IN THE TISSUE BECAUSE
WE KNOW WHAT THEIR STATE IS AT
THE TIME OF THE PRODUCT. AS
WELL AS BASICALLY IDENTIFYING
AND UPDATING AND WORKING WITH
THE SCIENTIFIC COVER FOR OUR --
FOR SIMPLIFYING AND ACCELERATING
MANUFACTURING POLICIES AND
THAT'S REALLY UP TO US TO DO
THAT AND LASTLY ACTIVITY FOR
ALLOGENEIC BANKS WE NEED TO TALK
ABOUT HOW TO MODIFY THE PRODUCT
OR THE PATIENT. AND I THANK
EVERYONE FOR OUR PROJECT. IT'S
A LARGE GROUP. AND WE'VE ALL
CONTRIBUTED SO THANKS VERY MUCH.
>> I WANT TO THANK ALL OUR
SESSION TWO SPEAKERS. WE'RE
GOING TO OPEN UP THE SESSION TO
QUESTIONS FROM THE FLOOR. AND
MARTHA IS GOING TO LEAD THE
DISCUSSION AND Q&A.
>> HEY. OUTSTANDING. I REALLY
ENJOYED HEARING ABOUT SCIENCE
THAT I'M NOT TOO UP-TO-DATE ON
SO I WOULD LOVE TO HEAR FROM YOU
FIRST BEFORE I DIVE INTO MAYBE
IDENTIFYING MY QUESTIONS OR
IDENTIFYING SPECIFIC THINGS. I
DO THINK THAT WE HAVE SOME
THINGS IN THIS SESSION THAT ARE
SIMILAR TO THE OTHER SESSION.
SO IF ANYONE WOULD LIKE TO ASK
ANY SPECIFIC SCIENTIFIC
QUESTIONS FIRST BASED ON WHAT
YOU HEARD TODAY OR WE COULD DIVE
RIGHT INTO THEMES. YES?
>> I JUST WANT TO ECHO MY
COLLEAGUE IN THE FIELD. SO MY
WORK FOCUS ON HUMAN RETINAL
IMPLEMENTATION INTO A RODENT
MODEL SO I SAID ONE OF THE
CHALLENGES WE HAVE OR I HAVE IS
WE CAN HAVE A LOW CELL SURVIVAL
AND ALSO VERY LOW CELL
INTEGRATION BECAUSE THERE'S A
LAYER MEMBRANE, THE DONOR CELL
TO THE LAYER. FOR THE DONOR
CELL WE USE THE INJECTION AND SO
TO OVERCOME THIS BARRIER, IT'S A
POSSIBLE WAY. ONE IS TO USE THE
ENZYMATIC DIGESTION TO DIGEST IT
THERE BECAUSE THIS IS ACTUALLY A
CELLULAR METRIC. HOWEVER,
IMMUNE ACCURATE INFORMATION
MIGHT HAPPEN SOMETIMES. AND
EVERYTHING IS MECHANIC REMOVAL
OF THIS MEMBRANE BUT LIKE IN
CLINIC PEOPLE USE A PATIENT YOU
CAN DO THIS. HOWEVER IT'S ALSO
CONSTANT RISK BECAUSE YOU CAN
REMOVE THIS MEMBRANE. SO IN
COLLABORATION WITH THE PHYSICIAN
SCIENTIST IN TOM AND JOHNS
HOPKINS WE TRIED TO DEVELOP A
METHOD TO APPROVE TO REMOVE THIS
MEMBRANE TO GET BETTER
EFFICIENCY. YEAH, I JUST WANT
TO ECHO MY COLLEAGUE IN THIS
FIELD, YEAH. THANK YOU.
>> DAN?
>> I WANTED TO FOLLOW UP,
ANOTHER COMMON THEME WHICH IS
SHARING OF INFORMATION. YOU
MENTIONED THAT IT'S VERY
DIFFICULT FOR ALL THE RIGHT
REASONS TO GET PROPRIETARY
INFORMATION FROM INDUSTRY TRIALS
AND THINGS LIKE THAT. BUT THIS,
I THINK THIS IS VERY IMPORTANT
IF WE CAN FIGURE OUT -- AND RUN
AROUND WITH SOMETHING NOW SO TWO
THOUGHTS. ONE IS PROBABLY
IMPOSSIBLE IS TO WHETHER OR NOT
THERE COULD BE ANY INFLUENCE OF
THIS GROUP IN THE CONSORTIUM ON
MAKING CLINICAL TRIALS.GOV MORE
ACCOUNTABLE. THERE ARE SO MANY
TRIALS. CELL BASED THERAPY.
GENE THERAPIES AND THE LIKE THAT
YOU JUST NEVER SEE THE LIGHT OF
THE INFORMATION BUT THE OTHER
WHICH I THINK MIGHT BE MORE
PRACTICAL AND REALISTIC IS
PATIENT REGISTRIES FOR CLINICAL
INVESTIGATIONS THAT ARE
ADDRESSING A COMMON THEME, AND
THROUGH -- IF IT'S GOING TO BE
WITH GOVERNMENTAL SUPPORT LET'S
PUT TOGETHER REGISTRIES, THE
BONE TRANSPLANT PEOPLE HAVE DONE
THAT SUCCESSFULLY, THE ONCOLOGY
INVESTIGATORS OF COURSE HAVE
DONE THAT TREMENDOUSFULLY
SUCCESSFULLY WE CAN DO THE SAME
THING AND WHAT IT GETS TO IS I
THINK REALLY STILL A PRESSING
QUESTION WHICH IS PATIENT
PHENOTYPE.
AND IT'S NOT ONE SIZE FITS ALL
SO IF WE BUILD INTO REGISTRIES
NOT JUST CLINICAL OUTCOME BUT GO
BACK TO BIOMARKERS, GO BACK TO
THE IDEA THAT ARE THERE
PREDICTIVE THINGS THAT WE COULD
OBTAIN ON DAY NEGATIVE ONE, ON
WHATEVER TRIAL YOU'RE GOING TO
DO THAT YOU CAN LINK WITH
SUCCESS AND THEN BUILD A BETTER
MOUSE TRAP.
>> ON THAT NOTE IN TERMS OF THE
CLINICAL TRIALS.GOV AS WELL AS
GETTING PHENOTYPE AND PREDICTIVE
MARKERS WHERE IS ARTIFICIAL
INTELLIGENCE IN TERMS OF THE
PREDICTIVE NATURE?
>> WAITING TO HAPPEN. I MEAN,
THIS IS WHERE WE CAN BE SMART
ABOUT IT. AI AND MACHINE BASED
LEARNING CLEARLY IS HERE AND IS
GOING TO BE WAITING IN THE
FUTURE. WE, AGAIN, IF WE CAN
FIGURE OUT AS A GROUP HOW TO
SUPPORT THE TYPE OF
INVESTIGATIONS THAT WOULD MAKE
THIS EFFECTIVE FOR CLINICAL
TRIALS BUT NOT ONLY CLINICAL
TRIALS IT'S COME UP A COUPLE
TIMES EARLIER IN THE
CONVERSATION IN MANUFACTURING.
ALL RIGHT. SO I THINK THERE'S A
LOT OF ROOM FOR THAT.
>> OKAY. THANK YOU. RICHARD?
>> JUST ONE POINT RELATED TO
CLINICALTRIALS.GOV THERE'S A
SMALL NONPROFIT CALLED TRUE
TRIALS WHICH JUST LAUNCHED AT
MESA ABOUT A MONTH AGO. AND
WITH TALKING TO FDA, THEY'RE
ONLY GOING TO LIST TRIALS WHO
HAVE INDS OR CELL THERAPIES AND
SO THE IDEA IS TO -- IT'S A, AS
I SAID, A NONPROFIT, TO KIND OF
ANSWER THAT QUESTION BETWEEN THE
MANDATE OF CLINICALTRIALS.GOV
AND THE PATIENT NEED TO FIND
TRIALS THAT ARE ONGOING.
>> I'M FROM SLOAN-KETTERING. I
WANTED TO FOLLOW UP ON THE NEED
FOR BETTER UNDERSTANDS A WAY TO
PRODUCT PERFORMS IN VIVO AND YOU
HEARD. I THINK THAT COULD BE AN
AREA WHERE THERE ARE COMMON
PROBLEMS THAT OCCUR JUST THE
WORK IN THE BRAIN. AND YOU HAVE
PARKINSON'S DISEASE AND THE
CRISPR SCREENING AND THEY FIND
THE PATHWAY AND THAT CAN BE
EASILY PHARMACOLOGICALLY
INHIBITED. AND I'M PRETTY SURE
THAT HAPPENS FOR MANY TISSUES.
IF THERE WERE INITIATIVES IN
THAT AREA TO LOOK AT WHAT ARE
THE COMMON PROBLEMS OF SURVIVAL
I THINK THAT WOULD BE SOMETHING
THAT WOULD BENEFIT MORE WITH THE
GROUPS AND THERE HASN'T BEEN
ENOUGH FOCUS ON THAT SO FAR.
>> SO AS A CONSORTIUM OR A GROUP
EFFORT YOU THINK THAT MIGHT BE
ADDRESSED A LITTLE BIT MORE?
>> YES. I MEAN, IT COULD BE
JUST SIMPLY GROUPS THAT ARE
ALREADY DOING THAT. THEY COULD
SHARE MORE INFORMATION. WE HAVE
A CONSORTIUM GROUP FROM JAPAN,
FROM EUROPE, FROM THE U.S. THAT
ALL HELPED EACH OTHER GET INTO
CLINIC AND NOW WE ARE ALREADY IN
THE PHASE ONE TRIAL SO FAR AND I
THINK IT HELPED ALL OF THEM TO
BE IN A COMPETITIVE BUT
COLLABORATIVE EFFORT WHERE THERE
IS, LIKE, I DON'T KNOW WHAT IS
THE RIGHT TERM BUT WHERE
EVERYONE SHARES A LIST THERE AND
ALSO ACROSS FIELDS BECAUSE OF
THE PATHWAY I MENTIONED IS GOING
TO BE LIKE THIS. AND IF ONE
GETS THAT INFORMATION, AND GETS
ACCESS TO THAT INFORMATION, YOU
KNOW, EARLY, AND THEY
SPECIFICALLY CALL AND LOOKING AT
THAT AREA NOT JUST MAKING THE
RIGHT CELL BUT ACTUALLY
INTEGRATION IS LIMITED I THINK
THERE'S A LOT OF SCIENTIFIC
KNOWLEDGE THAT IS TO SOME EXTENT
MISSING BUT WE COULD HAVE A
SIMPLE SOLUTION THAT WE CAN
UNDERSTAND A LITTLE BIT BETTER.
>> THANKS SO MUCH JUST FOR WHAT
LAUREN JUST TALKED ABOUT IN
TERMS OF SHARING DATA. SO ONE
OF THE CLUES WE GOT FROM -- TO
MAKE MULTILINEAGE TISSUE
ORGANOIDS WAS WORK THAT WAS
SHARED BY LAWRENCE IN THE
DIFFERENTIATION TO DEFINE THE
PRODUCT IN SINGLE CELL. WHICH
CAN JUST DEPOSIT INTO DB GAP OR
GEO, AND THE PUBLICLY AVAILABLE.
AND CS MAPS WHICH IS ALSO
PUBLICLY AVAILABLE AND ALSO USED
LAWRENCE'S DATA FOR US AND HELP
TO MAKE US SKIN. USING OTHER
PEOPLE'S DATA TO MAKE TISSUES
AND USING, AGAIN, AI APPROACHES.
I THINK REALLY IS THE WAY
FORWARD. BUT I HAVE TO SHARE
THE DATA. IT'S ALREADY OUT
THERE AND I THINK THAT'S JUST A
FOLLOW UP ON WHAT LAWRENCE SAID.
>> AND MAYBE ACCESSIBLE BUT NOT
DIGESTIBLE IS THAT WHAT YOU'RE
SAYING? IN TERMS OF DB GAP AND
OTHER.
>> I THINK THE QUESTION FOR US
IS -- SO WHAT IS THE -- SO THE
MINIMAL UNIT FOR CHEMICALS IS --
IS THAT ALWAYS -- MRI. FOR
CELLS WHAT'S THE MINIMAL UNIT?
AND I'D ARGUE IT'S EPIGENETIC
STATE AND SO BY USING THAT AS A
COMMON LANGUAGE WE CAN THEN
SHARE OUR DATA ACROSS TISSUE
PLATFORM CELL STATE TRAJECTORY
AND ALSO THEN MAKE PREDICTIVE
MARKERS FOR WHERE THE PRODUCT IS
NOW AND WHAT IT WILL DO IN THE
TISSUE WHERE WE CAN SCREEN FOR
THINGS LIKE CELL. I THINK
THAT'S WHERE WE ARE IN THE
TECHNOLOGY RIGHT NOW.
>> THANKS.
>> ONE MORE FOLLOW UP AGAIN
BECAUSE MANY OF YOU PROBABLY
KNOW THERE ARE NOW BIG CELL
ATLAS PROJECTS ONGOING FROM CCE
AND OTHERS AND THE PROBLEM IS
SOME OF THOSE IS NOT THEIR
PRIMARY RESULTS AND IF YOU MATCH
THEM. BUT THERE'S A LOT OF,
AGAIN, AREA WHERE WE, FOR
EXAMPLE, TRIED TO BUILD THAT AND
THAT YOU CAN VERY EASILY TAKE
YOUR DATA, PLUCK THEM IN AND IT
GIVES THE QUALITY SCORES AND YOU
KNOW HOW CLOSE YOU ARE TO MAYBE
THE GOLD STANDARD OF THE CELL
AND THAT'S AN OPPORTUNITY NOW
THAT'S COMING UP BECAUSE THERE'S
BEEN A HUGE INVESTMENT FROM CCI
IN ORDER TO BUILD THOSE ATLASES
AND THAT'S JUST GOING TO
EEXPLODE AND SO WE SOMEHOW, EVEN
WE HAD A BINGE OF RELEASE
CRITERIA MARKERS AND THEY'RE
VERY, VERY LIMITED TO DEFINE A
PRODUCT. ON THE OTHER HAND,
THERE'S THIS WEALTH OF
INFORMATION WHERE WE CAN GO
VERY, VERY DEEP AND I THINK HOW
DO TO CLOSE THAT GAP IN MY
OPINION IS A BIG QUESTION THAT
THE FDA NEEDS TO HELP US TOO TO
ADVANCE THOSE IN THOSE COMPLEX
FIELDS. I THINK THERE'S MORE
EFFORT NEEDED BUT THERE'S A LOT
OF DATA OUT THERE AND WE CAN
MAKE THAT MORE ACCESSIBLE AND
MAKE IT EASILY TOO TO GIVE YOU
SCORES. THAT'S ON THE CELL
SIDE, YEAH.
>> I HAVE A QUESTION FOR THE
SCIENTIST. DO YOU THINK WE KNOW
OR CAN IDENTIFY THE
CHARACTERISTICS OF THE VARIANCE
DIFFERENT CELLS SUCH AS SURVIVAL
FACTORS AS YOU MENTIONED OR
ENGRAFTMENT AND PROCESS
OUTGROWTH THAT ARE IMPORTANT FOR
REGENERATIVE MEDICINE SO THIS
SEEMS TO BE A VERY LIMITED SET.
THAT MAY NOT APPLY TO THE ATLAS
OF FACTORS OR CHARACTERISTICS OF
THE CELLS THAT WILL DRIVE THEIR
SUCCESS ACROSS DIFFERENT TIS
TISSUES. AND JUST TO ADD FOR
THAT, GETTING THOSE CATEGORIES
FIRST MAYBE WOULD BE A STEP
TOWARDS MORE AI ANALYSIS AFTER
>> IS ANSWER IS YES. WE TOOK
BASICALLY THE DIFFERENTIATION
LINE FOR LINE VARIANT IN THE
FIVE DIFFERENT PATIENT LICENSE.
GRAFTABILITY STUDIES, TAKE THE
ANALYSIS AND MAP THE CLUSTERS
WITH GRAFTABILITY, THERE'S TWO
OF THEM THAT ACTUALLY ARE
LOCALIZED USING THE MARKERS TO
THE FINAL CELL PRODUCT BUT FOR
POTENCY AND GRAFTABILITY
MARKERS. THAT'S DOABLE TODAY.
WE CIRCUMSTRENGTH OTHER PROBLEMS
THAT PEOPLE HAVE BUT IT'S
CERTAINLY IN ASSAY.
>> I THINK IT'S DIFFICULT TO GO
TOO DEEP INTO THE WEEDS WITH
THIS DISCUSSION BUT IN SOME
AREAS I THINK WE KNOW. IT'S AN
OBVIOUS MEASURE. EITHER THEY
SURVIVE OR THEY DON'T AND YOU
CAN TRY TO FIND THAT STATE BUT A
LOT OF IT IS ALSO EMPIRICAL AND
WE DON'T KNOW WE NEED TO LEARN
WHAT IS THE RIGHT STAGE OF EACH
OF THOSE FUNCTIONS. WHATEVER
THE FUNCTION IS. YOU CAN ONLY
DO THAT IF YOU HAVE A
WELL-DEFINED PRODUCT. IF WE
JUST TRY MANY, MANY TIMES
WITHOUT HAVING ENOUGH
INFORMATION TO THE PROCESS. IF
YOU CAN DO IT MORE PREDICTIVE
AND IDENTIFY THE IMMEDIATE
STAGES AND DISASSEMBLE THE RIGHT
CELL TYPES YOU CAN DO IT MUCH
MORE PREDICTIVE AND IT'S A
TRANSLATIONAL HAT. HOW DO YOU
MAKE THAT SCIENCE PRESENTABLE
AND INTRODUCIBLE AND FOLLOWING
ALL THE QC THAT YOU CAN ACTUALLY
BRING TO THE FDA THAT CAN BE
APPROVED?
>> SO, QUESTION BECAUSE I ALSO
THINK THAT WE NEED MARKERS THAT
WOULD SAY WHETHER A CELL'S GOING
TO BE TUMISA HER GENERALIC OR
GOING INTO A STATE OF SENES
SENESCENCE.
>> I THINK -- WE DEVELOPED A
WHOLE GENOME SEQUENCING PIPELINE
AND THEN THE PANEL RELEASED>> I
WHOLE GENOME SEQUENCING PIPELINE
AND THEN THE PANEL RELEASED
CRITERION FOR OUR PRODUCT. WE
HAVE DONE SEQUENCING AND THE
PATIENTS GET SQUAMOUS CELL IF
YOU DON'T TREAT THEIR WOUNDS.
THEY ALL HAVE PRECANCER REGIONS.
YOU CAN FIND THE BANKS THAT ARE
CLEAN AND GIVE THEM SOMETHING
BETTER THAN WHAT THEY HAD
BEFORE. THAT'S AN EXAMPLE OF
THAT.
>> OPTIMIZING THE ANIMAL MODEL
SYSTEM IT SEEMS TO ME THAT
THAT'S A MAJOR THEME ALSO FROM
THIS GROUP IS THAT OPTIMIZATION
OF THE MODEL SYSTEM IS WHAT'S
NEEDED AND THE KNOWLEDGE THAT
YOU'RE TALKING ABOUT IS WHAT
WOULD BE NECESSARY TO OPTIMIZE
YOUR MODEL.
>> THIS IS PREANIMAL. THIS IS
ALL TISSUE ORGANOIDS SO YOU CAN
DO A -- IT'S -- JUST, I JUST
WANT TO -- RATHER THAN -- I
THINK DOING A TON OF INSILLY KOE
ANALYSIS. AI. WE CAN DO SO
MUCH.
>> RIGHT.
>> IN THE END YOU NEED TO DO THE
FUNCTIONAL STUFF AND THAT'S
IMPORTANT. BUT I THINK THERE'S
A -- I THINK WE'RE MISSING A LOT
OF THE OPPORTUNITY TO DO A LOT
OF STUFF THAT'S THERE.
>> IT GETS SO EASY TO BE LOST IN
CERTAIN QUESTIONS. THIS HAS
BEEN MY EXPERIENCE WITH THIS
DEVELOPED TWO IPS LINES THAT
WE'VE BEEN TRYING TO GET
REGULATORY APPROVAL FOR AND
WHOLE GENOME SEQUENCING HAS
TLULT BEEN ABSOLUTELY BEEN A
PART OF THE TESTING FOR THAT.
WHERE'S THE LINE DRAWN? THERE
ARE CERTAIN GENES, CERTAIN
VARIANCES THAT ARE PROHIBITIVE
OF, YOU KNOW, AROUND THE LINES,
BUT, HOW MANY VARIANCE AND HOW
MANY GENES IS CONSIDERED
ACCEPTABLE? NOW HAVING SAID
THAT OBVIOUSLY YOU'RE GOING TO
GO FORWARD AND DO A SAFETY STUDY
AND TUMISA HER YES IN THIS
CASETY STUDIES WHERE WEATHER YOU
LIKE IT OR NOT AND THOSE WILL
HAVE CERTAIN OUTCOMES.
AND IT WOULD BE HELPFUL TO HAVE
SOME INITIATIVE THAT'S AI-BASE
THAT HAD WILL JUST SORT OF
DEFINE A BASELINE OF WHAT
CONSTITUTES A HEALTHY GENOME FOR
A CELL THERAPY PRODUCT.
AT LEAST IN AN ALOE YES NAYIC.
>> I APPRECIATE YOUR INSIGHTS.
YOU CAN LOOK AT ALL THE GENETICS
INFORMATION BY I APPRECIATE THE
POINT ABOUT, YOU KNOW, ANIMAL
MODEL BECAUSE, AGAIN, THE CELL
ENVIRONMENT IS WHAT KIND OF
ENVIRONMENT YOU OBSERVE IS
DEPENDENT ON WHICH MODEL YOU
PASSED. USING DIFFERENT ANIMAL
MODEL YOU CAN HAVE DIFFERENT
RESULTS. I THINK -- THE AI
CAN'T BE AS GOOD AS THE DATA
INPUTTING SO, YOU KNOW, I THINK
THAT IS CERTAINLY GOING TO BE
IMPORTANT METRICS TO CONSIDER.
>> YOU KNOW, I COULDN'T RESIST,
THIS IS RICHARD, COMMENTING
ABOUT NON-CLINICAL -- WHAT
PEOPLE CALL PRECLINICAL. I WISH
WE COULD CALL IT NON-CLINICAL.
IT ISN'T ALWAYS ANIMAL STUDIES.
I THINK IN THE AGENCY IT'S IN
THEIR GUIDANCE FOR NON-CLINICAL
STUDIES FOR GENE THERAPIES THEY
POINT OUT IT DOESN'T ALWAYS HAVE
TO BE AN ANIMAL STUDY BUT AN
IDEA OF EXPLAINING YOUR STUDIES
AND WHAT YOUR END POINTS ARE AND
HOW THEY SUPPORT CLINICAL TRIALS
AND DEVELOPMENT IS IMPORTANT AND
I HAVE GOT ONE QUESTION RELATED.
YOU SAID, WELL, OF COURSE YOU DO
TWO STUDIES WHETHER YOU WANT TO
OR NOT IS THERE ANYONE IN THE
ROOM WHO'S ACTUALLY FOUND
SOMETHING USEFUL DOING ANIMAL
TUMOR IN THIS CASETY STUDIES IN
THE LAST 30 YEARS BECAUSE IF
THERE ISN'T, MAYBE TAKING SOME
OF THE DATA THAT WE WERE ABLE TO
DO WITH THE MULTIPARAMETERS TO
PROVIDE JUST AS MUCH
PREDICTABILITY OF THE POTENTIAL
BAD EFFECT OF A TUMOR.
THAN DOING A TUMOR GENESISTY
STUDY WOULD MAKE MORE SENSE.
>> I HAVE NO CLUE OVER THE LAST
30 YEARS I KNOW THERE ARE IPS
STUDIES THAT HAVE BEEN DONE THAT
HAVE LOOKED AT THRESHOLDS OF
RESIDUAL IPSCS THAT WOULD RESULT
IN TUMORS IN ANIMALS AND I
BELIEVE THEY FOUND A THRESHOLD.
IN MY OWN ACTION WITH THE AGENCY
WE TRIED TO GET AWAY WITH AT
LEAST DOING IN VITRO SOFT TYPE
ASSAYS AND WE WERE TOLD WE HAD
TO DO FULL BLOWN RAT STUDIES
WHICH MAKES SENSE TO ME AT THIS
STAGE THERE AREN'T A WHOLE LOT
OF IPSC STUDIES GOING ON BUT
THERE HAS BEEN TUMORS FORMED AND
FOUND. SO. . .
>> (SPEAKER FAR FROM MIC).
>> ASK THE AGENCY.
>> TO FOLLOW UP ON SOME OF THIS
DISCUSSION I THINK ONE OF OUR
PRESENTERS, AT LEAST I WROTE
THIS DOWN WAS COMBINING RELEVANT
MODELS WITH ORGAN ON CHIP. WHO
WAS IT THAT SAID THAT?
ROSEMARY, YOU DIDN'T SAY THAT.
YOU DIDN'T COME UP HERE AND GIVE
A TALK. GO AHEAD. DOESN'T TO
SAY SOMETHING? YEAH. WELL,
OKAY. ALL RIGHT. YEAH. SO I
THOUGHT THAT WAS A THEME THAT
WAS INTERESTING. AND ALONG WITH
THAT THEME CAME, YOU KNOW, THE
CELL DELIVERY SYSTEMS AND
TRACKING AND ALL THAT GOOD
STUFF. ANYBODY ELSE HAVE ANY
CONTRIBUTIONS TO THAT THEME?
OKA
OKAY.
>> SO THE POINT THAT I GUESS I
WAS TRYING TO MAKE AND I WOULD
REALLY LOVE OTHER PEOPLE TO
CHIME IN WAS THAT THERE'S A
CERTAIN SET OF CHARACTERISTICS
THAT COME OUT OF DIFFERENT TYPES
OF STUDIES. AND, YOU KNOW, WHAT
WE NEED TO DO IS I THINK CAMPING
ON BUILDING ON SOMETHING
SOMEBODY ELSE SAID WHICH WAS,
YOU KNOW, TRYING TO DEFINE THE
MOST IMPORTANT CHARACTERISTICS.
TRYING TO DEFINE THE MOST
IMPORTANT DATA POINTS. EVERY
ONE OF US IS GOING TO HAVE OUR
OWN BIASES TO WHAT'S THE MOST
IMPORTANT. SO I THINK
THERE'S -- THERE SHOULD BE A
PRACTICAL WAY TO SORT THESE OUT
AT LEAST AS WE GET CLOSER AND
CLOSER TO THAT MORE KNOWLEDGE
BASE, MORE INFORMATION, GREATER
UTILITY OF THE INFORMATION WE
GET. BUT WE HAVE TO START
LOOKING AT IT IN AN UNBIASED
FASHION AND THAT'S ONE OF THE
WAYS THAT AI CAN REALLY HELP US
IS THE MORE DATA WE HAVE THE
MORE INTEROPERATIVE IT IS THE
MORE LOGICALLY IT CAN MAKE
PREDICTIONS FOR US AND I HAVE A
LITTLE MORE TO SAY ABOUT THAT
TODAY BUT THE POINT IS THAT WE
SHOULD COLLABORATE AS AN OPEN
ENVIRONMENT AS WE CAN. TO BE
ABLE TO REACH OUT TO PEOPLE WHO
HAVE INFORMATION THAT COULD BE
VERY HELPFUL TO US OTHER THAN
KEEPING THESE SILOS IN PLACE.
>> RIGHT.
>> BECAUSE THAT'S NOT GOING TO
BE USEFUL. IT'S INTERESTING
THAT I HAVE HEARD PEOPLE SAY,
WHAT ARE THE IMPORTANT
CHARACTERISTICS? YOU KNOW, WE
DON'T KNOW YET. BUT IN THE
WORLD OF MANUFACTURING THAT'S
CALLED A CRITICAL QUALITY
ATTRIBUTE AND THOSE ARE THINGS
THAT WE HAVE TO LOOK FOR AND
SEARCH FOR. ONE OF THE THINGS
THAT HAVE AN IMPACT ON THE
OUTCOMES THAT WE'RE LOOKING AT.
AND, YOU KNOW, THERE'S
DEFINITELY NOT ONE SIZE FITS
ALL.
>> THANK YOU. I DID WANT TO
MENTION THAT RECURRENT THEME BUT
A LITTLE BIT OF A TWIST WAS
EDUCATION OR WORKFORCE
DEVELOPMENT. I KNOW ARMY HAS A
WHOLE ARM COMPONENT OF THAT AND
THE INITIATIVE. BUT SOMEONE
SAID SOMETHING ABOUT
CROSSCUTTING FOR INVESTIGATORS
SO SILOED EXPERTISE. NOT BEING
ABLE TO TALK TO ONE ANOTHER IN
REALTIME. DO INVESTIGATORS
ESTABLISH -- IN ADDITION TO
CURRICULUM CHANGES FOR THE
STUDENT, BUT DO INVESTIGATORS
THAT ARE LOOKING TO STAY IN THE
RN FIELD DO THEY NEED ADDITIONAL
TRAINING, EDUCATION? OKAY?
I'VE RAISED SEVERAL HANDS.
THANK YOU FOR CALLING OUT
THAT THAT'S AN ASPECT OF THESE
MANUFACTURING INNOVATION
INSTITUTES BUT WE NEED TO
REMEMBER IT'S ALSO REALLY KEY
ASPECT IT'S BEEN THERE FOR
DECADES AT THE NATIONAL SCIENCE
FOUNDATION THROUGH THEIR
ENGINEERING RESOURCE CENTERS AND
THE ONES THAT ARE IN THIS SPACE.
THERE ARE A FEW OF THEM IN THIS
SPACE AND SO THEY HAVE BEEN
DEVELOPING THESE PROGRAMS FOR
YEARS AND SOME OF THE OTHER --
THE MMIS ARE DOING THEM AND
THERE ARE OTHER ORGANIZATIONS
THAT ARE FOCUSED IN THIS AREA
BECAUSE ANYTIME ANYBODY TRIES TO
DO THIS STUFF AT A HIGHER LEVEL
AT A GREATER SCALE THEY BUMP
AGAINST -- THEY BUMP UP AGAINST
THIS WORKFORCE DEVELOPMENT THING
RIGHT AWAY AT MULTIPLE LEVELS AS
YOU POINTED OUT YOU NEED TO
EDUCATE THE TECHNICIANS THAT ARE
PUSHING THE BUTTONS AND RUNNING
THE MACHINES BUT YOU ALSO HAVE
TO GET THE UPPER LEVEL
INVESTIGATORS TALKING TO EACH
OTHER ACROSS THE BARRIERS. AND
I HAVE TO ADMIT THE NIH HAS NOT
BEEN PARTICULARLY GOOD AT THIS
KIND OF THING BUT THE
SO, I'M ARON MARQUITZ.
CANDACE KERR FROM NIAID, AND
I'M INVOLVED IN THE IN-DEPTH
CELL CHARACTERIZATION.
>> THANK YOU.
ALL RIGHT.
SO, I THINK WE'LL STICK WITH THE
SAME FORMAT HERE, AND I WILL
CALL UP THE FIRST SPEAKER AND
THE ONES ON DECK.
FIRST UP IS DAN WEISS AND ON
DECK IS TYLER RAM.
THANK YOU TO THE ORGANIZERS, A PHENOMENAL MEETING.
I'M PROFESSOR OF MEDICINE,
UNIVERSITY OF VERMONT IN
PULMONARY AND CRITICAL CARE.
I'M AN ACADEMICIAN, LONGSTANDING
INTEREST IN LUNG REGENERATIVE
MEDICINE, HERE AS REPRESENTATIVE
OF THE INTERNATIONAL SOCIETY OF
CELL AND GENE THERAPY, WHERE
I'VE BEEN THE FORMER LONG-TERM
CHIEF SCIENTIFIC OFFICER.
THE ISET -- CAN WE -- GREAT,
OKAY.
FOR THOSE WHO ARE NOT FAMILIAR,
ONE OF THE LEADING GLOBAL
ORGANIZATIONS LOOKING TO MAKE
CELL-BASED THERAPY A REALITY.
NEXT SLIDE.
AGAIN, TO GIVE A SMALL
PERSPECTIVE, MULTI-THOUSAND
MEMBERS, GLOBALLY, WE FOCUS NOT
JUST ON SCIENCE BUT PARTICULARLY
ON REGULATORY COMMERCIALIZATION,
AND MANUFACTURING.
NEXT SLIDE.
AS SUCH HERE.
SO, NEXT SLIDE PLEASE.
WHAT I THOUGHT WOULD BE HELPFUL
WOULD BE A SWAT ANALYSIS
APPROACH, AND A LOT OF THE TOPIC
AREAS WE'VE TOUCHED ON, WHICH IS
IMPORTANT TO ME BECAUSE WE'RE
ALL THINKING THE SAME.
AND SO, IF YOU LOOK AT SECTOR
STRENGTHS, WHAT WE CAN LEARN,
THERE HAS BEEN TREMENDOUSLY
SUCCESSFUL CELL-BASED THERAPY,
TRANSPLANTATION, CAR-T,
GENE-MODIFIED HEMATOPOIETIC STEM
CELLS.
WE'VE HEARD ABOUT iPSCs,
MSCs, GENE-MODIFIED, EDITED
IMMUNOREGULATORY CELLS,
ENDOGENOUS TISSUE-SPECIFIC
PROGENITOR CELLS, EXOSOMES,
EXTRACELLULAR VESICLES IS,
THERE'S A STRONG PRE-CLINICAL
TRACK RECORD OF EFFICACY, BUT
ALSO IMPORTANTLY A GROWING
CLINICAL SAFETY RECORD.
GREAT, THANK YOU.
AND THE LIKE TOO.
SO, WHAT ARE THE WEAKNESSES,
RIGHT?
DESPITE MSC AS AN EXAMPLE, THERE
ARE THOUSANDS OF PRE-CLINICAL,
NON-CLINICAL STUDIES SHOWING YOU
CAN PICK YOUR DISEASE TARGET AND
ENDPOINTS, AND MSCs WILL SAVE
THE DAY.
BUT THEY JUST HAVEN'T WORKED
CLINICAL, YOU HAVE TO FIGURE OUT
WHY.
MULTIPLE UNRESOLVED ISSUES,
MANUFACTURING DOSE, DOSING, I
KEEP HARPING ON PATIENT
PHENOTYPE, NOT ONE SIZE FITS
ALL.
WE'VE TALKED ABOUT POTENCY OF
ACTION.
DELIVERY IS KEY, REGULATORY
HARMONIZATION, IT'S NOT JUST WE
THE INVESTIGATORS WHO DON'T
FULLY UNDERSTAND REGULATORY.
A LOT OF AGENCIES AND
INSTITUTIONS DON'T UNDERSTAND
THE REGULATORY AS WELL.
WORKFORCE, WE'LL TALK MORE ABOUT
AGAIN.
ALSO, IF YOU THINK ABOUT
IMPLEMENTATION, REGIONAL
DISPARITIES, ACCESS,
IMPLEMENTATION, ET CETERA, AND
THE LIKE TOO.
WHAT ABOUT THREATS?
FUNDING IS A THREAT, AND THE
LIKE.
APPRECIATE THE TRACK RECORD OF
FUNDING, THE RMIP AND THINGS
LIKE THAT, BUT IT'S NEVER
ENOUGH, RIGHT?
I WANT TO HIGHLIGHT THAT WE'RE
ALL DEPENDENT ON THE ECONOMY, A
GOVERNMENT SHUTDOWN IS GOING TO
AFFECT HOW NIH IS GOING TO HAVE
MONEY TO SPEND, SO TO SPEAK.
I ALSO WANT TO SHIFT GEARS, IF
YOU THINK ABOUT WHERE ELSE DOES
MONEY COME FROM FOR THESE
THINGS?
FROM INDUSTRY, INVESTORS, AND
THERE'S A BURNOUT BECAUSE SO
MANY TRIALS ARE NOT WORKED.
WE'RE NOT MAKING MONEY ON THIS.
THE OTHER THING TOUCHED ON NOT
ENOUGH I THINK IS EDUCATION.
YOU SAY THE WORD STEM CELL, IT
EVOKES ALL TYPES OF MAGICAL
POLICIES AND WHATEVER.
AND STEM CELL MEDICAL TOURISM
INDUSTRY IS A REAL THREAT AND
STILL OUT THERE, AND THE LIKE.
WHAT KIND OF OPPORTUNITIES ARE
THERE?
WE'RE A CON SHORT YUM APPROACH
GLOBAL REACH, AND TO GO THROUGH
THE THROUGH THE LAUNDRY LIST,
DEVELOPMENT, IMPLEMENTING,
MANUFACTURING IMPROVEMENTS, LOTS
OF WAYS TO DO THIS.
DELIVERY, I WANT TO HIGHLIGHT
ONE THING, SYSTEMIC NOT THE ONLY
WAY.
LOCAL DELIVERY, CAN YOU INJECT
OR ADMINISTER YOUR CELLS
SUBCUTANEOUSLY, FOR EXAMPLE, AND
THEY WILL HAVE DISTANT EFFECTS
THAT WILL AFFECT YOUR DISEASE OF
INTEREST OR DISEASE OF TARGET,
IF YOU WILL.
THIS IS NOT NECESSARILY LOCAL
INJECTION INTO A JOINT, BUT
INJECTION, AGAIN, SOMEWHERE ELSE
THAT WILL HAVE DISTANT EFFECTS.
HOW DOES THAT WORK?
YOU MODIFY IMMUNE AND
INFLAMMATORY PATHWAYS INVOLVED,
AND THEY HAVE SYSTEMIC EFFECTS,
IF YOU WILL.
WE HEARD LOCAL DELIVERY, HEARD
FINN TALK ABOUT CF.
TO GET THOSE CELLS ENGRAFTED
RIGHT NOW THEY HAVE TO USE
DETERGENT TO RIP OPEN HOLES IN
THE EPITHELIUM, THAT'S NOT A
CLINICAL STRATEGY, BETTER WAYS
TO GO.
LATE STAGE DEVELOPMENT,
COMMERCIALIZATION, RAPID
ANALYTICS ARE CRITICAL IN
QUALITY CONTROL FOR MASS
PRODUCTION.
REGISTRIES, SO MENTIONED
EARLIER, FOCUS ON PATIENT
SELECTION, POINT OF CARE PATIENT
ASSESSMENTS FOR ACUTE DISEASE
APPLICATIONS, GOES TO THE
BIOMARKERS.
RECENT TRIALS OF CELL-BASED
THERAPY FOR COVID, ACUTE
RESPIRATORY DISTRESS SYNDROME,
SOME TRIALS WORKED, SOME TRIALS
DIDN'T WORK.
HOW DO WE FERRET OUT WHO IS
GOING TO RESPOND?
IF WE COULD HAVE, FOR EXAMPLE, A
QUICK BLOOD TEST, FOUR OR FIVE
INFLAMMATORY MARKERS, YOU'RE
LIKELY TO RESPOND, YOU'RE LESS
LIKELY TO RESPOND, IT'S GOING TO
MAKE SUCCESS I THINK MORE
ACHIEVABLE.
PATIENT/CAREGIVER EDUCATION,
REGULATORY HARMONIZATION,
WORKFORCE DEVELOPMENT, TISSUE
ENGINEERING IN VARIOUS FORMS,
ORGANOID SCAFFOLD, HYDROGELS AND
THE LIKE.
THERE'S A HUGE OPPORTUNITY HERE
I THINK.
ALL RIGHT.
A COUPLE OF REPRESENTATIVE
NEAR-TERM PROPOSED SOLUTIONS FOR
TO HELP AND LEAD SOME EFFORTS,
MANUFACTURING AND ANALYTICS
WORKFORCE DEVELOPMENT,
ACKNOWLEDGING THE ARMY, ARMI,
HAS DONE A LOT OF WORK, NSF, AS
WAS ARTICULATED.
TECHNOLOGY IS CRITICAL, SUCCESS
FACTOR, THE IDEA TO HAVE CENTRAL
AND DECENTRALIZED MANUFACTURING
WITH QUALITY CONTROL AND AGAIN
ANALYTICS.
INDUSTRY IS A BROAD TERM,
INCORPORATING A.I.,
MACHINE-BASED LEARNING AND THE
LIKE.
ONE OF THE HURDLES IS EACH STEP
ALONG THE WAY, HAVING THE
QUALITY CONTROL SO YOUR PRODUCT
IS WHAT YOU WANT IT TO BE IN A
REPRODUCIBLE MANNER, IF YOU
WILL.
AGAIN, THINGS THAT WE'VE ALL
TALKED ABOUT, NOVEL
TECHNOLOGIES, CENTRAL QUALITY
ASSESSMENT, AUTOMATION, ET
CETERA.
EVOLUTION OF REGULATORY
STANDARDS AND PRACTICE,
EXPANSION OF THE ROLE OF
ACCREDITATION BODIES.
THERE'S NO -- IT'S LIKE THE WILD
WEST A LITTLE BIT OUT THERE IN
TERMS OF WHAT GETS APPROVED, WHO
DOES THE APPROVING.
SOME STANDPOINTS.
AND WE'RE THINKING BEYOND THE
U.S. BECAUSE AT SOME POINT THIS
WAS A GLOBAL THERAPY, AND SO
HARMONIZATION WITH EUA, EMA,
OTHER REGULATORY AGENCIES AROUND
THE WORLD IN WHICH WE WANT TO
CURE PATIENTS AS WELL AS IN THE
U.S.
AND MANUFACTURING AND
REGULATORY, ET CETERA.
ALL RIGHT.
OH, OKAY.
WORKFORCE DEVELOPMENT AND
TRAINING, I'M GLAD THIS CAME UP.
I'M GLAD YOU BROUGHT THIS UP
BECAUSE IT'S A HUGE ISSUE,
RIGHT?
AS AN ACADEMIC, I CAN'T FIND
PEOPLE, I CAN'T FIND LAB TECHS.
ROSEMARY'S POINT ABOUT THE
ASSEMBLY LINE IS AS CRITICALLY
IMPORTANT AS WHO IS DRIVING THE
BOAT, IF YOU WILL.
THIS IS WHERE LEARNING FROM THE
NSF, FROM ARMI, AND BEING ABLE
TO IMPLEMENT -- I DON'T KNOW IF
THERE'S A POINTER, BUT PRACTICE
PROGRAMS, SETTING STANDARDS FOR
FOCUSED TRAINING PROGRAMS,
HAVING WIDELY RECOGNIZED
ACCREDITATION SO THAT SOMEONE
WHO GOES THROUGH TRAINING
PROGRAMS SAYS HERE'S MY
CERTIFICATE, FOR EXAMPLE, NOT
NECESSARILY MY DEGREE BUT HERE
IS MY CERTIFICATE, I CAN DO WHAT
YOU WANT ME TO DO, GIVE ME A
GOOD JOB, A WIN-WIN SITUATION IF
WE CAN MAKE THIS WORK.
THERE ARE SOME OUT THERE, BUT TO
BROADEN THIS AND HAVE THE NIH
LEAD THE WAY IN SO MANY RESPECTS
CAN BE REALLY BENEFICIAL,
SOMETHING THE CONSORTIUM WITH
HELP, AN LONGITUDINAL TRAINING
FOR LONG-TERM DEVELOPMENT,
OBVIOUSLY.
MY LAST SIDE IS CELL SOURCE AND
QUALIFICATION.
I'VE NOT AN iPSC RESEARCHER
NECESSARILY BUT LISTENING TO
EVERYTHING GOING ON, IT'S THE
MANUFACTURING.
FIGURE OUT THE SCIENCE, IT'S NOT
ONE-SIZE-FITS-ALL, OF COURSE,
BUT WHO IS GOING TO, AGAIN, YOU
SAID -- MULTIPLE PEOPLE SAID
THIS, IF WE CAN WORK TO MAKE
THIS HAPPEN, THEN I THINK THIS
IS WHERE ISCT HAS THE
BACKGROUND, THIS IS A PEP TALK
FOR ISCT, THE BACKGROUND
EXPERIENCE, EXPERTISE AND THE
LIKE TO SHAPE MOLDS AND LEAD THE
EFFORTS.
THANK YOU FOR THE OPPORTUNITY.
>> UP NEXT WE HAVE TYLER LAMB
AND ON DECK IS GRANT HOLLEY.
>> GOOD AFTERNOON.
THANK YOU FOR THE INVITATION TO
PARTICIPATE IN THE WORKSHOP AND
OPPORTUNITY TO PRESENT.
I'M TYLER LAMB, DIRECTOR OF
POLICY FOR INTERNATIONAL SOCIETY
FOR STEM CELL RESEARCH.
I BELIEVE THIS IS THE FIRST
EVENT OF THE REGENERATIVE
MEDICINE INNOVATION PROJECT THAT
ISTSR HAS PARTICIPATED.
THE IDEAS WERE DEVELOPED FOR THE
WORK OF THE MANUFACTURING
CLINICAL AND TRANSLATION
COMMITTEE AND SOME OTHER AREAS
WHERE ISSCR IS MOVING FROM BENCH
TO CLINIC.
GIVEN THE GOALS OF THE WORKSHOP
WE THINK IT'S PARALLEL IF NOT
CONGRUENT AND POTENTIALLY
USEFUL.
FIRST JUST A QUICK INTRODUCTION
OF ISSCR, WE'RE GLOBAL, IN 80
COUNTRIES, COUNT 4700
SCIENTISTS, ETHICISTS AND
BUSINESS LEADERS, BEST KNOWN FOR
GUIDELINES, YOU MAY BE FAMILIAR.
WE HOST ONE OF THE LARGEST
GATHERINGS OF STEM CELL
RESEARCHERS IN THE WORLD, OUR
ANNUAL MEETING TAKING PLACE NEXT
JULY IN HAMBURG, GERMANY.
WE'RE GOING WITH THE FIELD AND
HAVE EXPANDED SCOPE TO INCLUDE
TRANSLATIONAL AND CLINICAL
OFFERINGS.
WE'RE FORTUNATE TO COUNT AS
MEMBERSHIP MANY PIONEERS
RESPONSIBLE FOR THE TRANSLATION
OF STEM CELL THERAPIES.
I WANT TO BRIEFLY TALK ABOUT OUR
STANDARDS INITIATIVE.
EARLIER THIS YEAR WE PUBLISHED
STANDARDS, DEVELOPED OVER TWO
YEARS WITH INTERNATIONAL
COLLABORATION, THIS DOCUMENT
IDENTIFIES QUALITY STANDARDS AND
OUTLINES, CORE PRINCIPLES FOR
LABORATORY USE OF TISSUE AND
PLURIPOTENT STEM CELLS AND IN
VITRO MODEL SYSTEMS THAT RELY ON
THEM.
EMPHASIS WAS A CREATING
RECOMMENDATIONS THAT WHEN TAKEN
TOGETHER ESTABLISH MINIMUM
CHARACTERIZATION AND REPORTING
CRITERIA FOR SCIENTISTS,
STUDENTS, TECHNICIANS, BASIC
RESEARCH LABS WORKING WITH HUMAN
STEM CELLS.
YOU CAN SEE THE SCOPE OF THE
DOCUMENT THERE.
WE'VE ALSO INITIATED A PHASE TWO
OF THIS PROJECT.
PHASE TWO IS UNDERWAY, ADDRESSES
BEST PRACTICES FOR TRANSLATION
OF PSC-BASED THERAPIES,
SCHEDULED TO BE COMPLETED IN
2025.
THIS DOCUMENT WILL PROPOSE
STANDARDS TO STREAMLINE THE
PROCESS OF DEVELOPING
PLURIPOTENT CELL DERIVED
CELLULAR THERAPIES, AND YOU CAN
SEE THE FOCUS OF PHASE TWO
THERE.
SO TO ENABLE OUR MEMBERS TO MAKE
ROBUST PCS THERAPIES THAT MEET
CURRENT AND FORTHCOMING
STANDARDS AND ADHERE TO GUIDANCE
BY REGULATORS WE'VE BEEN WORKING
WITH COMMITTEES RESPONSIBLE FOR
RESEARCH AND DEVELOPED
PROGRAMMING AND TRAINING AND
REGULATORY STRATEGY TO ADDRESS
DIFFICULTIES IN THE DEVELOPMENT
OF PSC THERAPIES.
IT'S FROM THE DEVELOPMENT OF
THESE MATERIALS THAT WE'VE
IDENTIFIED PAIN POINTS WE THINK
WOULD BE OF INTEREST TO
GOVERNMENT AND INDUSTRY PARTNERS
AND WOULD IF SOLVED OR
MITIGATED, ADVANCE THE FIELD FOR
PATIENTS IN NEED.
WE HEARD SEVERAL OF THESE
SUGGESTIONS ALREADY.
THOSE ARE SELECTING A CELL
LINE, AGUESSING GENETIC
STABILITY, UNDERSTANDING HOSE
IMMUNE RESPONSE.
SO IN THINKING ABOUT THE PROCESS
FOR DEVELOPING A CELL LINE,
SELECTING A LINE, ONE ISSUE
AFTER SELECTING A LINE THE MANY
STEPS, FOR EXAMPLE,
CHARACTERIZATION, TIME, MONEY,
LEVEL OF SPECIALIZED TECHNICAL
EXPERTISE, SMALL LABS AND
COMPANIES FEEL THE ISSUES MOST,
ESPECIALLY TIME AND COST.
A SECOND ISSUE IS INTELLECTUAL
PROPERTY AND LICENSING.
CELL LINES ESPECIALLY THOSE
GENETICALLY MODIFIED DERIVED CAN
BE PATENTED, AND TO USE PATENTED
CELL LINES RESEARCHERS NEED TO
ENTER INTO LICENSING AGREEMENT
WAS PATENT HOLDERS, TRACKING
DOWN INFORMATION.
FEE, ROYALTIES, AND RESTRICTIONS
ON SALE OF PRODUCTS DERIVED CAN
BE CHALLENGING, EVEN NEGOTIATING
CAN BE EXPENSIVE AND TIME
CONSUMING, TYPICALLY REQUIRING
LEGAL EXPERTISE.
THUS WE THINK AN AREA WHERE THE
TIMES OF PARTNERSHIPS DESCRIBED
HERE COULD BE USEFUL IS IN
DEVELOPING A BANK OF PUBLICLY
AVAILABLE PSC LINES.
WE THINK EASIER ACCESS TO A
VARIETY AND DIVERSITY OF PSC
LINES WOULD STREAMLINE THE
PROCESS FOR DEVELOPING CELL
THERAPY LEADING TO LOWER COSTS,
ENSURE SAFETY AND GENETIC
STABILITY AND CONSISTENCY.
AND COULD NEGOTIATE A BROAD
LICENSING AGREEMENT TO PROVIDE
CELL LINES WITH FEWER
RESTRICTIONS TO FACILITATE MORE
OPEN RESEARCH AND DEVELOPMENT
ACTIVITIES, COULD ALSO
POTENTIALLY ADVISE ON
RESTRICTIONS TO CELL LINES
OFFERED BY PATENT HOLDERS.
IF CELL LINES FROM THE
REGULATORY PERSPECTIVE, IF THEY
HAVE BEEN APPROVED FOR USE IN
CLINICAL TRIALS THIS CAN REDUCE
TIME AND COST ASSOCIATED WITH
REGULATORY FILINGS.
THE NEXT ISSUE I WANT TO TALK
ABOUT ABOUT IS ASSESSING GENETIC
STABILITY.
INTERESTED TO HEAR WHAT OTHERS
HAVE TO SAY ABOUT HOW A.I. CAN
CONTRIBUTE TO THIS PROCESS.
BUT GENOMIC STABILITY AND CON
CONTEXT REFERS TO VARIABILITY IN
A POPULATION OF PSCs AND
STABILITY REFERS TO HIGH
FREQUENCY OF MUTATIONS WITH
GENOME.
ENSURING GENETIC STABILITY OF
PSC LINE WHEN DEVELOPING A
THERAPEUTIC PRODUCT IS CRITICAL
AS INSTABILITY CAN AFFECT SAFETY
AND EFFICACY.
TO ENSURE A CELL LINE IS STABLE,
RIGOROUS SCREENING IS REQUIRED,
SOME WHOLE GENOME WHOLE EXOME
SEQUENCING AND YOU CAN SEE THE
DIFFERENT POINTS WHERE YOU MIGHT
DO GENOMICS ANALYSIS TO ENSURE
STABILITY OF CELL POPULATION.
ISSUE WE'VE MADE SIGNIFICANT
PROGRESS IN ABILITY TO DETECT
AND QUANTIFY MUTATIONS BUT
UNDERSTANDING OF CONSEQUENCES OF
MUTATIONS HASN'T KEPT PACE.
THE ONLY PURE POPULATION AS WE
KNOW HAPPENS EVERY TIME A CELL
DIVIDES, THERE'S A NEED TO
DEVELOP STANDARDIZED ASSAYS AND
REACH CONCLUSIONS ON WHICH
MUTATIONS ARE DOING SO COULD
POTENTIALLY LOWER FREQUENCY OF
TESTING, REDUCE COST, PROVIDE
GREATER CLARITY ON WHAT
REGULATORS ARE LOOKING FOR AND
CONSIDER AREAS OF CONCERN FROM
GENOMICS ANALYSIS.
LAST ISSUE I WANT TO DISCUSS IS
UNDERSTANDING HOST IMMUNE
RESPONSE, THE LAST PAIN POINT.
TO DEVELOP LARGE SCALE
COMMERCIALIZED THERAPIES,
SOLVING ISSUE OF IMMUNE
REJECTION IS CRITICAL.
IF CELLS ARE IDENTIFIED AS
FOREIGN, POTENTIALLY REJECTING
THERAPY, A FAILURE.
ALLOGENEIC REQUIRES GENE EDITS
TO CREATE DONOR CELLS, PERHAPS
KILLER SAFETY SWITCHES, EDITS
INCLUDE POTENTIAL COMPLICATIONS
NORMALLY ASSOCIATED WITH GENE
EDITING TO HAVE LONG LASTING
EFFECTS, IT'S IMPORTANT CELLS
CAN COEXIST FOR EXTENDED PIECE
OF TIME, THE DURABILITY PIECE.
A LACK OF WIDELY ACCEPTED AND
STANDARDIZED ASSAYS OR BETTER
PREDICTIVE VALUE, LEARNING ABOUT
COMPLEXITY OF IMMUNE SYSTEM AND
VARIABILITY BETWEEN PATIENTS
COULD BE USEFUL, SOLVING THESE
CHALLENGES WOULD ACCELERATE AND
DE-RISK DEVELOPMENT OF
CELL-BASED THERAPIES.
THANK YOU.
>> THANK YOU VERY MUCH.
THIRD SPEAKER IS GRANT HOLLEY,
ON DECK IS MIKE DURAN.
>> LET'S SEE IF I CAN MESS THIS
UP.
THERE WE GO.
I MADE NOTES.
PRESENTATION I PUT TOGETHER,
GREATLY ENJOYED DISCUSSION THIS
MORNING AND MAY CHANGE A COUPLE
THINGS TO HIT ON A FEW POINTS
THAT I FEEL REALLY NEED TO BE
HIT UPON.
I'LL TAKE IT FROM A DIFFERENT
PERSPECTIVE THAN MY PEERS, BUT
HOPEFULLY IN A WAY THAT'S GOING
TO HELP BUILD CONSORTIA MOVING
FORWARD.
WE'RE THE AMERICAN SOCIETY OF
GENE AND CELL THERAPY.
WE HAVE 6259 MEMBERS, WE'RE IN
THE MIDST OF RENEWALS RIGHT NOW,
IF YOU'RE OUT THERE PLEASE RENEW
YOUR MEMBERSHIP, JUST IN CASE OR
CEO IS TUNING IN, GOT TO SAY
THOSE THINGS.
WE HAVE A RELATIVELY YOUNG
MEMBERSHIP STARTING THIS YEAR
WITH 30 TO 39 BASE OUR AVERAGE,
WHICH IS YOUNG.
WHEN I FIRST CAME TO ASGCT THREE
YEARS AGO AVERAGE AGE WAS CLOSER
TO 55.
THERE'S NOTHING WRONG WITH 55.
BUT I'M LOOKING FOR RETIREMENT,
AND I WANT THESE YOUNG KIDS IN
BECAUSE THEY WILL KEEP THE
SOCIETY MOVING.
AT THE SAME TIME THEY ARE THE
ONES THAT ARE THE NEXT FACE AS
TO WHAT EVERYBODY IS DOING, AND
WE WANT TO MAKE SURE THESE
CONVERSATIONS ARE INCLUDING THEM
SO WE MADE A LOT OF EFFORT TO
BRING IN YOUNGER RESEARCHERS IN
HOPES OF BEING ABLE TO HAVE
THESE UNSILOED CONVERSATIONS,
THAT'S GOING TO BE A THEME.
SO OUR ANNUAL MEETING IN MAY, WE
ARE LOOKING TO BE ABLE TO
ATTRACT -- OH, IN MAY WE HAD --
I WAS LOOKING AT 8,000.
WE DID HAVE 8,000 PEOPLE AT OUR
ANNUAL MEETING, THE LARGEST
GROUPING OF CELL AND GENE
BIOLOGISTS IN THE WORLD.
BALTIMORE IS GOING TO BE COMING
UP IN 2024, GET YOUR HOTEL ROOM
NOW BECAUSE THERE'S GOING TO BE
WELL OVER 9,000 PEOPLE AT THIS
MEETING.
IT'S GOING TO BE A BIG ONE.
THESE ARE ALL IMPORTANT FACTORS,
NOT JUST COMMERCIALS.
BECAUSE WE JOINED THE BGTC IN
OCTOBER OF 2021, WE'RE VERY
HAPPY THAT WE DID.
WE LOVE THIS PARTNERSHIP.
WHAT WE DO WITHIN OUR ANNUAL
MEETING THAT ATTRACTS 9,000
PEOPLE NEXT YEAR IS THAT WE HOST
BGTC'S ANNUAL MEETING AS WELL.
ONE THING I KEPT HEARING
THROUGHOUT THIS MORNING IS YOU
NEED A VENUE, A PLACE WHERE YOU
CAN ALL COME TOGETHER AND TALK.
THAT'S WHAT ASGCT IS, A
COMMUNITY OF 55-YEAR-OLDS,
35-YEAR-OLD, DOESN'T MATTER
WHERE THEY COME FROM, THIS IS A
PLACE EVERYBODY COMES TOGETHER
TO BE ABLE TO DISCUSS GENE AND
CELL THERAPY.
YOU NEED THAT FOR YOUR UPCOMING
CONSORTIUM AS WELL.
YOU'RE GOING TO NEED IT A MEMBER
THAT'S ABLE TO HOST YOUR ANNUAL
MEETING AND IN SUCH A WAY YOU
CAN BRING THE ENTIRE COMMUNITY
TOGETHER TO HAVE THE
CONVERSATIONS THAT HAVE HAPPENED
THIS MORNING.
I DON'T KNOW IF IT'S JUST ME BUT
I FEEL THERE HAVE BEEN A NUMBER
OF CONVERSATIONS THIS MORNING
THAT YOU HAVE BEEN DYING TO
HAVE.
YOU NEED A VENUE FOR THIS TO BE
ABLE TO HAPPEN.
THIS IS MY NOTES.
I WAS GOING TO SAY THAT BUT I
HAVE THE WORD "STRONGER" AT THE
TOP TO DRILL THAT POINT HOME.
YEAH, THAT'S EVERYTHING WE DO.
THE KEY HERE, YOU NEED A VENUE.
WE LOVE WHAT WE'RE DOING WITH
THESE GUYS.
SO, WHAT I WAS SUPPOSED TO DO
WITH THIS WHOLE PIECE WAS GOING
TO OUR MEMBERS AND ASK WHAT ARE
YOUR RESPONSES, WHAT DO YOU WANT
US TO TAKE BACK?
WE GOT A FEW OF THOSE.
MY SECOND STRONGER POINT.
BUT THE FIRST ONE IS WHEN
APPLYING FOR NIH FUNDING
SUCCESSFUL PROGRAMS SEEM TO BE
HEAVILY WEIGHTED TO MECHANISTIC
HYPOTHESIS THEN DRIVEN STUDYING,
CHALLENGING FOR PEOPLE WHO WANT
TO DEVELOP NEW THERAPEUTICS TO
BE FUNDED.
THIS WASN'T JUST ONE RESPONSE.
WHEN I WANTED TO KNOW WHAT IT IS
THAT I SHOULD SAY UP HERE
REPRESENTING ASGCT I WENT TO 45
MEMBERS, 45 MEMBERS ALL SAID
SOMETHING TO THIS LINE.
IT WAS PRETTY FAR DOWN THE LINE.
THIS IS A VERY STRONG STATEMENT.
THIS IS HOW I GET THE DATA FOR
ASGCT.
I'LL STAY STRONGLY, IT DOESN'T
JUST COME FROM 27 YEARS OF BEING
A SCIENCE EDUCATOR, JUST DOESN'T
COME FROM ASGCT.
THIS IS COMING FROM HUNDREDS OF
SURVEYS, IN OUR SOCIETY OR NOT.
BETTER EDUCATIONAL PROGRAMMING
IS NEEDED AT PARTICIPANT LEVEL
SO CLINICIANS, PATIENTS, YOU CAN
READ, TO HIT ON THIS PIECE
STRONGER.
I WAS GOING TO USE THE
MICROPHONE BEFORE AS WELL.
YOU'VE BEEN SAYING WE NEED
EDUCATIONAL PROGRAM FOG
MANUFACTURING FOLKS, YOU'RE
ABSOLUTELY RIGHT.
THOSE THAT SAID WE NEED
EDUCATION PROGRAM FOR CLINICAL
FOLKS, YOU'RE ABSOLUTELY RIGHT.
THOSE THAT SAID WE NEED
EDUCATION PROGRAM BETWEEN US,
BECAUSE WE'RE SOMETIMES IN
DIFFERENT SILOS, GUESS WHAT,
YOU'RE ABSOLUTELY RIGHT.
IT DOESN'T MATTER THE
DEMOGRAPHIC.
DOES MATTER WHERE YOU ARE WITHIN
THE COMMUNITY.
THERE ARE LARGE EDUCATIONAL
POTHOLES, IF YOU WILL, THAT ARE
NOT PRESENT.
NOBODY DID IT ON PURPOSE.
THIS IS JUST MOVING SO
INCREDIBLY FAST.
BOAST CELL AND GENE THERAPIES
ARE MOVING SO INCREDIBLY QUICKLY
MOST FOLKS ARE PLAYING CATCH-UP,
AND YOU CAN'T EVEN GET CAUGHT UP
BECAUSE IT KEEPS MOVING SO
QUICKLY.
AS LONG AS EDUCATION PROGRAM,
ALONG WITH WHAT YOU'RE DOING,
DOESN'T MATTER THE DEMOGRAPHIC,
IS GOING TO BE AD HOC, WE'RE
NEVER GOING TO BE IN THE SAME
PLACE.
WHEN YOU'RE STARTING TO BE ABLE
TO LOOK AT PROGRAMS, STARTING TO
LOOK WITHIN A CONSORTIUM, BEING
ABLE TO EVEN LOOK AT A
THERAPEUTIC PRODUCTION,
EDUCATION HAS TO BE ONE OF THE
FIRST THINGS THAT YOU THINK OF.
TRYING TO DO THIS IN ARREARS IS
GOING TO CAUSE A HARSH LESSON, A
LESSON THAT GENE THERAPY IS
LEARNING QUICKLY TODAY.
IF YOU WANT MY THOUGHTS ON THAT,
WE'LL TALK LATER.
BUT NIH WILL BE IN A GREAT
POSITION TO BE ABLE TO DO THIS.
NIH'S NAME IS A TRUSTED NAME
AMONGST RESEARCHERS, CLINICIANS,
THE PUBLIC, PATIENTS, DOESN'T
MATTER WHO.
AND THIS CONSORTIUM CAN SET UP
THAT LEVEL OF PROGRAMMING TO BE
ABLE TO HELP US ALL GET ON THE
SAME PAGE, REDUCE THE SILOS,
SAME THINGS WE'VE BEEN HEARING
HERE TODAY.
ALL EDUCATION IS IS JUST
SPECIALIZED COMMUNICATION.
IT SOUNDS LIKE THAT'S WHAT THIS
CONSORTIUM CAN PROVIDE.
THANK YOU GUYS VERY MUCH.
>> NEXT SPEAKER IS MIKE DORAN.
ON DECK IS MARINA MADRID.
>> SO I DO PLAN TO ATTEND YOUR
MEETING IN BALTIMORE NEXT YEAR.
I LOOK FORWARD TO THAT.
>> [OFF MICROPHONE].
>> PROBABLY ALREADY.
I'M MIKE DORAN, I WAS AN
ACADEMIC IN AUSTRALIA,
INTERESTED IN STEM CELLS,
PRIMARILY CARTILAGE, I KNOW
SOME OF YOU IN THE AUDIENCE.
I'M A DIRECTOR OF CELL THERAPY
AT ASTRAZENECA.
I THOUGHT I WOULD COMMENT
GENERICALLY, AT ASTRAZENECA THE
WAY OF PRODUCT DEVELOPMENT
WORKS, WE HAVE R&D DEPARTMENTS
AND, FOR EXAMPLE, IN R&D
DEPARTMENT I'M PART OF WE MIGHT
BE WORKING WITH ANY NUMBER OF
CELLS, WE WILL USE QUITE OFTEN
LENTIVIRUS AS JUST THE MOST
EFFICIENT TOOL TO EXPRESS
TRANSGENE.
BUT THE BIOPROCESS DEPARTMENT IS
R&D CONCEPTS, TRANSLATED INTO
SOMETHING.
SO R&D DEPARTMENT WOULD TAKE OUR
OPTIMIZED TRANSGENE AND THEY
WOULD INSERT IT INTO THE CELL,
IF IT WERE A PLURIPOTENT CELL
USING PROBABLY A SINGLE OR
DOUBLE STRAND DNA TEMPLATE AND
CRISPR, RIGHT?
SO ALL I'M SAYING IS THAT WE
DON'T HAVE TO ASSIGN THIS, YOU
DON'T HAVE TO DO EVERYTHING,
BECAUSE YOU HAVE DIFFERENT
DEPARTMENTS THAT ARE PROBABLY
GOING TO PICK UP THE CLINICAL
TRANSLATION STEPS, AND MAKE SURE
THAT IT'S ALL DONE IN THE SAFEST
MANNER THAT MEETS ALL THE
REGULATORY REQUIREMENTS.
SO WHEN I THOUGHT WHAT CAN I SAY
HERE THAT I'M ALLOWED TO SAY,
I'LL SAY SOMETHING UNIQUE.
I HOPE IT'S UNIQUE.
I THOUGHT, MAYBE THE FIELD OF
REGENERATIVE MEDICINE IS BETTER
OFF INTERVENING EARLY.
MAYBE WE SHOULDN'T BE THINKING
OF LAST RESORT CELL REPLACEMENT
THERAPIES.
MAYBE WE SHOULD BE THINKING
ABOUT LONGEVITY.
AND MAYBE THE FUTURE OF
REGENERATIVE MEDICINE IS
COUPLING WITH THE ANTI-AGING
GURUS AND PHARMACEUTICAL
EXPERTS.
AND SO THE WAY I TRY RATIONALIZE
THIS, YOU REMEMBER GRADE SCHOOL
MATH.
YOUR TEACHER WOULD EXPLAIN TO
YOU A MILLION TIMES ZERO IS
ZERO.
BUT, YOU KNOW, 100 TIMES A
MILLION IS 100 MILLION.
SO IF WE WAIT TILL TISSUE IS SO
DEGRADED THERE'S ZERO
REGENERATIVE CAPABILITY, A
MILLION TIMES ZERO IS ZERO.
IF WE START INTERVENING EARLY,
WELL, THEN, A MILLION TIMES
WHATEVER IS LEFT COULD BE QUITE
MEANINGFUL.
I THINK THAT'S THE FIRST THING.
I THINK WE NEED TO INTERVENE
EARLY, AND MAYBE STOP THINKING
ABOUT JUST CELL REPLACEMENT AS
AN END STAGE STRATEGY.
THE SECOND POINT I WANTED TO TO
MAKE MAYBE WE SHOULD THINK ABOUT
SYNTHETIC CELLS, MAYBE SOMETHING
THE NIH CAN SUPPORT.
THERE WAS DISCUSSION ABOUT WHAT
IS THE IDEAL PHENOTYPE.
WELL, MAYBE THE IDEAL PHENOTYPE
IS NOT AN MSC, NOT A MACROPHAGE,
MAYBE IT'S SOMETHING ELSE
ALTOGETHER.
IN THE MSC FIELD, I THINK OUR
COLLEAGUE HERE FROM ONE OF THE
CELL THERAPY DEPARTMENTS
MENTIONED HOW MANY FAILED
STUDIES THERE WERE.
THERE'S THOUSANDS, RIGHT?
AND I HAVE A COLLEAGUE AT
ASTRAZENECA WHO HAS DONE
INTERESTING WORK, HE SHOWS WHEN
MSCs ARE INFUSED INTRAVENOUSLY
MOST GO THROUGH APOPTOSIS RIGHT
AWAY.
IN FACT, APOPTOSIS, BY THE
MACROPHAGES, PROBABLY ELICITING
THE IMMUNE DAMPENING RESPONSE,
INTERESTING BUT PROBABLY NOT
IDEAL.
THAT'S PROBABLY NOT WHAT YOU
WANTED.
SO INSTEAD I THINK THE IDEA THAT
THOUSANDS OF STUDIES AND
THOUSANDS OF INVESTIGATORS HAD
THAT WE WANT TO USE SIGNALS TO
UPREGULATE INTRINSIC REPAIR
PROCESS, I THINK THAT WAS ALL
RIGHT.
BUT I THINK INSTEAD OF USING AN
MSC WE SHOULD ACTUALLY
COMPLETELY SYNTHETICALLY
ENGINEER THE CELL TO SECRETE
WHAT WE WANT AND NOW WHEN THE
IMMUNE CELL THERAPY CAME GEAR AT
MAKING SURE CELLS GO WHERE WE
WANT.
SO WE SHOULD ENGINEER CELLS TO
GO WHETHER WE WANT AND SECRETE
WHAT WE WANT.
WE SHOULD DO IT EARLIER.
SO THAT'S BASICALLY MY MESSAGE
TODAY.
AND I THOUGHT, YOU KNOW, MAYBE
WE CAN MAKE MORE MONEY IF WE
ENTER THE ANTI-AGING GAME, SO I
THOUGHT I WOULD PUT THAT IN
THERE.
OKAY, THANKS, GUYS.
>> THANK YOU VERY MUCH.
UP NEXT WE HAVE MARINNA MADRID.
>> THANK YOU.
CO-FOUNDER AND CHIEF PRODUCT
OFFICER AT CELLINO.
I WAS EXCITED TO TALK ABOUT
AUTOLOGOUS THERAPY, WE'RE
BUILDING A BIOMANUFACTURING
PLATFORM TO SCALE PRODUCTION OF
AUTOLOGOUS iPSCs.
AND A QUICK NOTE ON AN EXAMPLE
OF CELL THERAPY THAT I THINK
SHOWS WHY MANUFACTURING
INNOVATION IS IMPORTANT, THE CAR
T SPACE.
WE SAW LIKE REMARKABLE CLINICAL
EFFICACY, CANCERS CURED.
WE'RE BASED IN BOSTON.
IF YOU GO TO A TOP HOSPITAL IN
BOSTON TODAY, OF THE TEN
PATIENTS THAT NEED A LIFE-SAVING
CAR T THERAPY, ABOUT TWO ARE AGE
TO GET ACCESS TO IT BECAUSE OF
MANUFACTURING BOTTLENECKS.
AND SO WE DON'T WANT THAT SCALE
CHALLENGE TO HAPPEN IN THE PSC
SPACE.
AND SO MANY OF YOU ARE AWARE OF
THE CHALLENGES WITH iPSC
MANUFACTURING, IT'S VERY MANUAL
LABOR INTENSIVE PROCESS,
DEPENDENT ON EXTREMELY SKILLED
OPERATORS.
WHAT WE'RE DOING IS AUTOMATING
THE PROCESS BY TAKING OPTICAL
APPROACH.
IF YOU CAN IMAGINE THESE CELL
CULTURE PROCESSES, ADHERENT CELL
CULTURE SERVICE, WE IMAGE THE
CELLS REGULARLY, WE DEVELOP OUR
OTHER THAN IMAGE-GUIDED MACHINE
ALGORITHMS THAT CHARACTERIZE
CELLS AND USE A LASER TO
ESSENTIALLY REMOVE UNWANTED
CELLS, MAYBE TO REMOVE ALL BUT
ONE COLONY TO RESULT IN A MORE
PURE POPULATION BUT IMAGE-GUIDED
MACHINE LEARNING IS USED TO MAKE
BETTER IN-PROCESS DECISIONS SUCH
AS WHAT CELLS TO REMOVE.
WE'RE TAKING A
MULTI-DISCIPLINARY APPROACH.
OUR TEAM IS MULTI-DISCIPLINARY,
MY BACKGROUND, Ph.D. IN
APPLIED PHYSICS, THIS SHOWS OUR
LAB FACILITY, TWO AUTOMATED WORK
CELLS, HEPA FILTERED ENCLOSURE,
BSL2 LAB.
WE HAVE WELL PLATES, ROBOTIC ARM
THAT MOVES FROM SUBSYSTEM TO
SUBSYSTEM, AUTOMATED INCUBATION,
IMAGING, LASER SCANNING, WHAT
WE'RE USING AUTOMATED WORK CELLS
TO DO IS DEVELOP AUTOMATED
REPROGRAMMING PROCESSES, SO WE
DEVELOPED FIRST AUTOMATED PSC
GENERATION PROCESS USING CD34
POSITIVE CELLS, TAKING LARGE
VOLUMES OF IMAGING TRAINING DATA
TO DEVELOP MACHINE LEARNING
ALGORITHMS.
WE HAVE A GRAPHICAL USER
INTERFACE, STEM CELL SCIENTISTS
USE TO INTERACT WITH IMAGES THAT
HAVE BEEN TAKEN AND THEY CAN
ALSO MAKE IN-PROCESS DECISIONS
IF NEEDED.
IT DOESN'T NEED TO BE A FULLY
AUTONOMOUS PROCESS, STEM CELL
SCIENTISTS CAN INTERACT.
THIS IS KATHERINE, A SCIENTIST
LOOKING AT COLONIES THAT HAVE
BEEN IDENTIFIED.
WE HAVE A DASHBOARD.
HUMANS ARE NOT ALLOWED INTO THE
HEPA FILTERED ENCLOSE YOU'RE, WE
HAVE A DASHBOARD THAT TELLS WHAT
EXPERIMENTS ARE HAPPENING THAT
DAY.
I WANTED TO GIVE A SENSE OF WHAT
IT LOOK LIKE.
ON THE LEFT THE AUTOMATED WORK
CELL, IN A BSL2 SETTING, OPEN
WELL PLATE FORMAT FOR R&D
DEVELOPMENT.
WHAT'S NICE ABOUT THE OPTICAL
APPROACH, IMAGE-GUIDED MACHINE
LEARNING AND LASER-BASED REMOVAL
OF CELLS, BOTH PROCESS ARE
COMPATIBLE WITH CLOSED
MANUFACTURING IN A WAY THAT
MANUAL SCRAPING JUST IS NOT.
SO WHAT WE'RE DOING IN PARALLEL
TO RUNNING THE AUTOMATED R&D
WORK CELL, WE'RE BUILDING A
CLINICAL-GRADE GMP MANUFACTURING
SYSTEM, GMP COMPLIANT, BASED ON
CLOSED CASSETTES.
SO USES THE SAME IMAGE GUIDED
MACHINE LEARNING, SAME LASER
PROCESSING BUT THE WAY FLUIDICS
ARE INTRODUCED TO CELLS ARE
DIFFERENT IN A CLOSED CONTAINER.
SO THIS IS SORT OF WORKFLOW ON
THE IMAGE-GUIDED MACHINE
LEARNING SIDE.
EXAMPLE OF WHAT YOU MIGHT DO IS
TAKE A BRIGHT FIELD IMAGE OF
CELLS.
WE HAVE ALGORITHMS THAT CAN
AUTOMATICALLY DETECT CONFLUENCE,
PREDICT EXPRESSION OF PLEURY
POTENCY MARKERS, A WAY OF
IDENTIFYING IF THEY ARE
DIFFERENTIATING, GET A MAYBE OF
LOCAL DENSITY, GENERATE LASER
SCANNING MAPS, MIGHT SEE
DIFFERENTIALING CELLS, LET'S
REMOVE THOSE, THIS AREA IS
BECOMING OVERLY DENSE, LET'S
LASER REMOVE AND THIN IT OUT.
THIS IS A COMPLICATED ONE TO
EXPLAIN.
TAKE A STEP BACK.
TO ENABLE THIS CLOSED
MANUFACTURING, WE HAD TO DEVELOP
A PASSAGE-FREE PROCESS.
YOU NEED TO ALLOW CERTAIN NUMBER
OF CELL DIVISIONS FOR VECTOR TO
CLEAR, NORMALLY MOVING ONE TO
ANOTHER.
BUT WE HAVE A CLOSED SYSTEM AND
CAN'T MOVE CELLS FROM ONE WELL
TO ANOTHER.
THEY HAVE TO STAY IN THE SAME
SURFACE AREA.
WE DEVELOPED A PASSAGE-FREE
PROCESS.
AS COLONIES GROW BIGGER WE LASER
REMOVE -- BLUE IS LASER REMOVE,
REMOVE A PIECE OF THE COLONY SO
REMAINING CELLS WITH GROW AND
DIVIDE, OVER AND OVER AGAIN,
UNTIL THE CELLS HAVE GONE
THROUGH ENOUGH DIVISIONS TO
CLEAR THE REPROGRAMMING VECTOR.
SO ONE REASON WE DO THIS IS
ENABLE CLOSED MANUFACTURING.
THE OTHER HYPOTHESIS IF WE TAKE
ENOUGH TIME-BASED SERIES DATA
THROUGH THE 60-DAY REPROGRAMMING
PROCESS WE WILL BE ABLE TO -- WE
AIM TO BE ABLE TO CONNECT ON
IMAGE-BASED DATA TO MEASUREMENTS
OF QUALITY AT THE END.
FOR EXAMPLE, BY SAYING, OH, THIS
COLONY HAS A GROWTH AND
PROLIFERATION THAT'S ABNORMAL
AND THEREFORE MORE LIKELY TO
KEROTYPICALLY DIFFERENT.
EVERYTHING IS DOING SOMETHING
SLIGHTLY DIFFERENT ON GENOMIC
STABILITY BUT THE REASON I MAKE
THIS POINT IS WE'RE USING
IMAGE-GUIDED MACHINE LEARNING TO
MAKE IN-PROCESS DECISION, NOT TO
REPLACE END STAGE RELEASE
TESTING.
I WOULD LOVE TO SEE THE INDUSTRY
MOVE THAT DIRECTION, BUT THAT
WILL TAKE MORE DATA.
AND THESE ARE PROTOTYPES OF THE
FLUIDIC CASSETTES FOR CLOSED
SYSTEM.
I'M GOING TO SKIP TO THE
QUESTIONS THAT WOULD BE
INTERESTING FOR POTENTIAL
RESEARCH AREAS.
ONE IS ESTABLISHING SET OF
STANDARD IDESSED QUALITY
SPECIFIC CASES AT THE iPSC
STAGE.
RIGHT NOW IF YOU START A
CLINICAL TRIAL, YOU START WITH A
CERTAIN STARTING MATERIAL OR
CERTAIN REPROGRAMMING VECTOR,
YOU WANT TO MOVE TO A NEW
STARTING MATERIAL OR NEW
REPROGRAMMING VECTOR FOR THE
NEXT PHASE THAT WOULD BE --
WOULD TRIGGER DEFINITION OF NEW
PRODUCT REQUIRING NEW IND.
IF WE COULD AGREE ON STANDARDS,
THAT COULD BE THE BASIS FOR
ENABLING INTERCHANGEABILITY
WHICH WOULD RESULT IN MORE COST
EFFECTIVE, MORE TIMELY DRUG
DEVELOPMENT.
RELATED TO THAT ON THE GENOMIC
STABILITY SIDE, DIFFERENT
POPULATIONS OF PATIENTS CAN
ACCEPT DIFFERENT LEVELS OF RISK,
BUT I THINK IT WOULD BE AMAZING
TO DO A MASSIVE META-ANALYSIS
BASED ON LITERATURE SEARCHES, IN
VITRO AND IN VIVO EXPERIMENTS TO
SAY HERE IS THE LIST OF
ONCOGENES, IF YOU HAVE THIS
MUTATION AND THAT ONCOGENE THIS
IS THE ASSESSMENT OF RISK
BECAUSE RIGHT NOW DIFFERENT
DEVELOPERS ARE MAKING THESE
JUDGMENTS BASED ON THEIR OWN
LITERATURE SEARCHES, IT WOULD BE
NICE TO HAVE A CONSENSUS FOR THE
FIELD.
ANOTHER WHY THE WHAT DATA WOULD
WE NEED TO ESTABLISH A SAFE
OPERATING SPACE FOR A.I.-BASED
OPERATING PROCESSES MOTIVATED BY
MEDICAL DEVICE FIELD.
CELL THERAPY MORE LIKE DEVICES
THAN SMALL MOL MOLECULES.
THEY ARE MUCH MORE COMPLEX AND
IN THE MEDICAL DEVICE SPACE
MEDICAL DEVICES ARE NOT STATIC.
MEDICAL DEVICE COMPANIES WILL
UPDATE THEIR ALGORITHMS AND BE
ABLE TO BASICALLY MAKE MEDICAL
DEVICES BETTER, IT DOESN'T
REQUIRE THEM TO DO AN ENTIRELY
NEW CLINICAL TRIAL BECAUSE UP
FRONT THEY HAVE ESTABLISHED A
SAFE OPERATING SPACE WHERE THEY
SAY IF WE ARE WITHIN THAT SAFE
OPERATING SPACE WE CAN CONTINUE
TO MAKE IMPROVEMENTS TO THIS
PROCESS AND THAT IS STILL
ACCEPTABLE.
SO I THINK THAT THINKING ABOUT
SAFE OPERATING SPACE WITHIN THE
CONTEXT OF CELL THERAPY
MANUFACTURING WOULD BE
BENEFICIAL.
THE LAST THING I HAVE HERE, OH,
POINT NUMBER 2 WHICH I SKIPPED
OVER, COULD HOW CAN CAN WE
REPLACE END STAGE PROCESSING,
REQUIRING ADVANCEMENTS IN
MACHINE LEARNING BUT GET
THERAPIES TO PATIENTS IN A
TIMELY MANNER AND COST EFFECTIVE
MANNER
WHAT IT WILL REQUIRE IS
ESSENTIALLY CORRELATED IN
PROCESS ANALYTICS SUCH AS
MACHINE LEARNING WITH END STAGE
TESTING SUCH AS KERYO TYPING.
THAT WAS EVERYTHING.
THANK YOU.
ON DECK RICH McFARLAND.
>> I WAS ASKED TO GIVE A NEEDS
FOR INTEGRATED NIH/FEDERAL
APPROACH TO REGENERATIVE
MEDICINE, I'M CHIEF OPERATING
OFFICER ON THE ARMI, I'M AT A
HALFWAY HOUSE FROM BEING AT FDA,
I'M GOING TO TRY TO MIX THOSE
TWO EXPERIENCES AND TELL YOU
WHAT I THINK.
I USED THIS TO REMIND MYSELF
THAT CELLS AND TISSUES ARE
COMPLICATED.
A COUPLE ORDER OF MAGNITUDES
MORE COMPLICATED THAN GENE
THERAPY.
I CAN'T BELIEVE I'M SAYING THIS,
SIMPLE GENE THERAPY.
IT ISN'T SIMPLE BUT IT'S SIMPLE
COMPARED TO THE TALKS THIS
MORNING ABOUT HOW DO YOU CONTROL
CELLS.
SOMETHING WE'VE BEEN WORRIED
ABOUT FOR A LONG TIME.
A GROUP GOING ON FOR 2 1/2
DECADES OR SO, FOLKS ACROSS THE
FEDERAL GOVERNMENT, THIS IS A
STRATEGIC PLAN THAT GOT
PUBLISHED IN 2007, THOSE FOLKS
WITH ME IN THAT GROUP KNOW THAT
IT TOOK A WHILE TO GET THERE.
BUT THE ROAD MAP SPURRED FUNDING
FORMING THE ARMED FORCES
INSTITUTE OF REGENERATIVE
MEDICINE, SUPPORTED NSF, ERCs,
SUCH AS C MAT, NINE YEARS AFTER
PUBLISHED SPURRED BIOFAB USA AND
NINBL, RELATED TO BIOTECHNOLOGY
AND REGENERATIVE MEDICINE, IT'S
CALLED TISSUE SCIENCE AND
ENGINEERING BECAUSE REGENERATIVE
MEDICINE DIDN'T EXIST WHEN THE
GROUP STARTED MEETING.
IT'S BEEN A FORMAL ORGANIZATION,
SHARING INFORMATION FOR 2 1/2
DECADES.
YOU SEE ALL THE AGENCIES THAT
HAVE BEEN LISTED AT THE TIME OF
THE PUBLICATION OF THE 2007
PLAN.
SO, THE BESPOKE GENE THERAPY
CONSORTIUM IS NOT COMPLICATED,
IT'S ALSO NOT SIMPLE.
I THINK I WILL SAY THIS IS A
GREAT EFFORT IN TERMS OF BOTH
PUBLIC AND PRIVATE PARTNERSHIP,
AND ARROWS BACK AND FORTH
BETWEEN THE TWO AIMS.
ESSENTIAL FOR AN EFFORT TO GET
WITH CELL THERAPY ISSUE.
THE EXECUTIVE ORDER CAME OUT IN
22, THIS REPORT ON BOLD GOALS
THAT CAME OUT IN 23.
AND YOU LOOK AT JUST COUPLE
HIGHLIGHTS FOR THE REGENERATIVE
MEDICINE SECTION, REGULATORY
PROCESS INCREASING CLARITY, AND
INCREASING EFFICIENCY, WE TALK
ABOUT THAT ALL THE TIME, WITH
FDA IT'S AN IMPORTANT DISCUSSION
TO HAVE WITH FDA.
THE THING THAT CAUGHT ME WHEN I
READ THIS WAS INCREASE THE
MANUFACTURING SCALE OF
CELL-BASED THERAPIES TEN FOLD
OVER 20 YEARS.
10-FOLD OVER 20 YEARS, THAT IS A
BOLD GOAL.
AND I THINK DOING WHAT WE'VE
BEEN DOING IN THE PAST, BREAKING
DOWN THE SILOS IS NEEDED TO GET
THERE.
THIS IS OFTEN SHOWN WITH RESPECT
TO INDIVIDUAL PRODUCTS AND
SO-CALLED VALLEY OF DEATH
BETWEEN THE INVESTIGATORS,
DISCOVERY SCIENCE, FUNDING, AND
INDUSTRY FUNDING.
IN REGENERATIVE MEDICINE PART OF
OUR GOAL IS TO START THE ENTIRE
INDUSTRY IF WE'RE GOING TO GET
CLOSE TO THE GOAL OF THE
BIOECONOMY.
GROWING THE WHOLE INDUSTRY IS
GREATER CHALLENGE THAN GROWING
INDIVIDUAL COMPANIES.
WE'VE TALKED ABOUT A LOT OF THE
CHALLENGES HERE, THEY RESONATE
WITH ME.
GAO DID A TECH ASSESSMENT LAST
YEAR, EARLIER THIS YEAR,
FINISHED UP NOTED CHALLENGES
RELATED TO STANDARD IDEATION,
RELATED TO STANDERIZATION AND
MANUFACTURING.
WHERE DOES THIS GET ME FOR
NEEDS?
CELL-BASED THERAPIES CONSORTIUM
SHOULD INCLUDE THE MATES
AGENCIES, THAT'S GOVERNMENT
ONLY.
MANY OF THE PUBLIC AND PRIVATE
PARTNERS IN THE BCTG, TC.
SHOULD LOOK AT THAT ASSESSMENT.
ADDITIONAL PARTICIPANTS,
DEPARTMENT OF LABOR AND
DEPARTMENT OF EDUCATION THAT HAS
COME UP ABOUT LEAVING WORKFORCE
FOR MANUFACTURING.
THOSE AGENCIES HAVE PRETTY MUCH
NOT BEEN VERY INVOLVED.
I SHOULD ALSO MENTION DEPARTMENT
OF COMMERCE IN HERE.
AND MOVING THIS FORWARD.
OTHERWISE IT BECOMES AN
INTERESTING IMPORTANT SCIENCE
PROJECT BUT DOESN'T BECOME AN
INDUSTRY.
I ALREADY MENTIONED TRUE TRIALS
AS A WAY TO FILL A GAP.
HELPING DEVELOP AND IMPLEMENT
STANDARDS AND I WILL SAY I
MENTIONED THOSE TWO SMALL
ORGANIZATIONS IN PARTICULAR
BECAUSE THEY ARE EXAMPLES OF FDA
IN THE WAY THAT FDA CAN WORK
WITH GROUPS TO MOVE THINGS
FORWARD.
AND I THINK AT THE ISSCR
PRESENTATION THERE WAS A SCREEN
SHOT OF THE STANDARDS DOCUMENT
FDA JUST JUST CAME OUT OF.
I DIDN'T MENTION ASCR.
IN TERMS OF SCIENCE AND
PATIENTS, ONE OF THESE I
MENTIONED IN THE GENE THERAPY
CONSORTIUM IS THERE ARE PATIENT
GROUPS THERE.
THERE'S THE ORPHAN DISEASES
THERE, IDENTIFYING PATIENTS
NEEDS, KNOWING WHERE WE'RE GOING
TO GO IS REALLY IMPORTANT.
THOSE WHO SLIDES OF THE SILOS
THERE, FAIRLY BIG SILOS AND
STRONG, SITTING IN THE MIDDLE OF
SOUTH DAKOTA HIGH PLAINS.
THERE ARE A LITTLE BIT OF
CONNECTIONS BETWEEN IT.
THAT'S WHAT HAPPENS HISTORICALLY
WHEN YOU COME UP WITH BIG
INITIATIVES.
THE LOWER PICTURE IS A TYPICAL
PICTURE OF NEW HAMPSHIRE, IF YOU
EVER WANT TO COME IN THE FALL.
THERE'S A PATH THROUGH, LOTS OF
TREES.
WHAT ISN'T OBVIOUS FROM THE
PICTURE IS THE COMMUNICATION
BETWEEN THE TREES, WHICH HAPPENS
IN FUNGI AT THE ROOT LEVEL IN
THE RHISOMES, A LOT HOW MATES
HAS WORKED OVER THE YEARS.
A SITUATION WHERE IT DOESN'T GET
TOP-DOWN.
IT GETS ACROSS.
WE TALKED ABOUT SILOS IN THE
COMMUNITY WRIT LARGE,
CREATING -- GETTING
CROSS-TRAINING.
THAT'S A REALLY HARD THING TO
DEVELOP BUT IT'S VERY POWERFUL.
AND I THINK THAT'S WHERE WE NEED
TO GO AND TO ENCOURAGE THAT KIND
OF CROSS-FERTILIZATION, AND GET
IDEAS WHEN THE CELL-BASED
THERAPY GETS HERE.
THANKS.
>> THANK YOU VERY MUCH.
LAST SPEAKER FOR THIS SESSION
WILL BE JOSEPHINE LEMBONG.
>> GOOD AFTERNOON, I'M SENIOR
MANAGER OF SCIENCE AND INDUSTRY
AFFAIRS AT ARM, NOT TO BE
CONCLUSIONED WITH ARMI, ALLIANCE
FOR REGENERATIVE MEDICINE.
WE'RE AN ADVOCACY GROUP,
SPECIFICALLY ADVOCATING FOR THE
ADVANCEMENT OF CELL AND GENE
THERAPIES.
WE'LL HAVE OVER 350 MEMBER
COMPANIES GLOBALLY, THAT ARE
COMPRISED OF DEVELOPERS, PATIENT
ADVOCACY GROUPS.
I'LL SAY LIKE MANY OF YOU IN THE
ROOM WE'VE BEEN THINKING ABOUT
PLATFORM APPROACHES A LOT.
SO PLATFORM AS IN LEVERAGING
DATA OR KNOWLEDGE OUT THERE TO
BE ABLE TO EXPEDITE DEVELOPMENT
PROGRAMS WITHIN DEVELOPER OR
ACROSS DEVELOPERS.
YOU'LL SEE IN THE TITLE, I USE
THE TERM BUILDING BLOCKS INSTEAD
OF PLATFORMS, A TECHNICAL TERM I
REALIZE BUT FOR A REASON I'LL
SHOW IN A COUPLE SLIDES.
SO, WE JUST FINISHED A MEETING
LAST WEEK WHICH WE CALL
SCIENTIFIC EXCHANGE.
THIS IS A NEW FORMAT OF
INTERACTION THAT WE CONVENE
AMONG OUR DEVELOPERS, MEMBERSHIP
AND FDA.
AND THE TOPIC OF THAT
INTERACTION THIS YEAR IS
UNLOCKING THE POTENTIAL OF
BUILDING BLOCKS TO EXPEDITE GENE
THERAPY DEVELOPMENT AND REVIEW.
YOU SHOULD ALWAYS START WITH
DEFINITIONS, BUILDING BLOCK IS
COMPONENT OF DEVELOPMENT PROGRAM
THAT CAN BE REUSED IN OTHER
PROGRAMS, EITHER BY THE ORIGINAL
DEVELOPER OR POTENTIALLY BY
OTHER DEVELOPERS AND STREAMLINE
NECESSARY EFFORTS TO VALIDATE
THE COMPONENT.
THE OBJECTIVE OF THE BUILDING
BLOCK TO IMPROVE TIME AND
RESOURCE SUFFICIENCY OF
DEVELOPMENT AND REGULATORY
REVIEW BY LEVERAGING ACROSS
PROGRAMS, ALSO TO MAKE VIABLE
PURSUIT OF ADDITIONAL RARE
DISEASE TARGETS.
SO WE ACKNOWLEDGE THAT BUILDING
BLOCKS CAN TAKE MULTIPLE FORMS,
SO IF YOU LOOK IN THE BOTTOM
LEFT, THE FIRST BULLET POINT IS
THE DESIGNATED TECHNOLOGY
PLATFORM, SO THERE'S A REASON
AMONG ITS PROVISIONS CALLS THE
FDA TO DESIGNATE PLATFORM
TECHNOLOGIES, AND THESE
PLATFORMS ARE ESSENTIALLY
ELEMENTS OF A DEVELOPMENT AGAIN
THAT CAN BE LEVERAGED ACROSS
DEVELOPERS, MUST BE ATTACHED TO
A BLA.
I THINK THE FDA IS SCHEDULED
TO -- HAS TO PUBLISH GUIDANCE
FOR THE YEAR, IT WILL BE
INTERESTING TO SEE WHAT KIND OF
THE RESTRICTIONS AROUND THIS
DESIGNATION PLATFORM IS.
THERE'S ALSO ALWAYS PRIOR
KNOWLEDGE.
WITHIN A DEVELOPER, A MECHANISM
A DEVELOPER CAN LEVERAGE RIGHT
NOW DURING THEIR INTERACTION
WITH THE FDA, ACROSS THEIR
INTERNAL PROGRAMS.
I ALSO MENTION MASTER FILES AS
POTENTIAL PLATFORM.
WE TALKED ABOUT CELL BANKS, A
COMMON PLATFORM DEVELOPERS HAVE
BEEN SUCCESSFULLY USING WITHIN
THEIR PROGRAMS.
SO, THESE ARE JUST TOOLS.
WE DON'T WANT TO LIMIT -- IT'S
WHY WE USE THE TERM BUILDING
BLOCKS, THE PLATFORM AS LANGUAGE
IS LIMITED TO USE OF ELEMENT OF
TECHNOLOGY ATTACHED TO BLA,
ORIGINAL DEVELOPER.
SO THIS MEETING WE HELD ON
NOVEMBER 1, JUST LAST WEEK,
YOU'RE THE FIRST GROUP TO HEAR
THE OUTCOME OF THIS MEETING, WE
PRESENTED CASE STUDIES AROUND
KEY TECHNOLOGY AREAS, ANY OF
THESE iPSCs AS WELL AS LNP,
REPRESENTATIVES FROM THE FDA
FROM THE DIFFERENT BRANCHES, AND
IT'S REALLY JUST TO DISCUSS THE
PRINCIPLES AROUND THE SELECTION,
WHAT COULD BE LEVERAGED AS A
PLATFORM IN A PROGRAM AND HOW DO
YOU IMPLEMENT THAT PLATFORM IN
YOUR INTERNAL PROGRAM OR OTHER
DEVELOPMENT PROGRAMS.
AND THE OBJECTIVE IS NOT REALLY
TO, YOU KNOW, SAY YES OR NO TO
WHAT IS A VIABLE PLATFORM
BETWEEN THE OPTIONS THAT ARE
PRESENTED BY DEVELOPERS, BUT
REALLY TO IDENTIFY THE PATH TO
FURTHER REFINE THE MOST
PROMISING BUILDING BLOCKS
PROVIDED BY THE DEVELOPER AND
SHED A LIGHT HOW THEY CAN BE
DEVELOPED, VALIDATED, DEPLOYED.
SOMEONE INTRODUCED THE FRAMEWORK
OF THE MEETING, WE WANT TO
PRESENT WHAT IS THE BUILDING
BLOCK, A CELL BANK, A TEST, IS
IT A PROCESS?
HOW IS IT CHARACTERIZED?
WHAT IS THE RIGHT
CHARACTERIZATION TO BE ABLE
TO -- FOR IT TO BE IMPLEMENTED?
WHO CAN REFERENCE AND WHAT
BASIS, AS WELL AS WHAT RESOURCE
SAVINGS DOES IT BRING TO THE
ORIGINAL DEVELOPER OR LICENSING?
THIS IS MAYBE A BIT OF A BUSY
SLIDE BUT IF YOU LOOK AT THE
BOTTOM THERE'S DESIGNATED
TECHNOLOGY PLATFORM AND WE LOOK
AT THE COLUMNS, WHO DEVELOPS IT,
WHAT IS NEEDED FOR IT TO BE
USED, AND WHAT IS THE VEHICLE OF
DISSEMINATION IN THE FIELD.
TECHNOLOGY PLATFORM IS NARROW,
WHY WE DIDN'T WANT TO FOCUS AT
THE MEETING ITSELF.
IT'S DEVELOPED BY THE MEDICINE
SPONSOR AND HAS TO BE TIED A BLA
SO IT'S TIED TO AN APPROVED DRUG
AND IT'S AN OFFICIAL STAND FROM
THE FDA, FDA-DESIGNATED
PLATFORM.
IT CAN BE USED FOR DEVELOPER
ITSELF OR OTHER DEVELOPER
LICENSING THE TECHNOLOGY.
PRIOR KNOWLEDGE IS A BROADER
BOX.
AS WE GET TO BROADER PROCESS
WE'RE TALKING ABOUT SECTOR-WIDE
EFFORTS, COALITIONS, CONSORTIUM
WHICH EVERYONE IS INTERESTED IN
AND WHAT CAN THAT DISSEMINATION
LOOK LIKE, WHO IS LEVERAGE AND
BENEFIT FROM THERE.
SO I THINK, AGAIN, WE REALIZE
THE BUILDING BLOCK CAN COME IN
MANY FORMS.
WE MUST BE NIMBLE IN HOW THIS
TOPIC IS EXPLORED.
IT CAN BE A SLATE OF TESTS TO
CHARACTERIZE A PRODUCT, SERIES
OF QAs ATTACHED TO A DRUG, CAN
BE A MANUFACTURING PROCESS
THAT'S PRESENTED BY SOME
DEVELOPERS, AND I THINK WE HAVE
KNOWLEDGE THAT SOME OF THESE
BUILDING BLOCKS WITH EASIER TO
DEPLOY AND BUILD BY A SINGLE
DEVELOPER VERSUS A COMPETITIVE
EFFORT, DIFFICULT TO ADVANCE
ACROSS DEVELOPERS, CAN BE LINKED
TO A COMPANY'S MANUFACTURING
PROCESS, PROPRIETARY AND
LIMITING BENEFITS.
I WANT TO PRESENT FOUR KEY
THEMES THAT EMERGED FROM THE
MEETING, WHAT A VIABLE BUILDING
BLOCK CAN LOOK LIKE.
CELL BANKS WITH A SET OF TESTS
AND SPECIFICATIONS, CELL BANKS
TESTING THAT INCLUDES GENOMIC
STABILITY AND INNOVATION OVER
TIME.
WHAT IS LEVEL OF GENETIC
IDENTITY FOR COMMERCIAL PRODUCTS
BROUGHT TO THE INDUSTRY?
AND, YOU KNOW, THE TEAM IN THAT
ROOM DURING THAT MEETING HAS
EXPRESSED INTEREST IN
ESTABLISHING AN INDUSTRY
CONSENSUS, WHAT THE PROPER
CHARACTERIZATION OF AN iPSC
CELL BANK IS.
THERE ARE LIMITATIONS ON
VARIABILITY OF CELLULAR MATERIAL
AND IF IT IS EDITED WE MUST PICK
THE BEST CLONE TO ELIMINATE
VARIANCE YEAH BIT AND WHAT IS
THE -- VARIABILITY.
THE CHANNEL OR LIMITATION WE
NEED AN IN VIVO/IN VITRO
CORRELATION ACROSS MULTIPLE
PRODUCTS UNDERSTANDING
TRANSLATABILITY AND VALIDATION
OF METHODS AND NEED FOR
REFERENCE STANDARDS.
THERE'S A LOT OF DISCUSSION
AROUND PLATFORM PROCESS, COULD
BE RELATED TO A SINGLE UNIT, AND
CHARACTERIZATION THAT IS NEEDED
IS THE ASSOCIATED CPPs,
OPERATING RANGES, EXPECTED
OUTPUT, CRITICAL QUALITY
ATTRIBUTES FOR CELLULAR
THERAPIES, BROUGHT UP MANY
TIMES.
ONE OPERATION TO THE OTHER, ONE
SERIES OF UNIT OPERATIONS,
CALLED THE PLATFORM, TO ANOTHER
PROCESS IS VERY CRITICAL.
AND THE LAST BUT NOT LEAST, GENE
EDITING PLATFORM IS BROUGHT UP
AS A POTENTIAL VIABLE BUILDING
BLOCK AS WELL.
SO THE LNP AND MANUFACTURING
PLATFORM WITH SWAPPABLE GUIDE
RNA.
AND UNDERSTANDING AGAIN THE
LIMITATIONS, UNDERSTANDING
OFF-TARGET EFFECTS FROM PRODUCT
TO PRODUCT IS CRITICAL.
ONE WAY TO MAKE A VIABLE
DEVELOPMENT FOR SMALLER
POPULATION TO HAVE A COMMON
SUPPLY OF CLINICAL TRIAL
REAGENTS PRODUCT AGNOSTIC
STREAMLINED ONCE THE INITIAL
QUALIFICATION WAS DONE.
I'M STANDING BETWEEN YOU AND
LUNCH, I'LL END THERE.
HAPPY TO STICK AROUND FOR
QUESTIONS.
THANK YOU.
>> ALL RIGHT.
THANK YOU VERY MUCH.
WITH THAT, WE'RE GOING TO CLOSE
THIS SESSION.
UNFORTUNATELY WE DON'T HAVE TIME
FOR DISCUSSION THIS SESSION BUT
I THINK THOSE WERE ALL GREAT
THANKS.
THANKS FOR SHARING YOUR IDEAS.
WE CAN INCORPORATE THOSE INTO
THE REST OF OUR DISCUSSIONS AS WE CONTINUE THIS MEETING.
IT'S TIME TO GET BACK TO WORK
WITH THE WORKING LUNCH.
WE'RE NOT GOING TO DO AN
INTRODUCTION BUT REALLY THANK
YOU FOR JOINING US.
THIS REQUEST GOT PASSED DOWN
SEVERAL TIMES.
SCOTT STEELE WAS INVOLVED IN
HELPING PLAN THIS, REALLY WAS
INVALUABLE.
BUT HE WAS TRAVELING, AND SO DR.
EKKO AGREED TO STEP IN.
HOPE YOU ENJOYED THE SESSION,
LOOK FORWARD TO HEARING THE FDA
PERSPECTIVE THOUSAND MOVE THE
FIELD FORWARD PARTICULARLY HOW
WE CAN DO IT COLLECTIVELY.
SO THANK YOU.
>> GOOD AFTERNOON.
I'M THE DIVISION DIRECTOR FOR A
CHEMISTRY MANUFACTURING
CLINICAL -- - CHEMISTRY
MANUFACTURING DIVISION WITHIN
OUR NEWLY FORMED REORGANIZED
OFFICE OF THERAPEUTIC PRODUCTS.
I THINK MY PRESENTATION, YOU'VE
COVERED ALL OF IDENTIFY DURING
TODAY'S TALKS SO FAR.
HOPEFULLY THERE WILL BE FOOD FOR
THOUGHT WHILE YOU'RE ENJOYING
YOUR LUNCH.
I DON'T THINK IT'S WORKING.
CAN'T SEEM TO ADVANCE MY SLIDES.
SO BEFORE I DELVE INTO SOME
ISSUES WE FREQUENTLY ENCOUNTER
AT FDA, FOR CELL THERAPY
PRODUCTS, I WANTED TO TOUCH UPON
THE NEW STRUCTURE, ONE OF THE
FIRST CHALLENGES I WILL DISCUSS
THAT WE ENCOUNTER.
THIS IS A QUICK OVERVIEW OF THE
CBER STRUCTURE, A SUPER OFFICE
FORMED THIS YEAR.
OFFICE OF THERAPEUTIC PRODUCTS
WAS PREVIOUSLY OFFICE OF TISSUE
AND ADVANCED THERAPIES.
OTAT TRANSITIONED INTO A SUPER
OFFICE THIS PAST FEBRUARY, NOW
CONSISTS OF SIX SUBOFFICES TO
HELP BETTER MANAGE THE GROWING
FIELD THAT YOU GUYS CALL -- THE
RAPIDLY GROWING FIELD YOU'VE
TOUCHED UPON.
THE OFFICE OF GENE THERAPY AND
OFFICE OF CELL THERAPY AND HUMAN
TISSUE FOR OCTHT WHERE I SIT,
HIGHLIGHTED HERE, WE USED TO BE
ACTUALLY JUST ONE DIVISION,
DIVISION OF CELL AND GENE
THERAPY, DCGT, WE'RE RESPONSIBLE
FOR CHEMISTRY MANUFACTURING
CONTROLS FOR CELL AND GENE
THERAPY PRODUCTS.
LIKE I MENTIONED
THERE ARE ADDITIONAL SUBOFFICES,
OFFICE OF CLINICAL EVALUATION
AND OFFICE OF PHARMACOLOGY AND
TOXICOLOGY, WHICH THE PT OFFICE
REVIEWS MAINLY PRE-CLINICAL
STUDIES, AND THAT USED TO BE
ACTUALLY A SINGLE DIVISION,
BECAUSE OF THE GROWTH THOUGH WE
NOW FORMED INTO THIS LARGER
SUPER OFFICE, WITH SUBOFFICES
WITHIN.
WHAT'S HIGHLIGHTED HERE IS THE
TOP RECTANGLE IS OUR NEW
SUPERSTRUCTURE OFFICE, OTP.
AND THEN THE SUBOFFICES BELOW IT
IN RECTANGLES.
SO YOU CAN SEE JUST HOW FAR
WE'VE GONE OVER THE YEARS, AND
WITHIN EACH RECTANGLE YOU'LL SEE
LINES UNDERNEATH IT, THOSE ARE
ACTUALLY BRANCHES.
WE'VE REALLY JUST GROWN
EXPONENTIALLY OVER THE YEARS AND
THIS IS STILL JUST CATCHING UP.
SOMEONE MENTIONED EARLIER IN THE
TALKS TODAY.
I'VE BEEN WITH THE CELL THERAPY
BRANCH FOR THE LAST FIVE YEARS,
AS A BRANCH CHIEF, AND WE'VE
GROWN FROM A SINGLE BRANCH
WITHIN A DIVISION FOR CMC -- I
HAVE TO COUNT.
THERE'S AT LEAST FOUR DIFFERENT
BRANCHES THAT WE'VE BROKEN UP
INTO FROM ONE BRANCH SO YOU CAN
IMAGINE HOW MUCH WE'VE GROWN
EVEN JUST IN THE LAST FIVE YEARS
AND JUST THIS PAST FEBRUARY.
AS YOU'RE ALL AWARE THE
DIVERSITY OF PRODUCTS WE REVIEW,
AND OTP IS WIDE, WE REVIEW STEM
CELLS, iPSC PRODUCTS, WE HAVE
XENOTRANSPLANTATION, ALSO
CELL-BASED IMMUNOTHERAPY
PRODUCTS FALL INTO MY DIVISION.
WE ALSO REVIEW CELL THERAPY
PRODUCTS THAT ARE -- I SHOULD
SAY JUST A DIFFERENTIATE FROM
OJT, WE REVIEW PRODUCTS THAT ARE
NOT GENETICALLY MODIFIED,
ALTHOUGH THERE ARE SOME ITEMS
LIKE XENOTRANSPLANTATION WHERE
YOU'RE GOING TO HAVE TO
MEDICALLY MODIFY ANIMALS THAT
THE FINAL ORGANS FALL INTO
OUR -- INTO MY DIVISION.
SO THERE'S SOME CROSSOVERS AND
MEANT MODIFICATION WITH
iPSCs AS WELL.
THIS ILLUSTRATES THE DIVERSITY
OF THE PRODUCTS WE HAVE TO BE ON
TOP OF WITHIN OUR SMALL OFFICES,
GROWING OFFICE, I SHOULD SAY.
SO, AS I MENTIONED, THE FIRST
CHALLENGE THAT I WANTED TO BRING
UP IS JUST HIGHLIGHTING AND
ACKNOWLEDGING THE RAPIDLY
GROWING FIELD.
AND ALL OF THE CONCERNS THAT
COMES WITH KEEPING UP WITH THE
GROWING FIELD.
AND THIS IS ILLUSTRATED BY THE
RAPIDLY INCREASING NUMBER OF
R&Ds WE SEE IN OUR OFFICE.
SO YOU'LL SEE ORANGE DEPICTING
EXPANDED ACCESS INDs THAT WE
WOULD SEE WITHIN THE GIVEN YEARS
AT THE BOTTOM, RANGES FROM 1963
TO 2002.
SO YOU CAN SEE JUST THE SHEER
AMOUNT OF FILES WE SEE IN OUR
OFFICE.
THE BLUE BAR IS REPRESENTATIVE
OF RESEARCH INDs WE SEE.
AND WHAT'S INTERESTING IS THAT
OVER THE RECENT YEARS YOU'LL SEE
THIS INCREASE IN EXPANDED IND
REQUEST WE'RE SEEING IN OUR
OFFICE, EXPANDED MEANS
COMPASSIONATE USE, ONE-OFF
RATHER THAN A REAL CLINICAL
STUDY OR A CONTROLLED CLINICAL
STUDY.
THE GROUP IS ALSO SEEN IN
DIFFERENT TYPES OF MEETINGS AND
REQUESTS WE RECEIVE IN OUR
OFFICE, IT'S REALLY DIFFICULT TO
KEEP UP, BUT THIS IS DEPICTING
EACH BAR FROM 2010 TO 2022.
SO, YOU CAN SEE JUST PICTORIALLY
THE GROWTH OF THIS FIELD THAT
WE'RE FEELING JUST FROM THE FDA
LENS.
ADDED TO THE CHALLENGES OF
GROWTH IS THE COMPLEXITY OF THE
FIELD.
YOU'VE ALL TOUCHED UPON THIS
TODAY, SOMETHING WE'RE ALL
GRAPPLING WITH.
SO, CELL AND GENE THERAPY
PRODUCTS NOT ONLY ENCOMPASS A
WIDE VARIETY OF PRODUCTS BUT
THEY PRESENT COMMON CONCERNS
WHETHER IT BE AUTOLOGOUS OR
ALLOGENEIC REGARDING COMPLEXITY
OF THE PRODUCTS, MECHANISM OF
ACTION, ALL ASPECTS OF
MANUFACTURING AND CONTROLS.
IN ADDITION, THERE'S
SPECIFICALLY CONCERNS RELATED TO
THE ORIGIN OF THE MATERIALS WE
HAVE TO BE MINDFUL OF.
AND SO THIS IS JUST A COMPLEX
AMOUNT OF MANUFACTURING
INFORMATION TO BE ON TOP OF.
IN ADDITION, THERE'S A
COMPLEXITY OF PRODUCT
DEVELOPMENT LIFE CYCLE THAT
NEEDS TO BE TAKEN INTO ACCOUNT
IN THE DEVELOPMENT OF CDCGT,
DIFFICULT TO COMPLETE, OFTEN
BLURRED BY A SMALL FEASIBILITY
PROGRESSING INTO A SMALL PIVOTAL
CLINICAL STUDY WITH INCOMPLETE
PRODUCT CHARACTERIZATION
INFORMATION THAT WE HAVE TO
DECIPHER.
AND SO THESE ARE ALL DIFFICULT
AREAS THAT MAKE IT HARD TO -- IN
PROGRESSING THE FIELD, CGT
PRODUCTS.
SO THE NEXT FEW SLIDES ALL
FURTHER BREAK DOWN THINGS INTO
CHALLENGES THAT WE OBSERVED
DURING EARLY PHASE AND ALSO IN
LATE PHASE STUDIES.
SO, DURING EARLY PHASE THE FOCUS
IS ON SAFETY.
SUCH AS DONOR ELIGIBILITY WHICH
YOU TOUCHED ON, DIFFICULT WITH
iPSCs AND DONOR THAT'S CHOSEN
FROM THE BEGINNING, NOT HAVING A
LOT OF CHOICES BEYOND THE DONOR
YOU HAVE.
THERE'S ALSO QUALIFICATION OF
SAFETY ASSAYS, MICROPLASMA,
ENDOTOXIN, ALSO REAGENT
QUALIFYIFICATION THAT'S VERY
IMPORTANT, FREQUENT OBSERVATION
FOR HOLD ISSUES THAT WE SEE.
AND I WAS VERY INTERESTED TO
HERE THERE ARE A LOT OF, YOU
KNOW, THAT THERE ARE AWARENESS
OF DELIVERY SYSTEMS AND THE
CONCERNS RELATED TO DELIVERY
SYSTEMS THAT YOU'RE
CONTEMPLATING BECAUSE THAT'S
ALSO AN AREA THAT WE FREQUENTLY
SEE THAT REQUIRES A LOT OF BACK
AND FORTH TO GET ADDITIONAL
INFORMATION REGARDING.
AND I JUST WANT TO MAKE SURE,
YOU KNOW, HIGHLIGHT THIS IS AN
ALL-INCLUSIVE LIST, JUST A
HIGHLIGHT OF THINGS WE'RE
SEEING.
SO, JUST TO TOUCH UPON DONOR
ELIGIBILITY, SO SINCE I'M A
REGULATOR I'LL THROW OUT
REGULATION NUMBERS FOR YOU.
FOR ALLOGENEIC PRODUCTS, NEEDS
TO MEET DONOR -- NEEDS TO BE
DETERMINED FOR DONOR TESTING AND
SCREENING PER 1221 CFR 1271.
THAT'S A REQUIREMENT THAT WENT
INTO EFFECT IN 2005.
SO FOR ANY DONOR MATERIAL THAT
YOU USE AFTER 2005, THERE IS A
STRICT REGULATION OF THINGS THAT
SHOULD BE MET.
AND THESE ARE FAIRLY WELL LAID
OUT IN OUR REGULATIONS AND
VARIOUS GUIDELINES, SOME
GUIDELINES I'VE PUT ON THE
SLIDE.
I APOLOGIZE, BUT THE LINKS, IF
YOU GET A COPY OF THESE SLIDES,
THE LINKS AREN'T ACTUALLY --
THEY ARE NOT CORRECT SO JUST
GOOGLE THE GUIDANCE NAME AND IT
WILL GET YOU TO THE RIGHT
DOCUMENT.
THERE ARE TWO COMPONENTS FOR
DONOR ELIGIBILITY.
SCREENING AND MEDICAL RECORDS,
AND THEN THERE'S DONOR TESTING
ASPECTS FOR THE SPECIMEN THAT'S
COLLECTED.
AND OUR REGULATIONS SPELL OUT
WHAT THE WINDOW OF TIME SHOULD
BE FOR THE COLLECTION OF THOSE
SPECIMENS FOR TESTING.
AND ALSO, THERE ARE SPECIFIC FDA
LICENSE KITS THAT SHOULD BE USED
AT CLIA-CERTIFIED LABS.
SO ALL THESE ASPECTS ARE
ACTUALLY FAIRLY WELL OUTLINED IN
OUR -- ON OUR WEBSITES AT FDA.
THEY MIGHT BE A LITTLE DIFFICULT
TO FIND, BUT THEY ARE OUT THERE
AND THEY DO SPELL IT OUT PRETTY
-- YOU KNOW, PRETTY SPECIFIC IN
TERMS OF THE NAME OF THE
COMPANY, THE MODEL, YOU KNOW,
THE KITS YOU SHOULD BE USING.
ALL THAT IS SPELLED OUT.
IT'S JUST A LOT OF INFORMATION
THAT YOU HAVE TO WADE THROUGH TO
UNDERSTAND EXACTLY WHAT NEEDS TO
BE DONE.
SO A LOT OF TIMES WHERE WE'VE
RUN INTO ISSUES WHEN THERE ARE
FOREIGN DONORS BEING USED, AND
ALSO WHEN THESE DONOR SPECIMENS
ARE -- DONORS ARE LOCATED IN A
FOREIGN LOCATION, SO, YOU KNOW,
ACCESS TO CLIA-CERTIFIED LABS
ARE MAYBE DIFFICULT TO FIND.
SO, BUT JUST THINGS TO BE
MINDFUL OF WHEN YOU ARE USING
ALLO DONORS.
ANOTHER AREA, BIG AREA,
ESPECIALLY WITH iPSCs,
REAGENTS, ANOTHER HUGE AREA OF
COMMUNICATION WE HAVE, RECOMMEND
SPONSORS USE THE HIGHEST QUALITY
REAGENT THAT'S AVAILABLE.
RESEARCH GRADE REAGENTS CAN BE
USED IF IT IS PROPERLY
QUALIFIED.
ALL HUMAN, ANIMAL REAGENTS THERE
ARE A MIR KWR5D OF SES.
MYRIAD OF CONSIDERATIONS.
IF THE VENDOR IS MISSING ON
CERTAIN TEST, EXPECTATION IS THE
SPONSOR OF THE CGD PRODUCT IS
ULTIMATELY RESPONSIBLE FOR
OBTAINING OR CONDUCTING THOSE
TESTS.
A LOT OF TIMES A LOT OF VENDORS
HAVE MASTER FILES WITH FDA FOR
SPECIFIC REAGENTS, AND WE ASK
THAT YOU DO USE THOSE RESOURCES
THAT ARE AVAILABLE.
AND WOULD YOU HAVE TO OBTAIN
THAT FROM YOUR VENDOR FOR A
LETTER OF AUTHORIZATION TO
CROSS-REFERENCE, SO THAT YOU
WOULDN'T HAVE TO PROVIDE THE
SPECIFIC INFORMATION.
THIS HAS BEEN TOUCHED UPON BY
ALMOST EVERYONE, AND IN A LOT OF
THE QUESTION-AND-ANSWER
DISCUSSIONS TODAY.
YOU KNOW, CAN'T STRESS ENOUGH
THAT YOU HAVE TO UNDERSTAND THE
PRODUCT.
EXPLORING PRODUCT ATRY BEAUTS
EARLY IN DEVELOPMENT WILL
IDENTIFY YOUR IFY YOUR CRITICAL
QUALITY ATTRIBUTES.
THIS WOULD HELP GETTING YOUR
PRODUCT THROUGH.
EXPLORING MULTIPLE PRODUCT ATRY
DUTIES DURING EARLY PRODUCT
DEVELOPMENT IS PARAMOUNT.
IF YOU NARROW DOWN THE CRITICAL
AT TRIBRUTES THAT MEANINGFULLY
DEFINE YOUR PRODUCT, SPONSORS
MAY FIND THAT SOME ASSAYS ARE
DIFFICULT TO VALIDATE AS WELL.
IT'S ALWAYS HELPFUL TO HAVE
CHOICES AND ALTERNATIVE
ATTRIBUTES AND METHODS YOU MIGHT
RELY ON.
ALSO CQAs HELP IN
DEMONSTRATING PRODUCT
COMPARABILITY WHICH I'LL GO OVER
REGARDING ESPECIALLY LLY WITH
LATE PHASE STUDIES, ALREADY
CHANGES FOLKS WILL ENCOUNTER AS
DEVELOPMENT PROGRESSES.
IN ADDITION TO THE CQAs
THERE'S A LOT OF SPECIFIC CASES
WHICH SOME CQAs COULD BE PART
OF YOUR LOT RELEASE SPECS.
THESE ARE IMPORTANT BECAUSE, YOU
KNOW, DURING EARLY PHASE
SPONSORS SHOULD EXPLORE AS MUCH
AS YOU CAN TO DETERMINE WHAT
ATTRIBUTES TO INCLUDE IN LOT
RELEASE SPECS, AND YOU WANT TO
SET THE CORRECT RELEASE CRITERIA
FOR SPECS AND, YOU KNOW, WHAT'S
CORRECT IS REALLY YOUR
MANUFACTURE EXPERIENCE, WHAT
MAKES SENSE, JUSTIFICATION,
JUSTIFICATION, JUSTIFICATION
WITH US.
SO SOME -- THESE ARE SOME COMMON
ISSUES THAT WE FIND WITH LOT
RELEASE CRITERIA AND
SPECIFICATIONS, WE JUST NEED A
LOT OF JUSTIFICATION, WHATEVER
YOU HAVE.
IT NEEDS TO MAKE SENSE,
SCIENTIFIC SENSE, AND HOW YOU'RE
SETTING UP.
DO YOU HAVE DATA TO SUPPORT YOUR
CRITERIA?
SO, LASTLY, ON THIS EARLY PHASE
PART, I WANT TO TALK ABOUT
ANOTHER COMMON COMMUNICATION
THAT I MENTIONED, WHICH IS HOW
IS THE PRODUCT BEING
ADMINISTERED.
EVEN FOR SIMPLE ADMINISTRATIONS
FOR INTRADERMAL INJECTION OR
EVEN IV INFUSIONS WE LIKE TO SEE
INFORMATION ON SYRINGE AND
NEEDLE GAUGE FOR EXAMPLE FOR
SOMETHING SIMPLE LIKE THAT.
IT'S REALLY TO UNDERSTAND THE
WORST CASE CONDITIONS THAT CELLS
WILL UNDERGO, AND DETERMINE THE
COMPATIBILITY OF THE CELL
PRODUCT WITH THE DELIVERY
SYSTEM.
FOR THINGS LIKE DELIVERY BY
CATHETERS, ARE SPONSORS USING
FDA CLEARED OR APPROVED DEVICES
INTENDED FOR DELIVERY OF A DRUG,
YOU KNOW, BECAUSE SOMETIMES THEY
ARE JUST -- THEY ARE NOT
INTENDED TO DELIVER DRUGS
THROUGH, IF SHEATHS ARE
INTRODUCERS AND YOU'RE PUTTING A
DRUG INTO THE LUMEN WASN'T
INTENDED OR CLEARED OR APPROVED
FOR THAT USE.
ARE THERE CUMULATIVE ENDOTOXIN
CONCERNS THAT WE NEED TO BE
CONCERNED ABOUT?
FOR INSTANCE, ANYTHING THAT'S
GOING INTO THE INTRAOCULAR
SPACE, THERE IS A LOWER
ENDOTOXIN LIMIT BECAUSE OF TOXIC
INTERSEGMENT SYNDROME, SO ARE
THOSE THINGS BEING CONSIDERED.
IN GENERAL, KNOW THE FDA REGULAR
THAT LOWER STATUS AND DELIVERY
SYSTEM AND PERFORM COMPATIBILITY
TESTING, WHICH MEANS PASSING THE
PRODUCT THROUGH THE DELIVERY
DEVICES AND SEEING THE PRE AND
POST PRODUCT AND MAKING SURE
THAT IT IS THE SAME AS WHAT YOU
PUT IN ONE END AND THAT YOU KNOW
HOW MUCH YOU'RE DELIVERING.
SO I'M GOING TO MAKE THIS VERY
QUICK BECAUSE I'M OUT OF TIME.
BUT REGARDING LATE PHASE, YOU
WENT OVER A LOT OF THIS SO I
THINK WHAT I'LL HIGHLIGHT IS
THAT BEFORE ENTERING YOUR PHASE
3 STUDIES OR CLINICAL STUDIES AS
INTENDED TO SUPPORT YOUR PRIMARY
EFFICACY FOR -- IN SUPPORT OF
BLA HAVE YOUR POTENCY ASSAY IN
PLACE BEFORE STARTING THAT
STUDY.
WHEN I SAY PLEASE HAVE YOUR
POTENCY ASSAY IN PLACE, IT MEANS
HAVING A QUALIFIED ASSAY IN
PLACE.
VALIDATION CAN OCCUR AT BLA, IN
YOUR BLA SITUATION.
AND I WON'T GO OVER THE
REGULATORY DEFINITION BECAUSE
YOU CAN LOOK UP THE REGULATORY
DEFINITION.
AND THE IMPORTANCE OF POTENCY
ASSAY ATTRIBUTE, I THINK WE'RE
ALL CLEAR ON THIS SO I'LL ALSO
GO OVER QUICKLY OVER THIS.
BUT HAVING A QUANTITATIVE
POTENCY ASSAY THAT ACTUALLY MAY
HAVE TIES TO CLINICAL EVIDENCE
OR MECHANISM OF ACTION IS VERY
HELPFUL FOR SUPPORT OF YOUR
PRODUCT DEVELOPMENT.
SO LET'S GO THROUGH
MANUFACTURING CHANGES, LIKE I
SAID, ARE INEVITABLE, AND THIS
IS WHERE POTENCY ASSAY WILL BE
HELP FOLLOW DO A PROPER
COMPARABILITY ANALYSIS.
COMPARABILITY STUDIES WILL BE
DEPENDENT ON HOW MUCH CHANGE
YOU'RE MAKING, WHAT PHASE OF
YOUR CLINICAL STUDY YOU'RE IN.
OBVIOUSLY THE LATER THE PHASE,
THE MORE COMPARABILITY STUDIES
OR DATA WOULD BE NEEDED TO
DEMONSTRATE.
BUT I'M GOING TO GO THROUGH
JUST -- THESE ARE LIMITATIONS ON
ESTABLISHING COMPARABILITY AND
THE CHALLENGES THAT WE ENCOUNTER
TYPICALLY.
BUT ONE OF THE THINGS ALSO TO BE
MINDFUL IS THAT IF AT ALL
POSSIBLE TO USE YOUR COMMERCIAL
MANUFACTURING PROCESS VERSION
AND ALSO YOUR INTENDED
COMMERCIAL MANUFACTURING
FACILITY, IN YOUR PHASE 3, YOUR
PIVOTAL STUDY IN SUPPORT OF BLA
WE SEE A LOT OF HICCUP ON THAT
WHEN FOLKS ARE COMING IN EVEN AT
THE STAGE WITH COMMERCIAL
MANUFACTURING FACILITY.
AND JUST ONE MORE SLIDE HERE, I
WANT TO HIGHLIGHT HERE REALLY TO
KEEP CMC DEVELOPMENT IN LINE
WITH CLINICAL DEVELOPMENT.
WE TYPICALLY SEE WHERE CLINICAL
DEVELOPMENT, WE HAVE CLINICAL
DATA AND THE DEVELOPMENT JUST
PUSHES FORWARD WHERE A CMC IS
STILL STUCK IN A VERY SMALL
FACILITY OR NON-SCALEUP OSH --
AND IT'S NOT JUST -- IT'S NOT IN
ALIGNMENT WITH WHERE THE
CLINICAL STAGE OF THE
DEVELOPMENT MAY BE.
SO, THAT'S ALL I HAVE BECAUSE MY
NEXT SLIDE IS A SUMMARY SLIDE
BUT I DO HAVE MY CONTACT
INFORMATION AT THE END OF THE
SLIDE DECK THAT EVERYONE IS
PROBABLY AWARE OF FROM PREVIOUS
FDA TALKS.
SO THAT'S IT.
THANK YOU.
>> THANK YOU.
AT THIS POINT WE'RE SHIFTING
GEARS FROM THINKING BIG IN TERMS
OF HOW NIH INSTITUTES AND
CENTERS AND FDA AND NIST CAN
WORK TOGETHER THINKING ABOUT
WHAT WE MIGHT DO IN THE
CELL-BASED THERAPIES CONSORTIUM.
TO LEAD US UP, THE BESPOKE GENE
THERAPY CONSORTIUM, THE MODEL
FOR THE CELL-BASED THERAPIES
CONSORTIUM.
I'VE HAD THE LUXURY OF WORKING
WITH COURTNEY ON A NUMBER OF
PROJECTS, SHE'S BEEN MADE THEM
HAPPEN.
SO IT'S AWFUL GREAT TO HAVE YOU
WITH US.
>> THANKS, BOB.
THANKS, EVERYONE, FOR THE
OPPORTUNITY TODAY.
ALL RIGHT.
AS BOB SAID, I'M COURTNEY
SILVERTHORN, FOUNDATION FOR
NATIONAL INSTITUTES OF HEALTH.
5 01 C3 NON-PROFIT MANDATED BY
CONGRESS IN THE 1990s TO
SUPPORT THE MISSION OF THE NIH,
WE DO THAT IN DIFFERENT WAYS BUT
ONE OF THE MOST IMPORTANT WAYS
WE'RE RESPONSIBLE FOR DESIGN,
FUNDRAISING, EXECUTION OF VERY
LARGE AND COMPLEX PUBLIC/PRIVATE
PARTNERSHIPS.
I ALSO SERVE AS DIRECTOR OF
THE -- WHICH WAY DO I POINT?
THERE WE GO.
EXPLORING MEDICINES PARTNERSHIP
PROGRAM, THIS IS A SET OF
PUBLIC/PRIVATE PARTNERSHIPS THAT
DATE BACK TO BEGINNING IN 2014,
THAT WERE DESIGNED TO ALIGN THE
RESOURCES OF THE NIH AND
RESOURCES OF THE PRIVATE SECTOR
TO SOLVE CHALLENGES IN FIELDS
THAT NEITHER THE GOVERNMENT OR
PRIVATE SECTOR COULD SOLVE ON
THEIR OWN.
SINCE 2014, WE HAVE HAD TEN
PROJECTS, REPRESENTING OVER $830
MILLION OF INVESTMENT BETWEEN
THE NIH AND PRIVATE SECTOR,
WE'RE ABOUT TO CELEBRATE OUR
10th ANNIVERSARY IN FEBRUARY
OF NEXT YEAR.
YOU SEE ACROSS THE BOTTOM LINE
THE LARGE NUMBERS OF FOR-PROFIT
ORGANIZATIONS, NON-PROFIT
ORGANIZATIONS, NIH INSTITUTES
AND CENTERS THAT PARTICIPATE IN
THESE PROJECTS, THAT SPEAKS TO
THE VALUE OF THE PUBLIC/PRIVATE
PARTNERSHIP ITSELF BUT ALSO THE
FOCUS ON PRE-COMPETITIVE
ADVANCEMENT SO WE CAN BRING
TOGETHER ORGANIZATIONS THAT
MIGHT BE COMPETITORS IN THE
MARKET BUT CAN COME TOGETHER IN
A NEUTRAL CONVENING AND SHOW
THEIR EXPERTISE AND GUIDE THE
PROJECT TO THINGS THAT BENEFIT
NOT JUST PARTNERS AND BROADER
FIELD.
THIS GIVES A SENSE OF PROJECTS
IN THE AMP PROGRAM TO DATE.
WE HAVE A NUMBER OF BCT PARTNERS
PARTICIPATING IN THIS WORKSHOP.
I WANT TO YOU TO KNOW THE
BGCT, IT'S DISEAS AGNOSTIC,
VEALING AAV GENE THERAPIES FOR
RARE DISEASES PARTICULARLY
FOCUSED ON MANUFACTURING AND
CLINICAL WORK INTO AN IND IN THE
FIRST-IN-HUMAN CLINICAL TRIAL.
JUST LAST MONTH WE HAD TWO NEW
NEUROSCIENCE PROJECTS APPROVED
IN PARKINSON'S DISEASE AND
RELATED DISORDERS, OUR SECOND
PHASE OF AMP PD PROJECT AND NEW
PROJECT IN ALS, YOU CAN SEE AT
THE BOTTOM WE HAVE SEVERAL OTHER
PROJECTS IN DEVELOPMENT AS WELL,
AN EFFORT TO ALIGN DATA ACROSS
MULTIPLE AMP PROJECTS TO LOOK
FOR COMMON PATHWAYS OF
INFLAMMATION AND THEN THE
CELL-BASED THERAPY CONSORTIUM
WHICH IS BEING BUILT SOMEWHAT
OFF THE BGTC MODEL.
THE CORE PRINCIPLES, SHARED
GOVERNANCE OF FUNDING BETWEEN
NIH AND PRIVATE SECTOR, MOST OF
THE AMPs HAVE PUBLIC-FACING
PORTALS OR OTHER WAYS OF
DISSEMINATING INFORMATION.
AND AGAIN KEEPING WITH THAT
PRE-COMPETITIVE ASPECT THAT WE
DON'T ALLOW PREEMPTIVE PATENTING
SO IT'S ACCESSIBLE TO THE
BROADER COMMUNITY AS POSSIBLE.
THIS OUTLINES A LOT OF WHAT
WE'VE BEEN HEARING ABOUT,
CHALLENGES AND SOLUTIONS IN CELL
THERAPY PRODUCTION SOURCES,
CONSIDERINGS ABOUT THE CELL
SOURCE, MODIFICATIONS, TESTING,
RELATED ACCEPTANCE CRITERIA, THE
DISTRIBUTION DELIVERRIVE
CELL-BASED THERAPIES AND
CLINICAL APPLICATION, THINGS
CONSIDERED AS WE'RE BUILDING OUT
THIS PARTICULAR SOLUTION.
AND WE'RE ESPECIALLY FOCUSED ON,
AGAIN, BECAUSE WE'RE LOOKING FOR
THE OVERLAP BETWEEN THE INTEREST
OF NIH AND INTEREST OF THE
PRIVATE SECTOR, SO VERY
ENCOURAGED TO HEAR ABOUT
MANUFACTURING AND PROCESSES,
THINGS THAT WE'LL PROBABLY BE
THINKING ABOUT AS WE BUILD OUT
THIS CONSORTIUM, POTENTIALLY
LOOKING AT PROCESS DEVELOPMENTS
FOR MANUFACTURING AND HOW THEY
SCALE, DETERMINING ALLOGENEIC
VERSUS AUTOLOGOUS AND TOLERANCE,
HEARING ABOUT BIOEQUIVALENCE
BETWEEN DIFFERENT TIMES OF
CELLULAR-BASED THERAPIES,
REGULATORY RISK IS A
CONSIDERATION AND WHEN WE'RE IN
DISEASE AGNOSTIC STATES THERE'S
A BROAD RANGE OF RISK
ASSESSMENTS DEPENDING ON THE
SPECIFIC DISEASE OR DISORDER.
TISSUE INCORPORATION OF
MANUFACTURING PRODUCTS AND
CLINICAL TRIAL DESIGN AND
INFORMED CONSENT FOR LIVING
THERAPIES.
SO A PRETTY LENGTHY LIST, THINGS
WE'RE EXCITED TO THINK ABOUT
TACKLING.
WE'RE NOT GOING ABOUT THIS IN A
VACUUM.
WE'VE HEARD ABOUT PRIOR WORK IN
THE CELL-BASED THERAPY SPACE,
LOOKING TO WORK ALREADY DONE.
GAO REPORTS AND FDA CONSENSUS
STANDARDS, PRIOR NIH EFFORTS IN
THE RMIP IMPACT PROGRAMS, WAS AS
A FORUM AT NATIONAL ACADEMIES
TWO WEEKS AGO ON REGENERATIVE
MEDICINE, PARTICULARLY
MANUFACTURING CHALLENGES IN
REGENERATIVE MEDICINE.
WE ALSO TO KICK OFF THIS DESIGN
EFFORT, THE FOUNDATION PUT OUT
AN RFI IN SEPTEMBER ASKING FOR
INFORMATION FROM THE STAKEHOLDER
COMMUNITIES ABOUT THE CELL-BASED
THERAPY APPROACH AND WHAT TYPES
OF MODELS, WHAT TYPES OF
QUESTIONS, WHAT CHALLENGES, ROAD
BLOCKS, POTENTIAL SOLUTIONS
COULD BE ADDRESSED WITHIN THIS
TYPE OF CONSORTIUM.
PULLING TOGETHER WHAT WE HOPE
WILL BE OBJECTIVES OF THE
RESEARCH PLAN WOULD LIKE TO
LEVERAGE THE WORK IN THE BESPOKE
THERAPY CONSORTIUM AS A MODEL
FOR THE INFRASTRUCTURE THAT WILL
GO INTO THE RESEARCH PLAN
BECAUSE WE'VE DONE A LOT OF WORK
WITH A LOT OF LESSONS LEARNED
FROM THE FISHES TWO YEARS OF THE
BGCT, WE HOPE THAT WILL
ACCELERATE A DESIGN PHASE.
WE START WITH A CONCEPT THAT'S
APPROVED BY RELEVANT EXECUTIVE
BODY, THAT TAKES US INTO BETWEEN
SIX TO TWELVE-MONTH DESIGN PHASE
THAT CULMINATES IN RESEARCH PLAN
WE USE TO SECURE COMMITMENTS AND
EXECUTE ON THE PROJECT.
BECAUSE OF THE BGTC AND WORK
THAT'S BEEN ACCOMPLISHED WE HAVE
WORK TO GET THROUGH THE GATE
QUICKLY, FOCUSING EFFORTS ON THE
TWO-DAY WORKSHOP BUILDING OUT
THAT DRAFT OF THE RESEARCH PLAN.
WE EXPECT SOME FOCUS ON BASIC
BIOLOGY AND UNDERSTANDING HOW
THAT APPLIES TO TARGETED
THERAPIES, BUT IN PARTICULAR
FOCUSING ON THAT PRE-CLINICAL
AND PRODUCT TESTING PIPELINE,
SELECTING ZIGSES AS PROVE OF
CONSENT AND EXECUTING ON PHASE
1-2 CLINICAL TRIALS TO SHOW A
STREAMLINED DEVELOPMENT IS
FEASIBLE.
STARTING TO OVERSOME SOME
BARRIERS THAT CAN HELP MOVE THE
FIELD FORWARD AND THEN ALSO LIKE
THE BGTC IN COMPLIANCE WITH
GOALS OF THE AMP PROGRAM
GENERATING A PLAY BOOK THAT
WOULD BE MADE PUBLICLY
ACCESSIBLE AND REUSABLE
INFORMATION IN TERMS OF
PROTOCOL, REGULATORY TEMPLATES
THAT WILL HELP INFORM OTHER
THERAPY DEVELOPMENTS OUTSIDE OF
THE ONES THAT ARE SELECTED FOR
THIS CONSORTIUM.
THIS IS THE BGCT MODEL, TOPLINE
BEING BASIC BIOLOGY OF AAV, ONE
THING WE'LL DISCUSS IS ALIGNING
ON MODEL FOR CONSORTIUM TO FOCUS
ON.
SO LIKE THE BESPOKE GENE
CONSORTIUM FOCUSED ON AAV GENE
REPLACEMENT TECHNOLOGY, CELL
BASED CONSORTIUM WILL NEED TO
SELECT A NARROW PATH BAY.
BGCT HAS TWO TRACKS IN THE
RESEARCH ASPECT, ONE ON
ENHANCING VECTOR GENERATION,
MORE TARGETED AT THE INFORMATION
PROCESSES, AND ONE THAT'S
FOCUSED ON ENHANCING GENE
EXPRESSION IN A PATIENT, MORE
TARGETED TO CLINICAL OUTCOMES.
BUT BOTH OF THOSE HAVE THE GOAL
OF PROVIDING A BETTER
UNDERSTANDING OF THE AAV BASIC
BIOLOGY THAT CAN TRANSLATE INTO
INCREASED EFFICIENCY OF THE
PRODUCTION AND USE OF AAV GENE
THERAPIES.
THE CRUX OF THE PROJECT THOUGH
IS THE CLINICAL PIPELINE.
WE STARTED OUT COMPLETELY WITH A
BLANK PIECE OF PAPER AS TO WHAT
DISEASES WOULD BE INCLUDED.
DID A BIPHASE COLLECTION THAT
STARTED OFF WITH INITIAL
SUBMISSION, DOWN SELECTION,
REQUEST FOR CLINICAL TRIAL
PROPOSALS.
ULTIMATELY LANDED ON A PORTFOLIO
OF EIGHT DISEASES THAT WE'LL BE
TAKING THROUGH MANUFACTURING
WITH CRITICAL QUALITY ATTRIBUTE,
PRE-CLINICAL TESTING PROTOCOLS
ON THE BASIS OF ROUTES OF
ADMINISTRATION, AND THEN INTO
PHASE 1 TRIAL USING A VERY
TEMPLATED SET OF REGULATORY
SUBMISSIONS, ALL MADE PUBLICLY
AVAILABLE SO OTHERS CAN USE THE
SAME FRAMEWORK.
AND SO YOU CAN IMAGINE A
CELL-BASED THERAPY CONSORTIUM
COULD LOOK SIMILAR TO THE WORK
THAT THE THE BGCT FRAMEWORK HAS
ESTABLISHED, POTENTIAL FOCUS ON
SOME BASIC BIOLOGY AND
TRANSLATIONAL IMPLICATION IN
ENHANCING TISSUE DELIVERY AND
INCORPORATION IN LOOKING AT
ALLOGENEIC VERSUS AUTOLOGOUS
MODELS.
AND THEN SIMILARLY CREATING THAT
END-TO-END MANUFACTURING
PRE-CLINICAL TESTING AND
CLINICAL TREATMENT PIPELINE THAT
CAN SERVE AS PROOF-OF-CONCEPT
FOR FUTURE USE.
AND SO THE CONCEPT OF THIS
CONSORTIUM WAS APPROVED ABOUT
TEN DAYS AGO, SO REPLACEMENT
EXCITED TO START TO BUILD OUT
THAT RESEARCH PLAN.
AND IN TERMS OF TIMING WE'RE
HOPING THAT WE'LL BE ABLE TO
FINALIZE THE RESEARCH PLAN FOR
THIS CONSORTIUM FAIRLY QUICKLY.
WE HOPE TO PRESENT THAT TO THE
AMP EXECUTIVE COMMITTEE FOR
APPROVAL IN MID-DISEASE,
AUTHORIZATION FOR FNIH TO BEGIN
FUNDRAISING, POTENTIALLY
LAUNCHING IN MID-2024.
WE THINK DELIVERABLES WOULD BE
OPTIMIZED BIOLOGY OF ONE OR TWO
CELL-BASED THERAPY MODALITIES,
DEFINING TESTING, ESTABLISHING
THAT PLAY BOOK THAT PUTS THE
LEARNINGS OUT INTO THE GENERAL
PUBLIC.
AND THAT'S MY LAST SLIDE.
REALLY EXCITED TO CONTINUE THE
DISCUSSION AND LOOKING FORWARD
TO HEARING THE OTHER COMMENTS
AND INPUTS FROM THE GROUP.
THANKS.
>> KRISHENDU ROY AND JOHNNY
HUARD WERE GOING TO MODERATE.
KRISHENDU ROY WAS UNABLE TO
TRAVEL, HE'S ONLINE.
WE'LL GET INTO THE DISCUSSION
PHASE.
KRISH GOES FIRST.
AND THEN -- OKAY.
SO KRISH, YOUR SLIDE'S UP, WE
MIGHT BE ABLE TO SEE YOU IN THE
LITTLE BOX.
>> ARE MY SLIDES UP?
I CAN'T SEE MY SLIDES.
>> YES, YOUR SLIDES ARE UP.
>> EXCELLENT.
THANK YOU, BOB.
THANK YOU, EVERYBODY.
I'M SORRY I COULDN'T BE THERE
TODAY.
SO, I'M JUST GOING TO START OFF
WITH REALLY THINKING ABOUT THE
MANUFACTURING CHALLENGE THAT YOU
JUST HEARD ABOUT.
AND GIVEN THE PLATFORM
TECHNOLOGIES ARE SOMEWHAT
DISEASE AGNOSTIC AND THERAPY
AGNOSTIC I THINK MANUFACTURING
IS PROBABLY A VERY STRONG
CHALLENGE TO ADDRESS.
AND I'M CURRENTLY AT VANDERBILT,
BUT MOST OF WHAT I'LL TALK ABOUT
TODAY COMES FROM -- NEXT SLIDE
PLEASE -- COMES FROM THE NSF
ENGINEERING RESEARCH CENTER THAT
I USE.
I CAN GET THE NEXT SLIDE?
GREAT, THANK YOU.
YOU CAN CLICK THROUGH IT.
YES.
SO, COMES FROM THE TWO LARGE
RESEARCH CENTERS THAT I HAVE THE
PRIVILEGE OF LEADING OVER THE
LAST SIX, SEVEN YEARS NOW.
ONE BEING THE NSF ERC, CELL
MANUFACTURING TECHNOLOGIES, AND
THE OTHER BEING THE MARKET
CENTER FOR CELL CHARACTERIZATION
MANUFACTURING, WHICH ARE
MULTI-UNIVERSITY NATIONAL,
INTERNATIONAL CENTERS, AND NOT
JUST IN THE U.S. BUT ALSO OTHER
UNIVERSITIES AND INSTITUTIONS IN
JAPAN AND CANADA AND IRELAND.
THAT HAS BEEN LASER FOCUSED ON
DEVELOPING TECHNOLOGIES AND
PLATFORMS FOR CELL THERAPIES,
INCLUDING FUNDING FROM NIH IDCC
HUB WHICH I'LL TALK ABOUT IN A
SECOND, AS WELL AS SEVERAL
PROJECTS FROM FDA CBER.
NEXT SLIDE.
SO, I THINK IF WE STEP BACK AND
THINK OF CELL-BASED THERAPIES
AND TISSUE-BASED THERAPIES, WE
IN VERY INTERESTING PRODUCT
REALM THAT DOES NOT REALLY
FOLLOW OUR CLASSICAL
BIOMANUFACTURING PARADIGM.
YOU HAVE AN INCREDIBLY VARIABLE
STARTING MATERIAL, EVEN FOR
ALLOGENEIC.
I THINK PEOPLE ARE INCREASINGLY
UNDERSTANDING THAT JUST BECAUSE
YOU HAVE A MASTER CELL BANK, YOU
MAKE AN iPSC CELL BANK, YOU'RE
NOT GOING TO GET THE SAME
STARTING MATERIAL TO MAKE YOUR
END PRODUCT ALL THE TIME.
CELLULAR DIFFERENTIATION IS BY
NATURE A STOCHASTIC PROCESS.
WE PUT THAT INTO A FIXED PROCESS
MANUFACTURING WITH MANY
DIFFERENT PARAMETERS, AND OUT
COMES A PROJECT WITH A THOUSAND
OR TWO THOUSAND BIOACTIVE
MOLECULES OF RNA PROTEINS, DNA
LIPIDS, METABOLITES, MANY OF
WHICHED FDA WOULD HAVE
CONSIDERED A DRUG, AND WE'RE
INJECTING THAT INTO A PATIENT, A
LIVING DRUG WHICH GETS MODIFIED
BY THE PATIENT'S DISEASE STATUS,
IMMUNE SYSTEM, PRIOR TEAMS,
MICROENVIRONMENTED IN THE
PATIENT.
HOW DO WE PREDICT FUNCTION, HOW
DO WE PREDICT CRITICAL QUALITY
ATTRIBUTES IS THE TREMENDOUS
CHALLENGE IN CELL THERAPY, MUCH
MORE THAN GENE THERAPY VECTORS,
MUCH MORE THAN MONOCLONAL
ANTIBODY, PROTEIN THERAPEUTICS
OR COMPLEX THERAPIES WE'VE EVER
MANUFACTURED, AND BECAUSE IT IS
A COMPLETELY VARYING AND DYNAMIC
MATERIAL.
NEXT SLIDE PLEASE.
SO, WE HAVE BEEN THINKING ABOUT
SO MANY UNANSWERED QUESTIONS
THAT I THINK AS A CONSORTIUM WE
COULD START ADDRESSING, FIRST OF
ALL I THINK IF YOU ASK ANYONE IN
THE CELL THERAPY INDUSTRY WHAT
ARE YOUR BIG CHALLENGES EVERYONE
WOULD AGREE THAT WE DO NOT KNOW
WHAT QUALITY MEANS IN CELL TERP.
AS A RESULT, PROCESS PARAMETERS
THAT CONTROL AND MECHANISM OF
ACTION LARGELY ARE UNKNOWN AND I
WOULD ARGUE THAT IT IS EVEN
LARGELY UNKNOWN FOR CAR T CELL
THERAPY WHICH WE HAVE SUCCESS
WITH THE LAST THREE OR FOUR
YEARS, EVEN THOUGH PATIENTS ARE
GETTING CURED, WE'RE YET TO
UNCOVER EXACTLY WHICH SUBSET OF
POPULATION THAT GIVES LONG-TERM
DURABLE RESPONSE, ANY CELL
THERAPY INCLUDING CAR T CELL,
HOW DO I CONTROL PROCESS
PARAMETERS AND MAKE SURE EVERY
BATCH ANYWHERE IN THE WORLD I
GET EQUIVALENT QUALITY OF
PRODUCT.
WE DON'T KNOW WHY SOME RESPOND,
OTHER RELAPSE, SOME DON'T
RESPOND, HOW DO WE PREDICT
WHETHER A PATIENT IS GOING TO
RESPOND OR NOT RESPOND?
WHICH ARE SOME OF THE BASIC
BIOLOGY QUESTIONS THAT WE HAVE
NOT YET BEEN ABLE TO UNDERSTAND
IN CELL THERAPIES, BECAUSE IT'S
SUCH A COMPLEX PRODUCT AND
PROCESS.
NEXT SLIDE PLEASE.
AND ALL OF THESE ALIGN VERY WELL
WITH THE U.S. NATIONAL STRATEGY
FOR ADVANCED MANUFACTURING, THE
BOLD GOALS RELEASED BY OSTP.
IF YOU LOOK AT MANUFACTURING,
GENE EDITING TECHNOLOGIES, THESE
ALL SQUARE VERY, VERY WELL WITH
THE CELL THERAPY CELL
BIOMANUFACTURING PROCESS AND THE
WHOLE ECOSYSTEM.
SO I THINK ANY EFFORT THAT WE
MAKE AT NIH OR FNIH, IT IS GOING
TO BE WELL ALIGNED WITH OUR
NATIONAL PRIORITIES.
NEXT SLIDE PLEASE.
SO, THIS IS SORT OF THE VISION
THAT AT THE NSF ERC HAVE TO
THINK ABOUT CELL THERAPIES.
FOR US TO CREATE A CONSIST DENT
REPRODUCIBLE PRODUCT EVERY TIME
WE MANUFACTURE, WE NEED TO BE
ABLE TO MEASURE QUALITY IN LINE
OR AT LINE IN REAL TIME.
I DO NOT SEE A WAY AROUND IT,
BECAUSE OF THE VARIABILITY OF
CELLS AND TISSUES AND THEIR
PROCESSES, UNLESS WE INTEGRATE
MEASUREMENTS AND CONTROL THE
PROCESS TO GET TO A FIXED
QUALITY PRODUCT OR CLOSE TO A
FIXED QUALITY PRODUCT, EVERY
TIME WE MANUFACTURE SOMETHING
WE'RE GOING TO GET A DIFFERENT
QUALITY PRODUCT.
JUST THE PHYSICS OF IT, THE
MATH, THE BIOLOGY OF IT,
DICTATES THAT.
SO FOR US IT'S CELL THERAPY
PROCESS NEEDS TO BE CLOSED LOOP
AUTOMATION SYSTEMS, THAT HAS
MULTIPLE DIFFERENT SENSORS
AND/OR PROCESS PARAMETER
MEASUREMENTS THAT ALLOWS US TO
UNDERSTAND THE PROCESS, THE
STATUS OF THE PRODUCT, AND
CONTROL THE PROCESS TO GET TO
EQUIVALENT OR CONTROLLED PRODUCT
QUALITY.
AND LAID UPON THAT IS THIS IDEA
OF THE SUPPLY CHAIN AND
LOGISTICS WHICH OFTEN WE IGNORE
BUT YOU CANNOT BECAUSE AGAIN
THAT IS GOING TO BE ONE OF THE
BIGGEST BOTTLENECKS DELIVERING
THERAPIES TO THE MASSES, WHETHER
YOU THINK ABOUT CENTRALIZED
VERSUS REGIONAL VERSUS
DECENTRALIZED DISTRIBUTED
MANUFACTURING, ONE NEEDS TO
THINK ABOUT IMPLEMENTATION OF
QUEUES THERAPIES, WHO GETS
TREATED FIRST, IN THE QUEUE
FIRST, SICKEST FIRST, WHO
DECIDES WHO IS THE SICKEST
PATIENT?
THERE ARE A LOT OF ETHICS
CONCERNED WHERE HE WE HAVE VERY,
VERY LIMITED MANUFACTURING
CAPACITY IN THE COUNTRY OR IN
THE WORLD.
IF YOU ASK MULTIPLE MYELOMA
PHYSICIAN TODAY, THEY SAY WE
HAVE HUNDREDS OF PATIENTS WHO
ARE GOING TO DIE, EVEN WITH TWO
APPROVED MYELOMA CAR T THERAPIES
THAT ARE FDA APPROVED.
BUT THEY WILL NOT GET IT BECAUSE
WE SIMPLY DO NOT HAVE
MANUFACTURING CAPACITIES.
AND PLENTY OF HOSPITALS HAVE
ENOUGH PATIENTS TO PUT ON THE
LINE, WE DON'T HAVE
MANUFACTURING CAPACITIES TO DO
THAT.
SO WHEN WE THINK ABOUT A LARGE
NATIONAL EFFORT IN THIS SPACE,
WE NEED TO THINK ABOUT ALL OF
THESE CONSIDERATIONS AND SYSTEMS
APPROACH AND NOT JUST THE
INDIVIDUAL BIOLOGICAL QUESTION,
BIOMANUFACTURING QUESTION,
SUPPLY CHAIN QUESTION, BUT ALL
OF THEM TOGETHER AS A SYSTEMS
PROBLEM.
NEXT SLIDE PLEASE.
SO, I'M GOING TO VERY QUICKLY GO
THROUGH A FEW OF THE WORKS WE'VE
BEEN DOING.
I GIVE THIS EXAMPLE, OTHERS, A
LOT OF FOLKS IN THE ROOM HAVE
SEEN THIS.
ON THE RIGHT THERE'S TWEETS FROM
PATRICK HANLEY, LIVE TWEETING
PETER MARKS A COUPLE YEARS AGO,
TALKING ABOUT THE CQAs, IN AN
IDEAL WORLD WE WOULD HAVE
SUPERCOMPUTERS, TAKES THE DATA,
FIGURES OUT WHAT CHARACTERISTICS
ARE ASSOCIATED WITH POSITIVE
OUTCOME.
WE'RE STILL WORKING ON THAT BUT
TAKING MAYBE STEPS TOWARDS THAT.
SO THERE ARE TWO LARGE
A.I.-DRIVEN EFFORT WE HAVE IN
THE NSF CENTER.
ONE IS CHARACTERIZING CELLS THAT
ARE GOING INTO PATIENTS TO THE
FULLEST EXTENT POSSIBLE, BOTH AT
THE BEGINNING OF THE PROCESS AND
AT THE END OF THE PROCESS.
AND PREDICTING PRODUCT QUALITY
AT THE END OF THE MANUFACTURING.
AND THEN TAKING THAT PRODUCT,
CHARACTERIZING THAT, AND LOOKING
AT PATIENT OUTCOMES AND PATIENT
VARIABLES TO UNDERSTAND WHAT
PRODUCT QUALITY IS MOST
PREDICTIVE OF A POSITIVE PATIENT
OUTCOME.
THESE REQUESTS, CLOSE
PARTNERSHIP WITH CLINICAL
TRIALS, THESE REQUEST REQUIRE
CLOSE PARTNERSHIP WITH BIOLOGIST
AND MANUFACTURING. WE HAVE A
NOT DONE CLINICAL TRIALS IN THIS
COUNTRY WITH THIS GOAL IN MIND
THAT WE NEED TO CONNECT PRODUCT
CHARACTERISTICS WITH PATIENT
OUTCOME.
THIS IS ONE OF THE BIGGEST
BOTTLENECKS FOR INDUSTRY BECAUSE
IF THEY CAN NOT PREDICT OR
CANNOT BE CONFIDENT THAT A
PRODUCT THEY MANUFACTURE IS
GOING TO WORK X AMOUNT OF TIME
IN A PATIENT POPULATION, IT
BECOMES A TREMENDOUSLY RISKY
PRODUCT FOR THEM TO TAKE ON.
NOT EVERY THERAPEUTIC PRODUCT
WILL HAVE THE EFFECT SIZE OF A
CAR T.
WE NEED TO TAKE A GRIP ON THAT.
THERE WILL BE MUCH CLOSER
THERAPEUTIC INDEX AND WE NEED TO
THINK ABOUT HOW DO WE GET THEM
INTO A CONFIDENT PRODUCT EVERY
TIME WE MANUFACTURE IT.
NEXT SLIDE PLEASE.
SO, A LOT OF EFFORT THAT WE HAVE
PUT IN, AND THIS IS NOT NEW TO
THE CHEMICAL ENGINEERS, WE DO
THAT IN BIOPROCESSING ALL THE
TIME, IS TO USE -- DESIGN
EXPERIMENTS AND MASSIVE PARALLEL
DESIGN, MULTIOMIC MEASUREMENTS
OF CELLS AND THE PROCESS, AND
THEN ITERATIVELY CONTINUOUSLY
IMPROVE THE PROJECT TILL WE
UNDERSTAND THE PROCESS DEEP
ENOUGH TO FIGURE OUT WHAT ARE
THE PROCESS PARAMETERS THAT
CONTROL QUALITY ATTRIBUTES OF
CELLS AND HOW REPRODUCE
REPRODUCIBLY DO THAT.
YOUR PROBABILITY INCREASES.
SO, WE HAVE OVER THE YEARS
THOUGHT ABOUT THIS, THIS IS
PUBLISHED WORK.
WE'VE LOOKED AT CAR T, FOR
EXAMPLE, USING THIS TYPE OF
MACHINE LEARNING TYPE APPROACHES
TO MEASURE BOTH METABOLOMICS
PARAMETERS AND LIPIDOMICS
PARAMETERS AND TRANSCRIPTOMICS
PARAMETERS, AND THEN IDENTIFYING
QUALITY ATTRIBUTES AND PROCESS
MEASUREMENT ATTRIBUTES THAT
PREDICTIVE OF END PRODUCT
QUALITY.
THAT'S THE LEFT SIDE OF THE
CARTOON I SHOWED.
NEXT SLIDE PLEASE.
WE HAVE PUBLISHED SEVERAL OF
THESE.
SO, FOR EXAMPLE, IN A CAR T
SETTING WE CAN PREDICT WHAT THE
PRODUCT QUALITY, THE PERCENTAGE
OF MEMORY T CELLS, TYPES OF
MEMORY T CELLS THAT WILL BE
GENERATED AT THE END OF THE
MANUFACTURING, AT DAY 14 BASED
ON MA TAP LOMBIC OR SECRET OMIC
MEASUREMENTS FROM DAY FOUR,
FIVE, SIX.
THIS IS CRITICAL, DE-RISKING
EFFORT FOR MANUFACTURING, MY
DIFFERENTIATION, PRODUCT
MANUFACTURING GOING IN THE RIGHT
DIRECTION.
IF I UNDERSTAND LIKE WE DO NOW
FOR iPSC PRODUCT AT FOUR
WEEKS, SIX WEEKS, EIGHT WEEKS,
I'VE JUST WASTED $5 MILLION, $2
MILLION, $10 MILLION IN
MANUFACTURING PROCESS FOR A
FAILED BATCH.
INDUSTRY WANTS TO UNDERSTAND A
FAILED BACK AT DAY 2, 3 4-RBGS,
SO THEY CAN RESTART.
A FAILED BACK IN
BIOMANUFACTURING OF CELL
THERAPIES EQUALS A DEAD PATIENT.
AND THAT IS A HUGE BURDEN FOR US
TO THINK OF WHEN WE ARE THINKING
ABOUT CAR T OR SIMILAR
MANUFACTURING PROCESSES.
NEXT SLIDE PLEASE.
SO, THIS IS A PAPER IN
PREDICTING T CELL QUALITY BASED
ON MULTI-OMICS, AND YOU CAN
CLICK ON THE NEXT SLIDE.
AND WE HAVE DONE THAT IN OTHER
PLATFORMS LIKE MSCs AND SO ON.
SO, THIS IS A PLATFORM TOOL OR A
WORK FLOW UNDERSTANDING EARLY
BATCH FAILURE OR TRAJECTORY, ONE
NEEDS TO BUILD IN MEASUREMENT
AND SENSORS IN MANUFACTURING TO
DO THAT AND CORRELATE THAT WITH
PRODUCT QUALITY.
NEXT SLIDE PLEASE.
AND THEN THE OTHER SIDE OF
THINGS -- SORRY, GO ANOTHER
SLIDE.
THANK YOU.
THE OTHER SIDE IS THAT
CORRELATION BETWEEN PRODUCT
QUALITY AND PATIENT OUTCOME, WE
STARTED THIS ACROSS FIVE
CLINICAL CENTERS USING THREE
PRODUCTS THAT ARE COMMONLY USED
IN THE STEM CELL QUOTE/UNQUOTE
MARKET, ADIPOSE BONE MARROW AS
ASPIRATE, EVERYONE SENT CELLS TO
GEORGIA TECH, SINGLE CELL, WE
CORRELATE THAT WITH THE CLINICAL
OUTCOME FOR EACH PATIENT.
THE BASE CLINICAL TRIAL RESULT
WAS PUBLISHED THIS WEEK IN
NATURE MEDICINE, OF THE
480-PATIENT TRIAL WE'RE WORKING
ON CORRELATES WITH THE
MULTI-OMICS MEASUREMENT,
INDIVIDUAL SPECIFIC PATIENT
OUTCOME.
A SHOUT OUT TO THE AMAZING
THINKING OF NIH TO ESTABLISH THE
HUB, WE SERVE AS IDCC AT GEORGIA
TECH, I JUST STEPPED DOWN FROM
THE P.I. OF THAT AS I MOVED TO
VANDERBILT, BUT THIS IS BRINGS
IN MANY OF THE PROGRAMS,
CLINICAL TRIALS AND PRE-CLINICAL
WORK AFTER CELLS GET SHIPPED TO
GEORGIA TECH FOR THIS DEEP
MULTIOMIC ANALYSIS.
AND I WOULD REALLY IMPLORE TO
MAKE SURE THESE TYPE OF DEEM
CHARACTERIZATION OF CELL THERAPY
PRODUCTS CONTINUE TO HAPPEN
ACROSS THE NIH, WHERE THERE'S A
CENTRALIZED PROGRAM, WHETHER N
NIH OR BGTC, A FUND OF FUND
MEMORIAL AS SECRETARY TO
UNDERSTANDING FOR REGULATORY
APPROVAL.
NEXT SLIDE PLEASE.
SO, THE BIGGEST ELEPHANT IN THE
ROOM IF YOU ASK OUR INDUSTRY
PARTNERS IS THAT OF QUALITY.
AND THAT REALLY MEANS WHAT ARE
MY CRITICAL QUALITY ATTRIBUTES
OF SUCH A COMPLEX DYNAMIC
PRODUCT THAT CHANGES AFTER
INJECTION INTO THE PATIENT, AND
THEN WHAT ARE THE RELATED
PROCESS PARAMETERS.
AND REALLY ANOTHER ISSUE AND
THOSE OF YOU WHO WERE AT THE
REGENERATIVE MEDICINE NATIONAL
ACADEMIES MEETING A FEW WEEKS
AGO, YOU KNOW, ALMOST EVERY
COMPANY SAID POTENCY, POTENCY,
POTENCY.
WE DON'T KNOW WHAT POTENCY
MEANS.
I REMEMBER A CONVERSATION WITH
FOLKS FROM U PENN WHO DID THE
ORIGINAL TRIALS IN PEDIATRIC ALL
AND ASKED POTENCY ASSAY FOR CAR
T.
WE'RE STILL THINKING ABOUT IT.
STEVE SAID MINE IS INJECTING
INTO THE KID.
I HAVE KNOWN OTHER THAT
PREDICTING ANYTHING WHAT WILL
HAPPEN IN THE PATIENT.
THIS IS FOR CAR T.
AND WHICH WE HAVE SO MUCH
EXPERIENCE ON.
SO UNDERSTANDING BETTER POTENCY
ASSAYS, NOW, WE NEED TO THINK
THIS IS DIFFERENT FROM RELEASE
ASSAYS.
RELEASE ASSAYS ARE DIFFERENT
THINGS WE STILL NEED TO DO
BETTER, CUT SHORT THE DURATION
OF THOSE ANALYSIS AND ASSAYS,
BUT PREDICTING POTENCY IS STILL
A HUGE GAP IN CELL THERAPY AND
AS A RESULT ALMOST MOST OF THE
CASES IN CELL-BASED THERAPY WE
DON'T KNOW THE MECHANISMS OF
ACTIONS VERY WELL, IN TERMS OF
THE NUANCES, ONE CAN SAY, YES,
CAR T CELL KILLS A TUMOR CELL,
FANTASTIC, BUT WHICH T CELLS,
WHAT FLAVOR OF T CELLS, WHAT
MAKES A DURABLE RESPONSE, WHY A
DURABLE RESPONSE IN MULTIPLE
MYELOMA PATIENT, WHY ONE PRODUCT
HAS LONGER DURABLE RESPONSE THAN
THAT OF ANOTHER COMPANY, BOTH
ARE CAR T, STILL AN ENIGMA AND
WE CAN'T DESIGN LARGE THERAPIES
WITHOUT UNDERSTANDING
FUNDAMENTAL BIOLOGIES.
NEXT SLIDE PLEASE.
AND IN MANY OF THESE CASES WHAT
WE HAVE BEEN DOING IN THE NSF
CENTER ARE BUILDING AN AREA OF
SENSORS THAT CAN BE INTEGRATED
IN THE MANUFACTURING PLATFORM.
I'LL GIVE YOU A FEW EXAMPLES.
I WILL NOT GO INTO DETAILS
BECAUSE OF TIME BUT REALLY
INTEGRATED WIRELESS SENSORS THAT
CAN GO INTO THE WALLS OF THE
BIOREACTORS AND IN REAL TIME
MEASURE PARAMETERS AND FEEDBACK
PARAMETERS, A LOT OF EFFORT IN
RAPID MICROBUILD DETECTION, NIST
HAS A CONSORTIUM ON THAT, THAT
WE'RE PART OF.
NON-DESTRICTIVE SENSORS FOR
MORPHOLOGY, CELL COUNTING, WE'RE
AT PRIMITIVE STAGES OF CELL
COUNTING.
THERE ARE FOUR, FIVE, SIX I
GUESS INSTRUMENTS FOR AUTOMATED
CELL COUNTING IN THE MARKET.
I CAN GUARANTEE YOU THEY ALL
COME IN WITH DIFFERENT ANSWERS
FOR A SINGLE VIAL OF CELLS.
THAT'S THE REALITY OF THE
TECHNOLOGY RIGHT NOW.
METABOLIC IMAGING,
NON-DESTRUCTIVE, SO MANY.
YOU CAN CLICK THROUGH THE NEXT
THREE OR FOUR SLIDES PRETTY
QUICKLY.
SO, YEAH, THE OTHER THING I WANT
TO MENTION, TAKE A LITTLE BIT OF
TIME HERE FOR A MINUTE, AND
THINK ABOUT POTENCY ASSAYS.
WE BELIEVE THAT THE ORGANOID
FIELD AND TISSUE CHIP FIELD HAS
A LOT OF POTENTIAL IN DEVELOPING
BETTER POTENCY ASSAYS, IF WE CAN
TAKE CARE OF MANUFACTURING OF
REPRODUCIBLE MANUFACTURING OF
ORGANOIDS AND TISSUE CHIPS.
SO THIS IS A VERY, VERY GOOD
COLLABORATION, POTENTIAL
COLLABORATION WITH NCATS THAT
CAN HAPPEN IN CREATING DISEASE
MODELS, WHERE CELL THERAPY CAN
TESTING YOU.
THIS IS MODEL OF BONE MARROW
WITH A BONE LAYER, VAST CAR ON
TOP.
THE NEXT COUPLE SLIDES, WE HAVE
BEEN WORKING ON CREATING PATIENT
SPECIFIC MULTIPLE MYELOMA MODELS
WHERE THE MULTIPLE MYELOMA CELLS
ARE PRIMARILY PERIVASCULAR.
AND THEN WE HAVE BEEN FLOWING
CAR T CELLS THROUGH THE
VASCULATURE TO LOOK AT THE BONE
MARROW MULTIPLE MYELOMA
MICROENVIRONMENT.
THERE ARE COMPANIES NOW, LARGE
PHARMA COMPANIES, MOVING IN THIS
DIRECTION, AN AREA I HOPE THE
NIH INVESTS ON.
THE LAST SLIDE OR SO I WILL TALK
ABOUT IS THIS IDEA OF IN-PROCESS
MEASUREMENT AND MODULATION.
THE IDEA HERE IS TO REALLY SHIFT
THAT GAUSSIAN DISTRIBUTION OF
PATIENT OUTCOMES FROM RESPONDER
TO NON-RESPONDER AND PUSH THAT
TO A MORE RESPONDER SIDE BY
CREATING A UNIFORM PRODUCT
QUALITY THAT IS REFLECTIVE OF
THE PATIENT'S OUTCOME.
THIS REQUIRES UNDERSTANDING
CQAs, UNDERSTANDING PROCESS
PARAMETERS, REQUIRES
UNDERSTANDING AND DEVELOPING
TOOLS FOR CONTINUOUS OR REALTIME
MEASUREMENTS, AND UNDERSTANDING
ABOUT PROCESS VERY WELL TO BE
ABLE TO CONTROL THE PROCESS TO
GET A FIXED QUALITY PRODUCT.
NEXT SLIDE PLEASE.
AND I WILL END AT THIS SLIDE SO
THIS IS, YOU KNOW -- YOU CAN
CLICK THROUGH THIS.
REALLY A BIOREACTOR SYSTEM,
MANUSCRIPT UNDER REVIEW, WE TIKE
A FIBER CELL REACTOR, BUILT IN
SENSORS, CREATED A DIGITAL TWIN
MODEL FULLY COMPUTATIONALLY
BASED ON STANDARD BIOREACTOR
EQUATIONS, AND THEN WE HAVE A
GLUCOSE AND LACTIC MEASUREMENTS,
OPTICAL MEASUREMENTS BUILT IN
TO ROBLE AT -- CONTROL AT A FIX
THE LEVEL RATHER THAN SPIKING IT
EVERY FEW DAYS, DATA AVAILABLE
IN THE CAR T SPACE AND MSC SPACE
LOOKING INTO EFFECT MUCH
CONTINUOUSLY CONTROLLED FEEDBACK
CONTROL BIOREACTOR.
I THINK THIS TO ME IS A PLATFORM
AGNOSTIC TYPE OF INVESTMENT THAT
IS WORTH HAPPENING AND WE'RE NOT
THE ONLY ONE.
FOLKS OUT OF CATAPULT AND UCL
ARE DOING THIS VERY WELL.
A LOT OF RECENT DEVELOPMENT IN
INDUSTRY IN TERMS OF CLOSED LOOP
MANUFACTURING SYSTEM STILL DON'T
HAVE ENOUGH SENSORS DEVELOPED
AROUND THAT AND WE THINK THAT IS
ABSOLUTELY NEEDED.
I WANT TO STOP TO GIVE FIVE
MINUTES FOR QUESTIONS, IF WE CAN
JUST GO AND CLICK THROUGH THE
LAST SLIDE, THAT'S FINE.
I HAD SEVERAL SENSOR EXAMPLES
BUT WE DON'T NEED TO GO THROUGH
THAT.
I'LL END HERE, AND HAPPY TO
ANSWER QUESTIONS OR LEAVE THEM
FOR THE DISCUSSION AT THE END.
>> DO WE WANT TO HOLD QUESTIONS
UNTIL THE END OF THE THREE
SPEAKERS OR DO WE WANT TO --
>> [OFF MICROPHONE].
>> OKAY, DO WE HAVE ANY
QUESTIONS FOR KRISH?
>> THANK YOU SO MUCH.
IT WAS A GREAT PRESENTATION.
I'M WONDERING IF YOU WOULD
ELABORATE ON YOUR DIFFERENT
DEFINITION FOR RESPONDERS AND
NON-RESPONDERS AND HOW TO LOOK
AT THAT ISSUE DIFFERENTLY IN THE
CONTEXT OF THIS TYPE OF
THERAPIES?
I'M NOT SURE I FOLLOWED WHAT YOU
WERE --
>> SO THE PROCESS, THERE ARE
MANY DIFFERENT KNOBS WE CAN
CONTROL.
OBVIOUSLY THERE'S HUGE PATIENT
VARIABILITY.
STARTING MATERIAL VARIABILITY.
DEPENDING WHETHER IT'S
AUTOLOGOUS OR ALLOGENEIC, MORE
VARIABILITY IN AUTOLOGOUS.
ONE OF THE THINGS WE SEE IS
VARIANCE IN OUR PRODUCT QUALITY,
RIGHT?
SO IF YOU TAKE CAR T, EVERYBODY
BATCH OF CAR T WE PRODUCE HAS
VERY DIFFERENT AMOUNTS OF MEMORY
T CELLS, CD8, CD4 T CELLS, ALL
KINDS OF LEVELS OF T CELLS IN
THERE.
IF YOU THINK ABOUT
iPSC-DERIVED CARDIOMYOCYTES
YOU'LL SEE A HETEROGENEOUS
DISTRIBUTION.
EVERY TIME WE HE MEASURE WE HAVE
A HETEROGENEOUS DISTRIBUTION.
VARIABILITY IN CLINICAL TRIAL
CAN COME FROM PATIENT OR PRODUCT
VARIABILITY, REALLY THROUGH
AUTOMATION PROCESS CAN WE CREATE
VERY UNIFORM REPRODUCIBLE
PRODUCT WITH A NARROW
VARIABILITY THAT CAN AT LEAST
TAKE CARE OF THAT VARIATION TO
GIVE A MUCH BETTER UNIFORM
RESPONSE IN THE PATIENT
POPULATION.
WE REALLY NEED TO LOOK AT
PATIENT VARIABILITY TO SEE WHAT
SUBSTRATA OF PATIENT CAN BE
BETTER RESPONDERS AND REALLY
PERSONALIZE OUR THERAPY TOWARDS
THAT STRATA OF PATIENTS.
>> ANY OTHER QUESTIONS?
OKAY.
THANK YOU SO MUCH FOR YOUR TIME
TODAY.
THE SECOND SPEAKER DOESN'T NEED
AN INTRODUCTION REALLY.
PROFESSOR OF ORTHOPEDIC SURGERY
AT WashU, A LEADER IN THE
FIELD OF MUSCULOSKELETAL SYSTEM.
>> THANK YOU, JOHNNY.
THANK YOU, BOB, AND THE
ORGANIZERS FOR THIS FABULOUS
CONFERENCE.
YOU'LL SEE RECURRING THEMES,
QUESTIONS THAT COME UP FOR ALL
OF US.
CAN WE GET THE SLIDES UP?
>> GIVE US ONE SECOND.
THANK YOU.
I'M GOING TO TALK ABOUT SOME
TOPICS DR. GOREMAN PROS IT,
REDESIGN STEM CELLS, MAKING
CELLS THAT HAVE SYNTHETIC
CAPABILITY FOR APPLICATION IN
REGENERATIVE MEDICINE.
WHEN WE TALK ABOUT MINIMAL
MANIPULATION, THIS IS THE OTHER
EXTREME OF MAXIMUM MANIPULATION,
HOPEFULLY TO ADDRESS A LOT OF
THESE ISSUES THAT KEEP COMING UP
IN TERMS OF REPRODUCIBILITY,
EFFICACY, SO ON, BUT AT THE COST
OF PROBABLY MAKING MORE COMPLEX
REGULATORY PROCEDURES.
AND PROCESSING SYSTEMS.
SO, OUR WORK IS FOCUSING ON THE
CONCEPT OF CELL-BASED THERAPY,
WE'VE HEARD ABOUT VARIOUS
APPROACHES TRYING TO REPAIR
FOCAL DEFECTS, WE'RE ALSO
INTERESTED IN TREATING
INFLAMMATORY JOINT DISEASES SUCH
AS RHEUMATOID ARTHRITIS AND OF
COURSE THE MOST DIFFICULT,
OSTEOARTHRITIS, WE HAVE TO
REGENERATE TISSUE, ALSO COMBAT
INFLAMMATION IN THE JOINT.
WE TALKED ABOUT UNPROVEN STEM
CELL THERAPIES.
I WOULD GO ON A LIMB AND SAY
THESE THINGS THAT ARE BEING
ADVERTISED AS STEM CELL
THERAPIES ARE NEITHER STEM CELLS
NOR THERAPIES.
THE PREMISE, IT WAS A GREAT
IDEA, JUST NOT TRUE YOU COULD
INJECT CELLS IN THE BODY, THEY
WOULD HONE TO THE SITE OF
INJURY, AUTOMATICALLY DO
EVERYTHING THEY NEED TO DO, AND
YOU SEE THESE ADS LIKE STRIP
MALL OR IN-FLIGHT MAGAZINE, THEY
KNOW WHAT YOU NEED IT, GO THERE
AND BECOME IT, AND IT'S NOT
TRUE.
THEY ALSO DO ALL THESE OTHER
THINGS, WE WERE TALKING AT LUNCH
ABOUT ADVERSE EFFECTS, STEM
CELLS CAN SHOW OVERGROWTH,
HYPERPLASIA, OSSIFICATION AND
MSCs ARE SUPPOSED TO FORM
CARTILAGE, BAD REPORTS OF
MUCUS-PRODUCING, ISSUES OF
VISION LOSS, INFECTION, WE
TALKED ABOUT THIS, VERY FEW
PROSPECTIVE RANDOMIZED CLINICAL
TRIALS, ONLY 40% ARE PUBLISHED.
SOME CLINICAL TRIALS ARE NOT
ACTUALLY HAPPENING, THEY ARE
JUST ADVERTISING FOR COMPANIES
TO USE IT TO GAIN INVESTORS OR
OTHER NOT-TRUE CLINICAL TRIALS.
SO YOU JUST HEARD FROM DR. ROY
ABOUT AN EXCELLENT CLINICAL
TRIAL THAT WAS PUBLISHED A FEW
DAYS AGO IN NATURE MEDICINE,
KRISH WAS PART OF THIS, THEY
COMPARED THREE COMMON CELL-BASED
THERAPY INJECTIONS IN THE KNEE,
BONE MARROW, ASPIRATE
CONCENTRATION, ADIPOSE STEM
CELLS, UMBILICAL CORD, YOU CAN
SEE THERE WAS NO EFFECT.
IN ANYTHING THERE WAS A PLACEBO
EFFECT WHICH IS SHOWN FOR
INJECTING ANYTHING INTO THE KNEE
OF ABOUT 30 OR 40%, WHICH IS
TYPICAL.
SO, THESE NAIVE CELL INJECTIONS
DON'T REALLY STICK AROUND.
THERE ARE ALL THESE ISSUES WITH
THESE NAIVE CELLS THAT WE'VE
TALKED ABOUT.
SORRY, THIS IS SLOW.
SO, CAN YOU BACK UP ONE?
ONE TOO FAR.
OKAY.
NOW ONE FORWARD.
SO, THE PROBLEM IS THAT THESE
CELLS ARE NOT UNIFORM.
WE'VE DONE A NUMBER OF
SINGLE-CELL STUDIES, YOU FIND
THE STANDARD PREP OF WHAT WE
CALL MSCs OR ASCs, NOT ONE
CELL TYPE AS DR. HUARD
MENTIONED, ONE IN 10,000 MIGHT
BE A TRUE MULTI-POTENT STEM CELL
BUT THIS IS A PLOT SHOWING AT
LEAST THREE TO FIVE TO SEVEN
CLUSTERS IN YOUR STANDARD MSC
PREP, WITH PASSAGE THEY CHANGE
FROM LABORATORY TO LABORATORY
THEY CHANGE, AND IF YOU INJECT
CELLS THEY ARE GONE IN A DAY OR
TWO.
MOSTLY APOPTOSE AND GET CLEARED,
DON'T HONE TO SITES.
AND THEY HAVE RELATIVELY LOW
THERAPEUTIC EFFECT.
SO, THESE LOW EFFECTS AND
INTERDONOR VARIABILITY IS A
CONSIDERABLE ISSUE TO TRY TO
ADDRESS.
SO, OUR TARGETS AND MANY OF THE
TARGETS OF THEM CELL INJECTIONS
HAVE BEEN INFLAMMATORY
PROCESSES.
SO, OSTEOARTHRITIS IN
PARTICULAR, ON THE RIGHT, GOING
FROM NORMAL JOINT TO ARTHRITIC
JOINT IS A VERY INFLAMMATORY
DISEASE.
IT'S DRIVEN BY A NUMBER OF OTHER
FACTORS SUCH AS BIOMECHANICS,
GENETICS, SO ON, BUT HAS
INFLAMMATORY COMPONENT THAT
LEADS THROUGH SOME OF OUR
CLASSIC CYTOKINES, INTERLEUKIN
1, TNF ALPHA, UPREGULATION OF
METALLOPROTEASE AND OTHER
INFLAMMATORY MEDIATORS THAT
BREAK DOWN THE CARTILAGE, CAUSE
BONE REMODELING, AND PAIN, WHICH
IS THE ULTIMATE OUTCOME IF
YOU'RE JOINT LOOKED LIKE THE ONE
ON THE BOTTOM BUT DIDN'T HURT
YOU WOULDN'T GO TO THE DOCTOR
AND WOULDN'T HAVE ANYTHING DONE
FOR IT.
SO IT'S ALL REALLY ABOUT THE
PAIN WE'RE TRYING TO TREAT.
SO, INFLAMMATION OF COURSE IS AN
IMPORTANT AND NECESSARY PROCESS
BUT WE WANT RESOLVING
INFLAMMATION.
THE CONCEPT OF WOUND HEALING OR
RESPONSE TO VACCINE OR ANYTHING
IS INITIAL INFLAMMATORY PHASE,
FOLLOWED BY A POST INFLAMMATORY
RESOLUTION, INFLAMMATION GOES
AWAY, YOU HAVE THE SECONDARY
INFLUX OF INFLAMMATORY CELLS,
CLEAN UP THE AREA SUCH AS
MACROPHAGES AND DENDRITIC CELLS.
THE PROBLEM IS NOT INFLAMMATION.
IT'S CHRONIC INFLAMMATION, OR
UNCONTROLLED INFLAMMATION.
SO, IN DISEASES SUCH AS
AUTOIMMUNE DISEASE,
OSTEOARTHRITIS, OBESITY, CARDIAC
DISEASE, MANY OTHER ONES, YOU
HAVE CHRONIC FAST --
INFLAMMATION DRIVEN BY THE SAME
CYTOKINES.
CHRONIC AND CYCLES SO YOU CAN
HAVE DIURNAL OR CIRCADIAN
VARIATION AND ENVIRONMENTALLY
TRIGGERED CHANGES IN
INFLAMMATION.
MOST THERAPIES ARE CONTINUOUS
PROTEIN.
IF HAVE YOU RHEUMATOID
ARTHRITIS YOU GET HIGH DOSES.
AS I MENTIONED THEY ARE GIVEN
CONTINUOUSLY BUT DISEASE FLARES,
GOES UP AND DOWN.
SO WE'RE GENERALLY OVERDOSING
WITH DRUGS AND WE DON'T KNOW
WHICH ONE OF THE TARGETS TO HIT.
SO WE SOMEHOW NEED TO MOMENT
MOMENT LEGS.
MULTIPLEX.
WE HAD A THOUGHT TEN YEARS AGO
WE COULD USE GENOME EDITING
METHODS TO REDESIGN THE SENSORY
APPARATUS ON A CELL, INTERNAL
GENE CIRCUITS, AND OUTPUT WHICH
COULD BE CYTOKINE INHIBITORS,
PAIN INHIBITORS, ANABOLIC
PROMOTERS.
AND LONG STORY SHORT WE STARTED
BEFORE CRISPR WAS MADE AVAILABLE
AND POPULAR BUT SWITCHED
IMMEDIATELY TO CRISPR-BASED
METHODS WHICH MADE MADE IT
EASIER, ABLE TO FIGURE OUT THE
NETWORK THAT DRIVES INFLAMMATORY
RESPONSES IN STEM CELLS ALMOST
ALL OUR WORK IN iPSCs TO
CLONE, HAVE UNIFORM POPULATIONS,
WHICH THEY ARE NOT UNIFORM BY
THE WAY, MUCH MORE UNIFORM THAN
MSCs BUT WE TALKED ABOUT THAT
EARLIER TOO.
THAT A POOL OF iPSCs IS
QUITE NON-UNIFORM.
WE CAN GO INTO GENE CIRCUITS AND
DIVERT INFLAMMATORY RESPONSES TO
A THERAPEUTIC RESPONSE AND
CREATE BIOLOGIC FEEDBACK LOOPS
WHERE WE CAN TREAT DISEASE
AUTOMATICALLY WITH THESE CELLS.
SO, BASICALLY LIKE TO THINK OF
IT AS A CELL, AS AN iPHONE YOU
CAN PUT SNIPPETS OF CODE IN,
APPS, THROUGH CRISPR OR VIRAL
METHODS.
THE FIRST ATTEMPT WAS BY A
Ph.D. STUDENT, FACULTY AT
VANDERBILT NOW, TARGETING TNF
AND IL-1 PATHWAYS, TRACK DOWN
THE GENES ACTIVITED, CAME UP
WITH TARGET GENES DRIVERS OF
THIS RESPONSE, REALLY GOOD
SURROGATES FOR CYTOKINE LEVELS
OUTSIDE THE CELL.
I WON'T GO INTO TEE OF DETAILS
BUT THIS IS PUBLISHED.
CCL2 IN PARTICULAR WAS AN
EXCELLENT SURROGATE MEASURE FOR
CYTOKINE LEVELS OUTSIDE THE
CELL, THIS WAS IN YEAR AFTER
CRISPR WAS MADE AVAILABLE, I
WENT IN USING CRISPR/CAS9 IN OUR
LAB, BASICALLY RE REPURPOSES TO
CREATE THE INHIBITOR OF TNF, SOL
I'M TNFR 1, MADE INTERLEUKIN 1
RECEPTOR AGONIST AS INHIBITOR.
THE TRICK BEHIND THAT IS TO CUT
OPEN THE CCL2 PROMOTER, PUT IN
INHIBITOR OF TLF OR IL-1, NOW
WHEN THE CELL SEES CYTOKINES IT
MAKES PROPORTIONAL AMOUNT OF
DRUG TO BLOCK THE CYTOKINE.
AND THROUGH A FEW TESTS WE WERE
ABLE TO MAKE IT PROPORTIONAL AND
AMPLIFY WITH MULTIPLE COPIES OF
THE GENE, WE CAN SUPPRESS AND
TUNE USING CRISPR CRAB, APPROACH
TO INHIBIT EXPRESSION OF
RECEPTOR.
WE SHOWED THIS WORKS WITH
INCREASING DOSE AND TIME OF TNF,
YOU MAKE MORE TNF INHIBITOR,
GENE EXPRESSION GOES UP AT FIRST
BUT SELF-REGULATES, YOU SEE ON
THE RIGHT SIDE GRAPH, AFTER A
FEW HOURS SHUTS OFF.
WE SHOWED IT COULD PROTECT THE
CARTILAGE FROM EITHER TNF OR
IL-1 INSULTS.
NEXT STEP WAS TO GO TO AN ANIMAL
MODEL, AND WE RAN INTO THE
PROBLEM OF CELL ENGRAFTMENT.
WE TRIED INJECTING CELLS.
IF I LISTENED TO THE FIRST HALF
I WOULD KNOW THEY WOULD NOT
ENGRAFT SO THEY DIDN'T AFTER TWO
DAYS ALL THE CELLS WERE GONE.
TO KEEP THEM IN PLACE, WE
ENGINEERED THEM INTO A SMALL
PIECE OF CARTILAGE.
THIS WAS ADVANTAGEOUS BECAUSE
CARTILAGE IS AVASCULAR, ANEURAL,
IT WILL SIT SUBCUTANEOUSLY OR IN
THE JOINT AND GET ALL NUTRIENTS
AND SIGNALS THROUGH DIFFUSION.
SO IT WILL SURVIVE WE SHOW OVER
SIX MONTHS WITHOUT ANY CELLS
CRAWLING OUT OR CELLS TURNING
OVER, AND WE IMPLANT THIS IN THE
BACK OF A MOUSE, SUCH AS A KBXN
MODEL OF RHEUMATOID ARTHRITIS
CAUSED BY INJECTION OF SERUM.
THIS IS DATA SHOWING INJECTION
OF CELLS, WITHIN THE CELLS --
CELLS RESPOND WITHIN 20 MINUTES
WITH THERAPEUTIC RESPONSE BUT
THEY ARE GONE WITHIN 24-48
HOURS.
IF WE USE IMPLANTS, THEY AGAIN
RESPOND WITHIN 20 MINUTES BUT
SIX MONTHS LATER THE IMPLANT IS
STILL THERE.
SO IT'S A NICE POTENTIAL FOR
VERY LONG-TERM SOLUTION.
SO, WHEN WE TEST IN THE HOUSE WE
LOOK AT PAIN SENSITIVITY, AND
WHAT WE FIND IS THAT OUR
TREATMENT GROUPS CAUSE A
SIGNIFICANT REDUCTION IN PAIN
SENSITIVITY CAUSED BY RHEUMATOID
ARTHRITIS, REDUCTION FROM
IMPLANTS, COMPLETE ELIMINATION
OF THE BONE EROSIONS CAUSED BY
RHEUMATOID ARTHRITIS.
THIS IS AN IL-1 R.A. DELIVERING
IMPLANT FOR THIS MODEL, VERY
IL-1 DEPENDENT.
NOW WE CAN MULTIPLEX.
HOW DO WE KEEP TRACK?
HOW DO WE SHUT THEM OFF IF WE
NEED TO?
WE CAN PUT IN THE OTHER APPS,
THESE ARE iPSCs, CAN BE
DIFFERENTIATED, OR VIRAL VECTORS
CAN GO INTO PRIMARY CELLS.
WE CAN BIND WITH LUCIFERASE OR
GFP, TIE TO THE THERAPEUTIC
MOLECULES TO GET A READOUT OF
INFLAMMATION AND SIGNAL.
WE CAN USE VARIOUS SMALL
MOLECULES TO TURN ON AND OFF
THOSE GENE CIRCUITS, IF YOU NEED
TO TEMPORARILY SHUT THEM OFF YOU
CAN.
WE IS A SYSTEM FOR SELF
DESTRUCT, WE KILL ALL THE CELLS.
WE GOT A TOUCH SENSOR,
MECHANICALLY SENSITIVE ENOUGH TO
MAKE DRUGS, AND I'LL TELL YOU
ABOUT THE TOUCH SENSOR AND CLOCK
APPS, WHY WE WANT THEM AND WHY
WE NEED THEM FOR DRUG DELIVERY.
THIS IS PUBLISHED A COUPLE YEARS
AGO.
MECHANOGENETICS, LIKE OPT
GENETICS, WE CAN TURN GENES ON
WITH MECHANICAL LOADING.
IF YOU HAVE CARTILAGE WHEN IT'S
LOADED YOU CAN MAKE A DRUG AND
BY LOOKING AT DIFFERENT LEVELS
OF LOADING YOU CAN GET DIFFERENT
DRUGS OR DIFFERENT AMOUNTS OF
DRUG.
WE HAVE TO IDENTIFY MECHANISMS,
THEY WERE ION CHANNELS,
DECONSTRUCT THE PATHWAY, FIND
THE HUB AND NODE GENES THAT
DRIVE THE RESPONSE TO MECHANICAL
LOADING, INSERT YOUR THERAPEUTIC
MOLECULE INTO THOSE DIFFERENT
HUBS, AND THEN SHOW THAT
MECHANICAL LOADING ACTUALLY
PRODUCES A RESPONSE.
SO, THE MECHANOSENSITIVE MOTIFS
WE FOUND A WHOLE BUNCH IN
NF-kappaB FAMILY THAT TURNED
OUT TO BE MECHANICALLY
SENSITIVE, AND OTHERS IN THE
SIGH CYCLOOXYGENASE.
AS WE ACTIVATE ION CHANNEL, OH,
WE CAN PUT THIS AS A VIRAL
VECTOR OR CRISPR.
THE BEAUTY IS WE DON'T HAVE TO
USE iPSCs.
WE DO BUT WE CAN ALSO PUT THEM
IN PRIMARY CELLS, CHONDROCYTES,
NERVE CELLS, ANYTHING, AS THEY
ARE MECHANICALLY LOADED THEY
GIVE OFF THIS THERAPEUTIC DRUG
WHICH CAN BE REPLACED WITH ANY
BIOLOGIC DRUG THAT'S A GENE
PRODUCT.
SO, WHEN WE DO THIS, I'LL SKIP
THROUGH THIS.
WE SHOW WE CAN LOAD THEM AND
WITH INCREASING LOADING THEY
MAKE THIS DRUG IL-1 R.A. WHICH
THEY DON'T MAKE NORMALLY IN ANY
QUANTITY.
WE HAVE A CIRCUIT TO MAKE THIS
DRUG.
I'LL TELL YOU ABOUT THIS NEW
AREA THAT WE FEEL WE'VE
DEVELOPED, CHRONOGENETICS,
DRIVING DRUG DELIVERY FROM STEM
CELLS WITH TIME.
AND AS YOU ALL KNOW, WE HAVE OUR
OWN CIRCADIAN CLOCKS IN OUR
BRAIN, THE MAIN CLOCK, 24-CYCLE,
RUN BY THE SUPER CHIASMATIC
NUCLEUS, IT CONTROLS PERIPHERAL
CLOCKS IN OUR BODY.
VIRTUALLY EVERY CELL HAS CLOCK
CIRCUITS, A COMPLEX TRIPLE LOOP
OF ACTIVATORS AND REPRESSORS BUT
CORE ACTIVATORS AND REPRESSORS
ARE THESE TWO GENES, THEY TURN
ON THEIR OWN REPEER REVIEWS
I OS -- REPRESSORS.
WHY DON'T WE USE THIS TO DELIVER
DRUGS AT SPECIFIC TIMES OF DAY
FROM OUR STEM CELLS?
OF ALL TISSUES, CARTILAGE HAS
ONE OF THE MOST STABLE AND
ROBUST CLOCKS.
ON THE RIGHT YOU SEE A MOUSE HIP
FROM A LUCIFERASE MOUSE, TAKEN
OUT OF THE MOUSE, SITTING IN A
BLACK BOX, WITH NO MEDIA
CHANGES, NO MOVEMENT, NO
NOTHING.
IT JUST CONTINUES TO CYCLE ON A
24-HOUR CYCLE FOR OVER A WEEK.
THE CELLS STAY ALIVE.
TURNS OUT DOWNSTREAM OF THESE
CLOCK GENES ARE HUNDREDS OF
OTHER GENES THAT ARE DRIVEN ON A
CIRCADIAN BASIS.
SO WE HAVE ALL OF THESE GENES IN
OUR BODY PARTICULARLY IN
CARTILAGE THAT GO UP AND DOWN,
MATRIX PROTEINS, ALL
INFLAMMATORY GENE CASCADES GO UP
AND DOWN ON THE 24-HOUR CYCLE.
THE TIMING OF DRUG DELIVERY AND
STEM CELL DELIVERY TURNS OUT TO
BE REALLY IMPORTANT BUT IF YOU
MISS THAT PEAK YOU'RE PROBABLY
NOT GOING TO GET AS MUCH
THERAPEUTIC EFFECT AS IF YOU HIT
IT DIRECT LIB ON THE -- DIRECT
LIP ON THE PEAK.
NEXT SLIDE PLEASE.
SO THIS HAS RAISED CONCEPT OF
CHRONOTHERAPY.
TIMING DRUG DELIVERY OR THERAPY
TO CIRCADIAN CLOCK.
THERE'S GREAT DATA NOW.
BACK ONE PLEASE.
ON AUTOIMMUNE DISEASE AND PEAK
CYTOKINE LEVELS AS YOU SEE ON
THE RIGHT-MOST GRAPH, ALL HALF
REALLY EARLY IN THE IMPORTANT, 1
TO 3 IN THE MORNING.
NO ONE TAKES DRUGS AT 1 TO 3 IN
THE MORNING.
THIS IS WHY PEOPLE HAVE MORNING
STIFFNESS, THE PEAK AFTER THE
DRUGS.
ATTEMPTS WITH DELAYED DELIVERY
DRUGS HAVEN'T WORKED.
OUR THOUGHT WHY DON'T WE
ENGINEER CELLS TO MAKE
ANTI-RHEUMATIC DRUGS AT SPECIFIC
TIMES OF DAY.
A OF iPSCs DON'T HAVE A
CLOCK, IF YOU DIFFERENTIAL INTO
A CONDO -- CHONDROCYTE THEY
FORM A CLOCK.
USING DIFFERENT PARTS WE CAN
SHIFT DELIVERY BY 12 HOURS OR
NOW WE FIGURED OUT HOW TO DO
3-HOUR INCREMENTS, TO SET UP THE
CELLS SO THEY DELIVER DRUGS AT
PRESCRIBED TIMES, ONCE A DAY,
TWICE A DAY, OR EVERY THREE
HOURS.
WE TESTED IN MICE.
BASICALLY MADE IMPLANTS, PUT
THEM IN A MOUSE, TRACKED THEM
WITH LIGHT/DARK CYCLES, TOOK
THEIR SERUM AND LOOKED AT DRUG
LEVELS.
NEXT SLIDE.
WE FOUND 6 TO 10 TIMES INCREASE
IN DRUG AT THE PEAK CLOCK HOURS
WHEN WE SWITCH THE DAYLIGHT ON
MICE, SYNCHRONIZE AND KEEP UP.
TO CONCLUDE, YOU CAN SEE HOW WE
CAN TAKE STEM CELLS, iPSCs,
EDIT GENOME, EDIT EPIGENOMEI
IT'S PUBLISHED, CREATE GENE
CIRCUITS, REPACKAGE AS CELL
THERAPY, GENE THERAPY, IMPLANT
THERAPY, AND HOPEFULLY ONE DAY
MAYBE EVEN A MULTI-IMPLANT
THERAPY.
QUESTIONS THAT COME UP, THE SAME
QUESTIONS WE'VE BEEN TALKING
ABOUT.
CAN WE CREATE CUSTOM DESIGNED
CELLS?
SOME CAN BE DELIVERED AS
NON-CELL THERAPIES TO TO
AUTOGENOUS CELLS.
GENE THERAPIES ARE AFFECTING
CELLS BUT NOT A CELL THERAPY PER
SE.
QUELLS FOR THESE CELLS ARE
PRIMARILY SAFETY AND EFFICACY,
QUALITY ASSURANCE AND SCALEUP,
WE'RE WORKING ON A SINGLE CELL
BANK THAT'S EDITED SO WE CAN DO
A LOT OF THAT ALLOGENEICALLY
OFFLINE BUT REGULATORY ISSUES
ARE CRITICAL HERE.
IT'S PROBABLY A COMBINATION
PRODUCT BUT CELLS THEMSELVES, WE
TALKED ABOUT CRISPR OFF-TARGET
EFFECT, WHICH CELLS, HOW DO WE
DELIVER.
WE'VE DEVELOPED GELS THAT WE CAN
INJECT TO MAINTAIN THE CELLS AND
THEN CELL THERAPY AND COST IS
AN ISSUE.
I THANK THE COLLABORATORS,
PEOPLE IN THE LABORATORY AND
FUNDING, AND HAPPY TO ANSWER
QUESTIONS IF WE HAVE TIME.
>> [OFF MICROPHONE].
>> CONGRATULATIONS ON THE
ADVANCES YOU MADE.
I LOVE THE IDEA OF WHERE YOU
SHOWED DOING DRUG DELIVERY IN
CARTILAGE BUT I WONDER WHETHER
IT'S WORTH THINKING GRANDIOSELY,
ESPECIALLY FOR THE SAKE OF
CONSORTIUM, WHAT IF THERE WAS A
CELL LINE THAT COULD BE MADE FOR
UNIVERSAL SYSTEMIC DRUG DELIVERY
AND DRUG COMPANIES ALL THEY HAD
TO DO WAS CLONE INTO MULTIPLE
CLONING SITE PROTEIN THEY WANT
TO DELIVER AND MAYBE PROMOTER
THEY WANT TO -- THAT WOULD
TRIGGER THAT EXPRESSION,
THINKING GENERALLY OF THE
APPROACH YOU STARTED.
WHAT ARE YOUR THOUGHTS ON THAT.
>> .
>> FABULOUS IDEA.
WE HAVE SOME BASE TECHNOLOGIES,
IT'S NOT AS PERFECT AS YOU'RE
DESCRIBING.
I KNOW WHAT YOU'RE SAYING, PLUG
AND PLAY.
WE HAVE THIS PROMOTER SITE, THIS
AMPLIFIER, MY BACKGROUND IS
ENGINEERING SO CIRCUITS AND
AMPLIFIERS.
WE CAN INSERT THESE.
WE'RE DOING THAT BUT IT'S SUCH A
LONG PROCESS WITH ALL THIS
ASSURANCE THAT WE GET IT RIGHT.
AND SO THERE MAY BE VIRAL
TECHNIQUES, SOMEONE WAS TALKING
ABOUT USING LENTIVIRUS TO GET
THINGS INTO CELLS QUICKLY,
BEFORE THE ONE-YEAR PROCESS OF
CRISPR-ING THEM IN.
IT'S PLUG AND PLAY, DIFFERENT
FOR DIFFERENT CELLS.
MOI, YOUR TRANSDUCTION
EFFICIENCIES AND EVERYTHING, BUT
I LOVE THE CONCEPT.
IF WE CAN GET DO THAT, MAYBE WE
CAN DISCUSS MORE HOW TO GET TO
THAT, THAT WE HAVE SORT OF ALL
OF THE PARTS AND THEN YOU CAN
JUST PUT IN YOUR
STIMULUS/RESPONSE.
>> SO, TO FOLLOW UP ON THE
CIRCADIAN ASPECT, FASCINATING.
I WONDER IF THINKING BROADLY IF
YOU LOOK AT DISEASES THAT HAVE
BEEN TARGETED FOR CELL-BASED
THERAPIES, THINK, FOR EXAMPLE,
ANOTHER CHRONIC INFLAMMATORY
STATE LIKE GRAFT-VERSUS-HOST
DISEASE, IS THERE EVIDENCE
THERE'S A CIRCADIAN ASPECT TO
THAT, AND THEN THE PARALLEL
QUESTION IS WHETHER OR NOT IN AN
ACUTE HYPERINTENSE INFLAMMATORY
STATE, LET'S SAY SEPTIC SHOCK OR
ARDS, IS THERE STILL A CIRCADIAN
ASPECT?
BECAUSE THIS LETS US RETHINK HOW
WE APPLY CELL THERAPIES?
>> BECAUSE THE CLOCK IS GOING UP
AND DOWN, HUNDREDS OF GENES,
MAIN DRIVER GENES ARE GOING UP
AND DOWN, IT'S A QUESTION OF THE
EXTENT.
BUT GREAT STUDY MY COLLABORATOR
DID, GLIOBLASTOMA, FOUR MONTH
HIGHER SURVIVAL IN 10 A.M., SAME
DRUG, EVERYTHING ELSE.
THE TUMOR IS CYCLING.
THE BODY IS CYCLING.
I'M SURE ANY OTHER INFLAMMATORY
PROCESSES ARE GOING TO BE
CYCLING.
WE NEED TO DECONSTRUCT TO SAY
WHEN DO YOU WANT TO DELIVER
WHAT?
WE BUILT BOTH HALFS, BOTH AT THE
SAME TIME.
TURNS OUT MECHANICAL LOADS RESET
THE CLOCK.
GETTING UP AND WALKING AROUND IN
THE MORNING RESYNCHRONIZES THE
CLOCK IN YOUR JOINTS AND GETS
EVERYTHING SORT OF HEALTHY AND
GOING AGAIN WHICH IS ANOTHER
REASON EXERCISE IS GOOD.
IT'S OBVIOUSLY LIKE EVERYTHING
ELSE, WAY MORE COMPLICATED THAN
WE HOPED INITIALLY BUT ALSO
MAKES IT REALLY INTERESTING THAT
YOU HAVE MULTIPLE TARGETS TO GO
AFTER.
AND THEY SEEM TO BE AT LEAST
ADDITIVE IF NOT SYNERGISTIC.
WE DON'T HAVE TO GET ALL, BUT
EVEN ONE PART OF THAT DYNAMIC
CHANGE IN INFLAMMATION WILL BE
HELPFUL.
IF WE GET BOTH PARTS THAT THE
EVEN BETTER.
>> FABULOUS WORK.
I'D LOVE TO DIVE MORE INTO IT.
BROADER QUESTION, YOU MENTIONED
THE VARIABILITY WITH iPSC,
WHICH IS GOING TO MIRROR THAT --
THE DONORS.
AND JUST WONDERING, WHAT IS THE
DEGREE OF VARIABILITY AND ARE
YOU LOOKING AT THESE FOR
AUTOLOGOUS APPLICATIONS?
PERSONALIZED ENGINEERING OR ARE
YOU LOOKING INTO MORE SIMILAR TO
AN ALLOGENEIC OR UNIVERSAL
ENGINEERED CELL?
>> GREAT QUESTION.
WE'VE MADE THE DECISION THAT FOR
IT TO BE CLOSE TO -- IN CURRENT
SYSTEM, CLOSE TO BEING TIME
EFFECTIVE, COST EFFECTIVE, WE
HAVE TO HAVE A TESTING
ALLOGENEIC CELL.
IT WAS PART OF THE DISCUSSION
EARLIER, WHERE WE CAN DO ALL OF
THESE EDITS, DO, YOU KNOW,
SEQUENCING TO SHOW WE DON'T HAVE
OFF TARGET EFFECTS, RUB IT --
RUN IT THROUGH A PROCESS AND
SCALE UP.
IF WE HAD TO DO AT THIS POINT
AUTOLOGOUS EDITED iPSC FOR
THIS TYPE, IT WOULD BE COST
PROHIBIT I CAN.
POET-- PROHIBITIVE.
ALLOGENEIC UNLESS GREAT
TECHNOLOGY COMES THROUGH.
FOR OUR APPLICATIONS, WE USE
LARGE LOTS OF CELLS, GET A NICE
AVERAGE, HAVE MILLIONS OF CELLS
WHERE WE SEE HOMOGENEITY POP UP
IN DIFFERENTIATION.
IF WE TAKE iPSCs ANDS HUMAN
ONES, HIT THE ENTIRE DISH WITH
ALL OUR FAVORITE GROWTH FACTORS,
YOU GET SOME CHONDROCYTES,
NEUROGENESIS, AND THEN OUR
PALATES GROW MY ANOCYTES.
THEY ARE ALREADY EPIGENETICALLY
GOING DIFFERENT DIRECTIONS, AND
WE'RE FINDING WAYS TO GET OVER
THAT, BUT JUST TO KNOW YOUR
STARTING CELL IS
EPIGENETICALLY -- BOTH FROM
RNAseq BUT ATAC-SEQ
MEASUREMENTS, DIVERSE WHEN YOU
FIRST START.
>> THE FINAL QUESTION [OFF
MICROPHONE].
>> THAT'S A GREAT QUESTION.
AND, YOU KNOW, I THINK IF WE
KNOW SOME BIOLOGIC DRIVERS, AND
INHIBITORS OF SENESCENCE, I
DON'T SEE WHY YOU COULDN'T.
IT'S ALMOST ANY BIOLOGIC
FEEDBACK LOOP, IF WE KNOW IT, WE
CAN TINKER WITH IT, RIGHT?
LIKE DIABETES IS A GREAT TARGET,
BASICALLY WHAT IT IS ALREADY.
IF WE KNOW FEEDBACK LOOP FOR
SENESCENCE, IT'S LIKE EVERYTHING
ELSE, YOU DON'T WANT TO
COMPLETELY SHUT IT OFF, WHY
HAVING A CONTROLLED LOOP IS
BETTER THAN BLASTING IT WITH
DRUGS.
SO THAT'S A GREAT IDEA.
WE SHOULD TALK MORE.
>> GREAT.
>> QUICK QUESTION, AND QUICK
COMMENT.
WHEN YOU TAKE THE EXPLANT OF
CARTAGE, STILL LIGHTING UP FOR
SEVEN DAYS, AFTER THAT THE CELLS
FOLLOW THEIR OWN PATH?
OR DOES THE EXPLANT REMAIN
SYNCHRONIZE.
>> THEY SLOWLY START TO
DESYNCHRONIZE.
IT'S A HARD EXPERIMENT TO GO
PATH THAT AMOUNT OF TIME BECAUSE
YOU HAVE TO CHANGE THE MEDIA AT
SOME POINT.
AND THE SHOCK OF CHANGING THE
MEDIA WILL OFTEN RESYNCHRONIZE
OR PARTIALLY RESYNCHRONIZE, SO
PLAYING AROUND MAKES IT
DIFFICULT TO STUDY THEM PAST
THAT TIME POINT BUT THEY JUST
START TO SLOWLY GET OFF CYCLE SO
THAT PEAK STARTS TO BECOME MORE
OF A -- SMOOTHER.
IT'S REALLY INTERESTING.
IT'S THE WORST EXPERIMENT FOR A
GRADUATE STUDENT TO TAKE
THREE-HOUR TIME POINTS FOR 72
HOURS.
MY STUDENT DID THAT TWICE.
SHE SLEPT IN THE LAB THOSE THREE
DAYS.
>> A COMMENT, HEART ATTACKS ALSO
HAPPEN MORE OFTEN IN THE EARLY
MORNING, EARLY HOURS OF THE
MORNING.
SO ALSO MAYBE SOMETHING TO THINK
ABOUT IN THE BACK OF YOUR MIND
AS YOU'RE MANIPULATING THESE
THINGS.
MAYBE IT COULD BE ANOTHER
BENEFIT.
>> YEAH, EXACTLY.
THERE'S SO MANY
CHRONOTHERAPEUTIC POSSIBILITIES.
WE DON'T EVEN KNOW ALL OF THEM.
SOME MIGHT JUST BE ACCIDENTAL,
BUT JUST ONE LAST COMMENT, SHIFT
WORK IS ONE OF THE WORST THINGS
YOU CAN DO.
WHEN YOU TOTALLY DISRUPT YOUR
CYCLE, PEOPLE WHO DO SHIFT WORK
ARE BEING SHOWN TO BE AT HIGHER
RISK FOR VIRTUALLY EVERY
DISEASE, WE JUST MINED THE U.K.
BIOBANK, INCREASE FOR OBESITY,
ALL THESE OTHER THINGS FOR SHIFT
WORK.
>> OKAY.
SO THE FINAL SPEAKER IN THE
SESSION DOESN'T NEED ANY
INTRODUCTION EITHER.
DR. TONY ATALA, WAKE FOREST.
HE IS THE DIRECTOR OF WAKE
FOREST INSTITUTE FOR
REGENERATIVE MEDICINE.
>> THANK YOU.
GREAT TO SEE YOU.
GREAT TO SEE GOOD FRIENDS AND
COLLEAGUES AND THANK YOU FOR
THIS KIND INVITATION.
WHAT I THOUGHT I WOULD DO IS
GIVE AN OVERVIEW OF THE WORK
WE'VE BEEN DOING WITH
TISSUE-SPECIFIC CELLS, TALK
ABOUT THE OPPORTUNITIES AND
CHALLENGES.
THIS IS A PICTURE OF OUR
INSTITUTE.
IT'S THE WHOLE BUILDING
DEDICATED TO THE INSTITUTE.
WE HAVE ROUGHLY LAST COUNT OVER
500 PEOPLE WORKING TOGETHER TO
BRING TECHNOLOGY TO THE BEDSIDE.
PRIMARY APPOINTMENT OF FACULTY
IS AT THE INSTITUTE.
SO, AND THEN CROSS-APPOINTMENT
IS ANOTHER DEPARTMENT SO YOU CAN
WORK WELL TOGETHER.
WE DO EVERYTHING FROM IDEA TO
PROOF-OF-CONCEPT TO PRE-CLINICAL
WORK IN ANIMAL STUDIES TO GMP
MANUFACTURING FACILITY WHICH IS
AN FDA COMPLIANT FACILITY AND
RUN CLINICAL TRIALS FROM THIS
FACILITY, OUR OWN CLINICAL TRIAL
GROUP THAT RUNS THE TRIALS AND
COORDINATES TRIALS THROUGHOUT
THE U.S.
SO, WHEN WE TALK ABOUT REGEN
MED, USING CELLS ALONE, AND A
COUPLE SLIDES TALKED ABOUT, YOU
KNOW, THE USE OF OTHER STEM
CELLS BUT I DELETED THEM KNOWING
YOU WERE SPEAKING.
AND WE HAVE TO DEAL WITH PLACEBO
EFFECT, ABOUT 35%.
THAT'S CHALLENGES WITH THESE
UNDIFFERENTIATED CELLS.
MY FOCUS IS ORGAN SPECIFIC
CELLS, INCORPORATED INTO TISSUE
ITSELF AS OPPOSED TO GOING
THROUGH THE TISSUES IN THE BODY.
SO THIS IS SOME EXAMPLES OF
TECHNOLOGIES WE HAVE PURSUED.
I'D LIKE TO TELL YOU CHALLENGES
AND OPPORTUNITIES FOR THESE.
BASICALLY WE'VE DONE WORK WITH
SKELETAL MUSCLE.
WE GO BACK MANY YEARS WITH THESE
TECHNOLOGIES, TECHNOLOGY
APPROACH WE TOOK ON EARLY ON WAS
TO TAKE A MUSCLE BIOPSY FROM THE
PATIENT, EXTEND THE CELLS
OUTSIDE THE BODY, PLACE CELLS
RIGHT BACK INTO THE PATIENT.
WE'VE DONE NOW THAT FOR MANY
DIFFERENT APPLICATIONS USING
DIFFERENT STRATEGIES BUT THE
FIRST TO GET THE CRITERIA DOWN
FOR THE CELLS TO MAKE SURE WE
HAD THE RIGHT CELLS AND RIGHT
POPULATION, IT TOOK 25 YEARS TO
GET THESE CELLS INTO PATIENTS.
ONE OF THE CHALLENGES WAS ANIMAL
MODELS, BECAUSE THE PROBLEM IS
SMALL ANIMAL MODELS DO NOT
REFLECT PATIENT OUTCOMES.
YOU HAVE TO GO TO LARGE ANIMAL
MODELS, WE SPENT A LOT OF TIME
WORKING ON THESE ANIMAL MODELS,
MODELS FROM THE TURN OF THE
CENTURY, 2000s, SO WE RESECTED
ENTIRE SEGMENT OF THE SPHINCTER
CIRCUMFERENTIALLY.
THIS SHOWS THE CANINE MODEL.
YOU CAN SEE THE SAME THING IN
THE CYSTOGRAM WHERE THE MRI AND
NERVE STIMULATION, CONSISTENT
WITH THIS INFORMATION OF MUSCLE
TISSUE THERE IN A LARGE ANIMAL
MODEL THAT WILL NOT RESOLVE ON
ITS OWN.
NEXT SEVERAL YEARS LOOKING AT
RELEASE CRITERIA, MAKING SURE WE
HAD THE RIGHT CELLS, HAVING THE
RIGHT CELL, THE SAME CELL TYPE
EVERY TIME.
THIS IS PART OF OUR STUDY WE HAD
TWO PATIENTS THAT HAD DEFICIENT
BLADDER, 7 AND 8, FIRST HAD
TYPICAL STRESS URINARY
INCONTINENCE, SHOWING SUCCESS
WITH THESE PATIENTS.
ONE OF THE CHALLENGES WAS THAT
IT'S A VERY EXPENSIVE
TECHNOLOGY.
YOU HAVE TO GO THROUGH A LOT OF
EXPENSES TO GET THIS TECHNOLOGY
OUT.
AND THERE ARE OTHER ALTERNATIVES
OUT THERE THAT MAY BE, YOU KNOW,
VERY INEXPENSIVE, MAY NOT BE AS
GOOD, NOT AS EXPENSIVE, THAT'S
WHEN WE START LOOKING AT PROOF
OF -- AT, YOU KNOW, JUST DOING
THIS AT THE PATIENT'S BEDSIDE.
WE TAKE THE BIOPSY FROM BEDSIDE,
PROCESS CELLS RIGHT THERE,
INJECT CELLS WHERE YOU NEED
THEM, TAKING THEM WHERE THERE'S
PLENTY OF TISSUE AND PUTTING
THEM IN OTHER AREAS.
WE'VE DONE THEM FOR ROTATOR CUFF
INJURY.
IF YOU HAVE A ROTATOR CUFF
INJURY, YOU HAVE A LOT OF MUSCLE
WEAKNESS, EVEN AT THE TIME OF
REPAIR BECAUSE THE PATIENT'S
ALREADY LOST THAT MUSCLE TISSUE,
CONVERTED TO FAT, INCREASED
MUSCLE FORMATION, DECREASED FAT
INFILTRATION AT THE SURGERY, AN
EXISTING CLINICAL TRIAL AT WAKE
FOREST.
AND ANOTHER TRIAL IS FOR FECAL
INCONTINENCE USING THE SAME
STRATEGY.
THIS IS ONE TISSUE, THREE
APPLICATIONS, SEVERAL PROCESSES
AND PROCEDURES.
THIS TOOK DECADES TO DEVELOP, TO
GET KIDNEY CELLS TO GROW AND
EXPAND OUTSIDE THE BODY.
YOU CAN IMAGINE CELLS EXTREMELY
DIFFICULT, TO HARVEST BECAUSE
THERE'S SO MANY CELL TYPES IN
THE KIDNEY.
WE SPENT YEARS DEVELOPING THIS
CELL BIOLOGY FOR THESE CELLS,
THEY COULD NOT BE EXPANDED.
WITH WE STARTED THIS WORK, THE
CELLS WERE NOT EXPANDABLE.
WE HAD TO DO GROWTH FACTOR
BIOLOGY TO GET THEM TO GROW AND
EXPAND, PLACED THEM INTO THE
DEVICES, MADE OUT OF COLLAGEN
IMPLANTED INTO COWS AND STEER.
THEY STARTED TO FORM NORMAL
KIDNEY ISSUE CREATING DILUTE
URINE.
THIS IS AN EXAMPLE OF THIS IN
TERMS OF HISTOLOGICALLY WHAT YOU
SEE, ON THE TOP LEFT IF WE USE A
NON-ALLOGENEIC, IT WILL REJECT,
SAME ON BOTTOM LEFT.
IF YOU CREATE USING AUTOLOGOUS
CELLS YOU WITH FORM NORMAL
PRIMARY AND DISTAL, YOU CAN SEE
THE DISTAL TUBULE AND SECRETION
OF DILUTE URINE, AND YOU CAN SEE
THE UPREGULATION AND
IDENTIFICATION OF MOLECULAR
MARKERS AND GENES PRESENT IN
KIDNEY TISSUE.
AND SO THAT WAS PUBLISHED IN THE
JOURNAL NATURE BIOTECHNOLOGY.
WHERE ARE WE TODAY?
WE CAN GO TO A 75-YEAR-OLD
PATIENT OF PATIENT, NEEDLE
BIOPSY, RETRIEVE A SLIVER OF
TISSUE WITH SMALL NEEDLE BIOPSY
AND GET CELLS TO EXPAND OUTSIDE
IN LARGE QUANTITIES, COLLAGEN
CARRIER, RESOLUTION OF KIDNEY
FAILURE, THIS SHOWS
HISTOLOGICALLY WHAT'S GOING ON,
YOU SEE TWO NATIVE GLOMERULI,
NEPHRON UNITS, PLACE A COLLAGEN
CARRIER WITH NEW KIDNEY CELLS,
YOU SEE NEW NEPHRON UNITS THAT
GET FORMED.
THIS TECHNOLOGY IS ENTERING
PHASE 3 HUMAN CLINICAL TRIALS,
NOW PUBLIC HEALTH COMPANY, TAKE
A KIDNEY BIOPSY, GROW CELLS
OUTSIDE THE BODY, PUT THEM BACK
INTO THE KIDNEY.
THE NICE THING ABOUT THIS
TECHNOLOGY, PATIENT'S OWN CELLS,
THEY ARE NOT GOING TO REJECT,
BASICALLY INK THE CELLS WHERE
THEY ARE GOING TO TAKE UP
RESIDENCE AND BE PERMANENT CELLS
THAT PRODUCE FUNCTION.
THE OUTCOME OF PHASE 1 AND 2
CLINICAL TRIALS HAVE BEEN
PUBLISHED SHOWING DELAY
BASICALLY PREVENTING PATIENTS
FROM GETTING TO DIALYSIS.
WE'VE USED A LOT OF STRATEGIES
USING BIOMATERIALS.
SO HERE IS AN EXAMPLE OF THAT.
WE TAKE A SMALL BIOPSY FOR
REPAIR, EXPAND CELLS OUTSIDE THE
BODY, TAKE A SCAFFOLD THAT WE
TUBULARRIZE, COAT THE OUTSIDE,
THE INSIDE, PUT IT RIGHT BACK
INTO THE BODY, THE PROCESS TAKES
FOUR TO SIX WEEKS.
WE BASICALLY USE MATERIALS, WE
HAVE ABOUT 60 BIOMATERIALS THAT
WE MIX AND MATCH TO CREATE THE
STRUCTURE, REVERSE ENGINEERING.
NORMAL TISSUE SAMPLES FROM HUMAN
PATIENTS, REPLICATE PROPERTIES
TO CREATE THE BIOMATERIALS THAT
WE NEED, AND WILL BE BEST FOR
THESE TISSUES.
OBVIOUSLY MATERIAL FOR BLOOD
VESSELS WILL BE DIFFERENT THAN
FOR A PIECE OF BONE.
FOR THE URETHRA, A MAJOR INJURY
WITH MOTOR VEHICLE ACCIDENT,
SCAFFOLD, THE URETHRAL, AND SIX
YEAR FOLLOW-UP, THE PILOT SERIES
WITH INJURIES ON TOP, EARLIEST
POST-OP THREE MONTHS LATER,
LATER SIX YEARS LATER SHOWING
GOOD FUNCTION JUST DID --
FUNCTIONALITY LONG TERM.
AND WITH BLOOD VESSELS, WE
EXPAND AND CREATE THESE TRILAYER
STRUCTURES.
THIS IS ACTUALLY SOME OF THE
VERY EARLY BIOREACTORS IN THE
EARLY 1990s, CREATED TUBULAR
STRUCTURES THEY WOULD COLLAPSE.
WE WENT TO OUR BIOMECHANICAL
COLLEAGUES AT CHILDREN'S
HOSPITAL BOSTON, WE NEEDED
SOMETHING TO KEEP THESE PUMPING.
THIS IS AN EARLY BIOREACTOR YOU
SEE FOR BLOOD VESSELS.
THEY CONDITIONED BLOOD VESSEL
BEFORE IMPLANTED, CAROTID ARTERY
IMPLANTED USING THESE
STRATEGIES.
SO MUCH WORK HAS BEEN DONE IN
THIS AREA OF BLOOD VESSELS,
CHRIS BREWER IS HERE WHO I'M
SURE IS PRESENTING HIS WORK WITH
SHALL HEART VALVES, A LOT OF
THINGS GOING ON WITH
TISSUE-SPECIFIC CELLS.
WE'VE TALKED ABOUT SOME OF THESE
STRUCTURES.
FLAT STRUCTURES LIKE SKIN ARE
THE LEAST COMPLEX.
TUBULAR STRUCTURES LIKE BLOOD
VESSELS SECOND LEVEL OF
COMPLEXITY.
HOLLOW NON-TUBULAR ORGANS, CELLS
ARE MORE COMPLEX, ARCHITECTURE
MORE COMPLEX, COULD NOT GET THEM
TO GROW OUTSIDE THE BOTH, HAD TO
GO TO GROWTH FACTOR BIOLOGY.
THIS IS WHAT LED US TO BE ABLE
TO EXPAND CELLS, AGAIN MATCH
WITH BIOMATERIALS, FIRST IMPLANT
CELLS IN A THYMIC MICE.
ONCE WE SEE IT RECONSTITUTES IN
THE BACK OF A MOUSE WE GO TO
LARGER ANIMAL MODEL.
WE NEVER DO A SUBSTITUTION IN
RODENT MODEL BECAUSE EVERYTHING
WE GENERATES.
EVEN IN A RABBIT YOU HAVE TO GO
TO CRITICAL DEFECT, EVEN PARTIAL
REPLACEMENT WON'T DO.
YOU HAVE TO GO TO FULL
REPLACEMENT TO SHOW THAT THE
TECHNOLOGY WILL WORK.
ANYTHING UP TO HALF A SENT
MEETER FROM THE EDGE WILL
REGENERATE ON ITS OWN.
IN RODENTS THAT'S FAIRLY EASY TO
DO.
THIS IS A RABBIT MODEL.
WE TOOK THE ORGAN OUT.
WE THEN IMPLANTED NEW ORGAN.
X-RAYS SHOW BEFORE, DON'T SEED
IT WON'T WORK.
BY ONE MONTH IT'S NOT YET
COMPLETE.
YOU CAN SEE HERE ON THE TOP LEFT
THAT YOU CAN STILL SEE THROUGH
THE THIN MUSCLE LAYER, YOU CAN
RIGHT THROUGH TO THE SCAFFOLD
ITSELF.
IT KEEPS REGENERATING IN THE
BODY, BY SIX MONTHS FULLY
FORMED, BY THEN THE SCAFFOLD IS
DEGRADED, AND THEN THAT'S WHEN
YOU ACTUALLY CAN START TO
ANALYZE THESE LOOKING AT THE
PHENOTYPES, NORMAL BY SIX
MONTHS, MOLECULAR MARKERS AND
GENES ALSO APPROXIMATING NORMAL
BY SIX MONTHS.
MATRICES DEGRADED BY SIX MONTHS.
YOU'RE SEEING EXTRACELLULAR
MATRIX, AT SCAFFOLD DEGRADES THE
CELLS DO WHAT THEY DO IN YOUR
BODY, LAY DOWN ITS OWN MATRIX.
YOU CAN SEE THE COLLAGEN ONE,
TWO, THREE, COLLAGEN DISTRIBUTES
THAT OF A NORMAL ORGAN.
BIOMECHANICAL TESTING,
APPROXIMATES NORMAL BY SIX
MONTHS.
WE'LL LOOK AT INNERVATION,
APPROXIMATES NORMAL ORGAN BY SIX
MONTHS.
CRITICALLY IMPORTANT YOU TEST
INNERVATION IN VITRO.
WE TAKE SAMPLES AND DO STUDIES
TO SHOW INNERVATION IS COMING
FROM THE TISSUE YOU ARE
ENGINEERED NOT THE PERIPHERY,
TAKING TO PATIENTS, AN MRI, A
PATIENT WITH VAGINAL AGENESIS,
YOU SEE THE RECTUM ON THE RIGHT,
BLADDER ON LEFT, AND IT'S A
RUDIMENT TEMPORARY STRUCTURE,
TAKE A BIOPSY, EXPAND CELLS
OUTSIDE THE BODY, CREATE THE
CONSTRUCT, THE TEENAGE PATIENT
HAD THE ENGINEERED IMPLANT ONE
YEAR LATER, THAT'S WHAT YOU SEE
RIGHT THERE.
WE FOLLOWED THESE PATIENTS FOR
EIGHT YEARS.
WE FOLLOWED THESE PATIENTS WITH
YEARLY ENDOSCOPY AND BIOPSY AND
MOLECULAR TESTING, YEARLY
MRIs, AND YEARLY FUNCTIONAL
TESTING TO SHOW ORGANS CONTINUE
TO DO WELL OVER TIME.
AND SO FUNCTIONALLY THEY DID
VERY WELL, AND WE PUBLISHED THAT
IN " THE LANCET," MANY PEOPLE
ASK WHY DID YOU WAIT EIGHT YEARS
FOLLOW UP?
IF YOU'RE DOING TYPICAL
RECONSTRUCTIVE SURGERY USING
BOWEL OR SKIN, YOU SEE FAILURE
UP TO YEAR FIVE.
WE WANTED TO MAKE SURE WE WERE
WAY PAST THAT TIME LINE TO MAKE
SURE THERE WERE NO CHALLENGES.
WE'RE CONTINUING THIS WORK,
IMPLANTED ENGINEERED VAGINAL
ORGANS THROUGH SIX WEEKS AGO AT
WAKE FOREST.
THE FIRST ORGAN WE IMPLANTED WAS
A BLADDER BUT I'M SHOWING ORDER
OF COMPLEXITY.
WITH BLADDER, THE SAME STRATEGY,
SMALL BIOPSY OF THE BLADDER,
EXPAND CELLS OUTSIDE THE BODY,
CREATE CONSTRUCT, SEED WITH
EPITHELIAL CELLS, OUTSIDE WITH
MUSCLE CELLS, PLACE IN
BIOREACTOR, BACK INTO THE
PATIENT.
PUBLISHED PRE-CLINICAL WORK IN
NATURE BIOTECHNOLOGY, IF WE HAD
KNOWN WE WOULD HAVE NOT STARTED
WITH LEVEL 3 BUT IT HELPED US
DEVELOP THE OTHER ORGANS.
THESE WERE PATIENTS WITH END
STAGE BLADDER DISEASE AND SO
THEY RECEIVED THEIR TREATMENT,
AND THIS IS ACTUALLY THE STUDY
THAT GAVE US THE IDEA TO DO
IMAGING.
THIS IS A LONG TIME AGO, WE DID
NOT HAVE THE ABILITY TO
DETERMINE WHAT SIZE OR CONSTRUCT
WE SHOULD BE SO THEY WOULD FIT
INSIDE THE PELVIC CAVITY.
WE WENT TO OUR COLLEAGUES,
PHYSICISTS IN RADIOLOGY, ALSO AT
BOSTON, TO RECONSTRUCT AND THE
PELVIC CAVITY, ENGINEERS
CONSTRUCTS SPECIFICALLY FOR EACH
PATIENT.
WE SIZE THEM BASED ON WHAT WE
THOUGHT THE PELVIC CAVITY WOULD
ACCOMMODATE.
THIS IS ENGINEERED BLADDER
IMPLANTED, AAP AND LATERAL VIEW,
SCAFFOLD ON TOP, ON THE BOTTOM
LEFT YOU SEE THE ENGINEERED
BLADDER BEING IMPLANTED WITH
OMENTUM, SHOWING THE PATIENT
BEFORE AND AFTER SURGERY A YEAR
AFTER SURGERY.
MOST IMPORTANT WAS KEEPING THOSE
PRESSURES DOWN.
THERE'S ACTUALLY A PAPER
PRESENTED BY DR. ALLEN REDDICK,
SURGEON IN CHIEF CHILDREN'S
HOSPITAL IN HARVARD MEDICAL
SCHOOL, AS CHILDREN GREW
GLADDERS CREW -- BLADDERS GREW
WITH THE PATIENTS.
YOU NEED NEED TO CYCLE.
THIS WAS OUR ORIGINAL PAPER IN "
THE LANCET," AND IT'S TAKEN A
LONG TIME BECAUSE WE TRANSFERRED
THIS TO A COMPANY, AND THEN THE
COMPANIES END UP SPENDING
INORDINATE AMOUNTS OF MORE --
AMOUNTS OF MONEY TO GET IT OUT
THE DOOR.
WHEN DO YOU REACH TECHNOLOGY TO
INDUSTRY?
ANOTHER DISCUSSION.
THIS IS ACTUALLY SHOWING THE
FORMATION OF SOLID ORGANS.
BY FAR THE THOSE COMPLEX ORGANS
ARE SOLID ORGANS, THE THALL USS
IS VASCULAR.
THIS GAVE YOU WILLS THE IDEA
USING SOLID ORBANS, IN -- IN
THE ORGANS.
WE HAD THE IDEA, WHY DON'T WE
TAKE A DONOR SOLID ORGAN, MILD
DETERGENTS, WASH CELLS AND REUSE
THAT STRUCTURE FOR THE ORGAN.
THIS IS A TOTAL REPLACEMENT
SHOWING ON THE TOP LEFT THE
NORMAL CONTROL, AND TOP RIGHT
THE ENGINEERED.
THIS SHOWS VASCULARITY, CONTROLS
DID NOT DO WELL.
BY SIX MONTHS PRESSURES WERE
SIGNIFICANT, WE WERE ABLE TO
MATE THESE ANIMALS WITH FEMALE
PARTNERS, WERE ABLE TO SHOW
PREGNANCY RATES THROUGH THESE
ENGINEERED ORGANS, AND THIS IS
NOW APPROVED BY FDA TO PROCEED
TO PHASE 1 HUMAN CLINICAL
TRIALS.
BASICALLY THIS IS WORK FUNDED BY
THE DoD DUE TO IMPROVISED
EXPLOSIVE DEVICES.
THIS SOLID ORGAN STRATEGY WE
STARTED WITH THE PHALLUS WE
TRANS TRANSFERRED TO THE
DELIVER.
IT WORKED WITH SMALL MODELS LIKE
FERRETS.
IT ONLY WORKS WELL FOR THE LARGE
AREA WHERE THE CAPILLARIES ARE
AT.
IF YOU GO TO THE END CAPILLARIES
THEY START TO CLOT OFF.
AND THEN A SITE FOR THROMBI.
WE'RE ABLE TO REPRODUCE ALL THE
ELEMENTS, IN TERMS OF HEPATOCYTE
DIFFERENTIATION FROM HUMAN FETAL
LIVER, THEY DO SECRETE ALBUMIN
AND UREA, YOU'RE STILL NOT READY
FOR PRIME TIME IN HUMANS, THE
SAME FOR KIDNEYS AND OTHER
ORGANS.
IT'S GOOD FOR THE PHALLUS
BECAUSE IT'S SPONGY TISSUE
WITHOUT END CAPILLARY.
TECHNOLOGY TWO DECADES AGO WE
LOOKED AT PRINTING THESE
STRUCTURES, CREATING PRINTERS TO
DO THIS IN A BETTER WAY.
THIS WAS A 14-YEAR PERIOD TO
CREATE PRINTERS WHERE THEY HAVE
FIVE FEATURES, NUMBER ONE SMALL
NOZZLES, RISK WE CAN DEPOSIT
CELLS WHERE NEEDED, THAT'S
FEATURE 2.
THAT'S VERY IMPORTANT TO DO THAT
REPRODUCIBLE.
NUMBER 3 THEY RETAIN INTEGRITY,
THEY DON'T SPLATTER.
NUMBER 4 CREATE MICROCHANNELS,
TO MAKE SURE THE NUTRITION
IMPOSE TO CENTRAL PORTION OF
CONSTRUCT.
AND FEATURE NUMBER 5 IS WE USE
CURRENTLY AVAILABLE 3D IMAGING
SYSTEMS LIKE TERRA RECON
AVAILABLE IN EVERY MAJOR
HOSPITAL, CREATE OUR SOFTWARE
PROGRAM TO PRINT STRUCTURES
SPECIFICALLY FOR THIS SPECIFIC
DEFECT.
THAT WAS ALSO HIGHLIGHTED IN
NATURE BIOTECHNOLOGY IN 2016.
A RECENT PAPER JUST COME OUT
THREE WEEKS AGO.
THERE'S A PAPER WHERE WE'RE ABLE
TO PRINT, PUBLISHED IN SCIENCE,
TRANSLATIONAL MEDICINE, PRINT
FULL THICKNESS SKIN, SHOWING CAN
YOU IN FACT CREATE FULL
THICKNESS SKIN WITH ALL SIX
LAYERS WITH ALL THREE LAYERS,
ALL SIX CELL TIMES.
THIS JUST GOT PUBLISHED A FEW
WEEKS AGO.
THIS PRINTER, THERE'S A
CHALLENGE NASA PUT OUT TO CREATE
SOLID TISSUE TO REMAIN ALIVE
OUTSIDE THE BODY FOR ONE MONTH,
CRITICAL FOR NASA.
IN TERMS OF SPACE TRAVEL, YOU
THIS WAS A CHALLENGE FOR US,
ANYTIME WE ENGINEER TISSUE WE
PUT IT BACK INTO THE PATIENT.
HERE WE WERE ASKED TO KEEP IT
FOR A MONTH AND ALSO SOLID
TISSUE.
TWO ENTRIES IN COMPETITION.
WE ENTERED TWICE, TWO OUT OF 22
ENTRIES WERE OURS.
ONE YEAR BEFORE THE CHALLENGE
WAS OVER, THERE WERE STILL 17
STANDING.
ONLY TWO TEAMS MADE IT TO THE
END.
THEY NEVER AWARDED THIRD PRIZE
BECAUSE NO OTHER TIME COULD
ACHIEVE IT.
BOTH TEAMS WERE OUR TEAMS AT THE
INSTITUTE.
AND THE REASON WE WERE ABLE, WE
HAD SPENT 14 YEARS DEVELOPING
THESE PRINTERS THAT REALLY DO
ALLOW YOU TO HAVE THIS VASCULAR
NETWORK THAT IS NECESSARY.
SO JUST IN MAY OF THIS YEAR THE
ACTION ROCKET WENT UP INTO SPACE
WITH PRINTED KIDNEY AND LIVER
STRUCTURES, AND WE HAD FOUR MORE
MISSIONS FUNDED BY NASA AND THE
INTERNATIONAL SPACE --
INTERNATIONAL LABORATORY.
EVERYTHING IS A USE OF
ORGAN-SPECIFIC CELLS THAT I'VE
DESCRIBED.
WE CAN DIFFERENTIATE INTO
TISSUE-SPECIFIC CELLS, THAT'S
ALSO GOOD STRATEGY.
AND WE PREFER OF COURSE FIRST
STRATEGY BECAUSE YOU USE
AUTOLOGOUS CELLS THAT WON'T
REJECT, THEY KNOW WHAT THEY ARE
BUT THIS IS A PRACTICAL
STRATEGY, EXTREMELY USEFUL, JUST
LET ME SHOW THIS WORK WE JUST
PUBLISHED ALSO THIS YEAR.
THIS IS FOR STAGE 4 CARTILAGE
DEGENERATION.
HERE WE TAKE CELLS FROM THE
PATIENT, WE DIFFERENTIATE INTO
CARTILAGE PHENOTYPE.
AND BY DIFFERENTIATING CELLS
THEN THE CELLS ARE ABLE TO GET
INCORPORATED AND THEY DO GET
RETAINED INSIDE THE BODY.
THIS IS ONE OF THOSE PATIENTS, A
TRIAL THAT WAS DONE, YOU CAN SEE
THE AREA OF THE EROSION ON THE
LEFT, AND THE REGENERATED AREA
ON THE RIGHT.
YOU CAN SEE FUNCTIONAL DAILY
LIVING, SYMPTOM IMPROVEMENT,
IMPROVEMENTS OF THESE PATIENTS,
PUBLISHED IN SCIENCE ADVANCES IN
APRIL OF THIS YEAR.
YOU CAN SEE THIS WAS A PATIENT
SERIES WITH ALL THE WORK THAT
WENT BEHIND IT, FORMING TRUE
ELASTIC CARTILAGE.
NOW WE REPEATING WITH PLACENTAL
STEM CELLS, DOING THE WHOLE
THING, DIFFERENTIATE CELLS.
WE POSTULATED ABOUT 25 YEARS AGO
WHETHER THERE WOULD BE A STEM
CELL PRESENT IN AMNIOTIC FLUID
AND PLACENTA, AND IT WAS A
FISHING EXPEDITION BUT DID FIND
A STEM CELL WITHIN THE AMNIOTIC
FLUID AND PLACEBO THAT WOULD
GIVE RISE TO ALL THREE GERM
LAYERS.
THIS IS A SEED KIT ISOLATION
THAT ALLOWS YOU TO GO INTO ALL
THREE GERM LAYERS.
THE CELLS, THIS SLIDE YOU SEE
HERE TOOK THREE YEARS TO CREATE.
YOU HAD TO PROVE THE CELLS WERE
CLONAL AND YOU COULD GET ONE
CELL FROM ONE CELL TO HAVE
CLONALITY UNTIL THREE GERM
LAYERS IN THE DERM.
THE CELLS HAD MARKERS CONSISTENT
WITH EMBRYONIC CELLS INCLUDING
SOX2, MARKERS CONSISTENT WITH
ADULT STEM CELLS.
WHEN YOU LOOK AT A STEMLESS
ANALYSIS IT'S VERY CLOSE LIP
RELATED TO iPS AND HSLs, NOT
AS MUCH ADULT CELLS.
PRESERVE TELOMERE LENGTH, BUT
THEY DON'T FORM THE TUMORS.
THAT'S THE KEY.
THEY DON'T FORM THE TERATOMAS.
AND SO THESE CELLS CAN BE USED
AS ANTI-INFLAMMATORY CELL, LIKE
YOU WOULD OTHER CELL TYPES BUT
THEY HAVE MUCH HIGHER
ANTI-INFLAMMATORY PROPERTIES,
AND YOU CAN USE THEM FOR
IMMUNOMODULATION, OR YOU CAN USE
THEM TO DIFFERENTIATE THEM AND
TO TAKE THEM INTO SPECIFIC
TISSUE TYPES.
AND SO THESE CELLS, YOU CAN GET
THEM JUST AT THE TIME OF BIRTH,
STORE THEM.
THEY DON'T FORM THE TUMORS, LIKE
OTHER CELL TYPES RAPID LIP
EXPAND AND DO GO INTO THREE GERM
LAYERS AND CAN BE STORED AT THE
TIME OF BIRTH, AND CLONAL SO YOU
CAN KEEP THEM GOING FOR LONG
PERIODS OF TIME.
NO CELL IS PERFECT, NEITHER IS
THIS ONE.
THE WEAKNESS WITH THE CELL IS
THAT IT REALLY TAKES YOU LONGER
TO DRIVE IT.
SO, FOR EXAMPLE, WITH A HUMAN
EMBRYONIC OR iPS CELL YOU CAN
DRIVE TO LIVER CELL WITHIN 14
CELLS, 10 DAYS EVEN, WITH THESE
IT TAKES 20 TO 21 DAYS TO DRIVE
TO THAT PHENOTYPE, THAT'S ALSO
THE SAME PROPERTY THAT ALLOWS
CELLS TO -- CELLS ARE JUST NOT
AS PRIMITIVE, MORE ESTABLISHED.
THIS ALSO IS HIGHLIGHTED IN
NATURE BIOTECHNOLOGY, STEM CELLS
FROM THE WOMB, AFTER ALL THESE
YEARS ENTERING THE CELLS INTO
THE CLINIC, CLINICAL TRIALS, WE
HAD TO PROVE SAFETY BEFORE DOING
THAT.
SO TO SUMMARIZE WHAT I'VE TRIED
TO DO TODAY IS GIVE AN OVERVIEW
OF USING TISSUE-SPECIFIC CELLS.
THE ADVANTAGE IS THAT ONCE YOU
DRIVE THEM, THEY ARE GOING TO
GET INCORPORATED INTO THE TISSUE
AND BE THERE LONG TERM.
CHALLENGES ARE COST OF
PRODUCTION AND ABILITY TO MAKE
SURE THAT YOU HAVE THE
FACILITIES NECESSARY TO PRODUCE
THESE.
THIS IS A MULTI-DISCIPLINARY
TEAM, I'VE PRESENTED A LOT OF
WORK IN THIS AREA.
THIS IS, YOU KNOW, IT TAKES CELL
BIOLOGISTS, MOLECULAR
BIOLOGISTS, PHYSIOLOGIES, WE
HAVE OUR OWN FACILITY WITH A
TEAM THAT ALLOWS YOU TO RUN
THESE TRIALS.
AND THIS IS A LIST OF OUR
FACULTY AND STAFF, AND OUR
FUNDING SOURCES THAT MADE THIS
WORK POSSIBLE.
THANK YOU FOR YOUR ATTENTION.
>> THANK YOU, TONY.
WHEN YOU TRANSPLANT THE LIVER
CELLS, YOU SAID THAT YOU COULD
ONLY GET THROUGH THE LARGEST
VESSELS BECAUSE OF CLOGGING.
IF YOU DO THAT, YOU WAIT SOME
TIME WHILE IT'S IN THE ANIMAL OR
WHEREVER YOU'RE PUTTING IT TO
ENSURE IT DO YOU GET
REGENERATION IN THE LIVER IN
SUCH TREMENDOUS REGENERATION ON
ITS OWN, SO DOES THAT ACT AS
FEEDER OR SEED POPULATION FOR
REGENERATING THE LIVER
ALTOGETHER?
>> IT DOES.
IT REALLY DOES, ROSEMARY IS
QUICK TO SEE.
I MUST SAY, I THINK THE KEY
THERE IS TO REPLACEMENT TAKE THE
CENTRAL PORTION OF THE LIVER
THAT HAS ALL THOSE LARGE VESSELS
BECAUSE FURTHER OUT YOU GET, THE
SMALLER CAPILLARIES.
SO I THINK THERE'S A STRATEGY
THERE WHERE YOU CAN TAKE THE
CENTRAL PORTION WHERE YOU HAVE
THE LARGE VESSELS, USE THAT AS A
SEED.
AS YOU KNOW, THAT'S THE STRATEGY
WE USE WITH THE KIDNEY, YOU
DON'T GET INTO KIDNEY FAILURE
TILL OVER 90% OF ORGAN IS GONE.
YOU WANT THE EXTRA 10%.
SO I THINK THAT WOULD BE THE
RIGHT STRATEGY TO PURSUE.
>> FABULOUS TALK.
iPS VERSUS STEM CELLS, IF YOU
CAN EXPAND TISSUE STEM CELLS TO
ENOUGH CLINICAL SCALE CAN YOU
OVER ADVANTAGES AND
DISADVANTAGES?
>> ABSOLUTELY.
THANKS, TONY.
GOOD TO SEE YOU AS WELL.
THE INTERESTING THING IS, YOU
KNOW, PLUSES AND MINUSES, RIGHT?
WE NEED TO THINK THAT THERE'S NO
PERFECT CELL.
THAT'S THE BOTTOM LINE, RIGHT?
THEY ALL HAVE THEIR PLUSES AND
MINUSES.
I THINK IT DEPENDS ON THE
PATIENT INDICATION, RIGHT?
AND THE CONDITION.
AND IT ALSO DEPENDS ON, YOU
KNOW, IT'S PERSONALIZED
MEDICINE.
FOR SOME PEOPLE YOU DON'T HAVE
THOSE CELLS TO HARVEST.
THEREFORE STEM CELLS ARE GOING
TO BE A GREAT RESOURCE.
FOR SOME PATIENTS YOU DO HAVE
THOSE CELLS YOU CAN HARVEST, A
PERSONALIZED APPROACH USING
THEIR CELLS IS THE BEST.
WITH PERSONALIZED APPROACH IT IS
PATIENT SPECIFIC.
YOU HAVE TO GROW THOSE CELLS
EVERY TIME.
BUT YOU ARE -- YOU DO HAVE
ADVANTAGE OF NO REJECTION.
WITH THEM CELL POPULATION YOU
CAN HAVE UNIVERSAL BANK BUT
STILL DEALING WITH PROBLEMS OF
REJECTION.
I THINK THESE ARE SOME
CHALLENGES WE HAVE, AND IT
DEPENDS, IF I'M LOOKING AT A
20-YEAR-OLD, YOU KNOW, AS
OPPOSED TO 70-YEAR-OLD, WHAT
WOULD I DO?
WHAT WOULD YOU DO?
THE SAME THING, ARE YOU LOOKING
AT SOMETHING LIKE KIDNEY FAILURE
OR SOMETHING LIKE DIABETES?
AND SO ALL THOSE FACTORS COME
INTO PLAY, YOU CAN'T DISCARD ANY
ONE CELL CATEGORY.
YOU HAVE TO SAY THIS IS THE MENU
WE HAVE, AND WHAT IS THE BEST
APPROACH FOR THE FUTURE.
>> WOW!
THAT'S ALL ONE CAN SAY FOR
EVERYBODY YOU'VE DONE.
MAYBE I MISSED THIS.
WHEN YOU'RE GROWING THE
AUTOLOGOUS KIDNEY CELLS YOU'RE
IMPLANTING, HOW ARE THOSE
ACTUALLY IMPLANTED WITH THE
QUESTION HOW DO THEY KNOW HOW TO
HOOK UP WITH COLLECTING SYSTEM,
EVERY OTHER PART OF THE ANATOMY?
>> IT'S REALLY INTERESTING.
THIS WAS THE BILLION DOLLAR
QUESTION WHEN WE STARTED THIS
WORK 30 YEARS AGO, 33 YEARS AGO,
STARTED TO THINK WE STARTED
KIDNEY WORK 33 YEARS AGO AND
COULDN'T GET THE CELLS TO GROW,
USING MAGNETIC SORTERS TO
ISOLATE THE GLOMULERAR LINE, WE
GAVE UP, LET'S GROW THE CELLS
TOGETHER, THAT'S WHAT WORKED,
GROWING ALL THE CELLS TOGETHER
IS WHAT ALLOWED US TO GET CELLS
TO EXPAND.
WHEN WE STARTED IMPLANTING INTO
DEVICES IN THE LABORATORY, THEY
STARTED FORMING TUBULES.
AND ACTUALLY FILTERING THE BLOOD
IN THE MEDIA, SERUM AND MEDIA,
JUST AMAZING.
BOOM, THERE IT WENT.
THE CELLS REALLY DO HAVE ALL THE
GENETIC INFORMATION TO CREATE A
WHOLE NEW YOU, DOLLY WAS CLONED
WITH ONE CELL.
THE CELLS HAVE THE PROGRAMMING.
IF YOU TAKE THE TISSUE, SEVEN OR
EIGHT LAYERS, NINE MAX, YOU TAKE
THE CELLS, THAT'S WHAT THEY DO,
THEY ARE PROGRAMMED TO DO THAT.
AND SO IT'S INSIDE PROGRAMMING
THAT ALLOWS CELLS TO DO WHAT
THEY NEED TO DO, AND YOU SAW THE
SLIDES.
YOU SAW THE NEW NEPHRONS.
THEY DO RECONNECT.
I THINK PART OF THE PROBLEM IS
THAT WE HAVE BEEN TAUGHT, YOU
KNOW, FOR SO MANY DECADES, YOU
KNOW, LIKE PLASTIC SURGEONS,
RIGHT?
PLASTIC SURGEONS ARE TAUGHT
THAT, YOU KNOW, YOU'RE GOING TO
CREATE A TISSUE TRANSFER, AND
YOU'RE PUTTING A FLAP, AND YOU
ARE MOVING A FLAP OVER.
THE WAY YOU MOVE THE FLAP YOU
HAVE TO MAKE SURE IT HAS THE
RIGHT WIDTH COMPARED TO LENGTH,
THE RIGHT VESSELS TO SURVIVE.
WE THINK WILL REGEN MED, IT IS
END OF THE DAY YOU'RE PUTTING
IN CELLS, NOT TISSUE, YOU HAVE A
BETTER CHANCE THAN WITH A FLAP.
>> IT'S A GREAT QUESTION.
OTHER EXAMPLES.
WE GO IN, WE DO KIDNEY SURGERY,
RIGHT?
AND IN THE OLD DAYS YOU WOULD
OPEN THE KIDNEY UP BEFORE YOU
COULD SHOCK THESE KIDNEY STONES,
THE ONLY WAY COULD YOU GET A
KIDNEY STONE OUT WAS TO GO IN
AND OPEN THE ENTIRE KIDNEY UP
LIKE A -- YOU KNOW, AND JUST
FILLET IT OPEN, GO IN AND GO
THROUGH THE WHOLE THING AND TAKE
THE STONES OUT AND PUT IT BACK
TOGETHER.
AND GUESS WHAT, YOU GO BACK FOR
ANOTHER KIDNEY STONE, YOU CAN'T
TELL THAT THERE'S A SCAR INSIDE
THE BODY.
YOU CAN'T SEE ANYTHING.
AND SO THE BODY HAS A NATURAL
HEALING ABILITY.
LIKE WHAT WAS SAID ABOUT THE
LIVER, REGENERATE.
YOU KNOCK A THIRD OUT, YOU COME
BACK WITH AN MRI, THERE IT'S THE
NEW LIVER AGAIN.
HOW DID THAT HAPPEN, RIGHT?
IT HAPPENS ONE CELL AT A TIME.
CELLS GET IN THERE, DO WHAT THEY
ARE SUPPOSED TO DO AND RECONNECT
LIKE THEY ARE SUPPOSED TO.
WE SEE IT EVERY TIME WE DO
SURGERY.
EVERY TIME YOU CUT, YOU'RE
SPLITTING THE TISSUE, AND YET IT
HEALS BACK.
SO, THAT'S JUST THE WAY THE BODY
IS DESIGNED.
IT'S VERY HARD TO CONCEPTUALIZE
ACTUALLY BUT THAT'S WHAT OCCURS.
>> THANK YOU.
MY QUESTION, CONNIE, STANFORD,
MY QUESTION IS RELATED TO
TRANSPLANTATION OF THE KIDNEY
CELLS, PUTTING IT BACK IN A
DISEASED KIDNEY.
IS THERE A POINT WHERE THE
KIDNEY IS SO DISEASED THAT IT
WOULD COMPROMISE THE CELLS SO
THAT'S ONE SIDE OF THE QUESTION,
AND THE OTHER SIDE IS ARE THE
CELLS YOU PUT IN, DO THEY
ACTUALLY HAVE A POSITIVE EFFECT
ON THE SURROUNDING DISEASE
TISSUE?
>> AMAZINGLY GOOD QUESTION.
THAT'S A GREAT QUESTION.
I'LL TAKE THAT ONE STEP AT A
TIME.
THE FACT IS THAT THE WAY THAT
TISSUES END UP WITH FAILURE IS
DUE TO SCAR.
PROGRAMMED CELL DEATH,
APOPTOSIS, REGARDLESS OF
INSURANCE, HIGH BLOOD PRESSURE,
DIABETES, PROGRAMMED CELL DEATH,
FIBROTIC POSITION, YOU DO AWAY
WITH NORMAL TISSUE.
SO I'M GOING TO JUST SHIFT OVER
HERE A LITTLE BIT, TO TELL YOU
THAT IT'S NOT THAT THE CELLS
DON'T REPRODUCE.
THAT'S NOT WHAT IS REALLY
HAPPENING.
WHAT'S HAPPENING IS THAT YOU
HAVE TOO MUCH SCAR TISSUE FOR
THE CELLS TO REGENERATE.
THAT'S WHAT'S GOING ON.
PRIME EXAMPLE IS DIABETES,
RIGHT?
JUVENILE DIABETES.
IT'S BEEN SHOWN, RIGHT?
THIS WAS OUR HYPOTHESIS BUT WE
FINALLY SAW IT OCCUR IN
REAL-TIME LIFE.
WHAT HAPPENS IN JUVENILE
DIABETES THE CELLS, IT'S NOT
THAT YOU STOP PRODUCING CELLS,
IT'S THE IMMUNE SYSTEM IS
ATTACKING THE CELLS THAT YOU
HAVE, YOUR BODY KEEPS PRODUCING
CELLS, YOUR BODY KEEPS ATTACKING
THEM, KEEPS FORMING SCAR TISSUE
AND THEN YOU END UP WITH A SCAR
TISSUE, HIGH SUGAR.
IT'S NOT THAT YOUR CELLS STOP
REPRODUCING.
THE FIBROTIC CHALLENGE IN REGEN
MED IS THE NUMBER ONE CHALLENGE
BECAUSE REGARDLESS OF THE
DISEASES YOU'RE ENCOUNTERING AT
THE END OF THE DAY IS THE
DISEASE THAT IS BASED ON
FIBROSIS, IF YOU CAN GET RID OF
FIBROSIS YOU CAN GIVE THE TISSUE
POWER TO REGENERATE.
FOR THE KIDNEY, GETTING BACK TO
THE KIDNEY, PHASE 1 IS TO USE
THESE CELLS THAT YOU CAN PUT IN,
AND YOU'RE BASICALLY CREATING
NEW SPACE WITH THE COLLAGEN
YOU'RE PUTTING IN, CREATING NEW
SPACE FOR CELLS TO GROW INTO.
PHASE 2 IS TO CREATE A WAFER
THAT YOU CAN PUT IN, PLUG AND
PLAY TYPE OF THING.
AND IT DEPENDS ON SEVERITY,
RIEPT NOW THEY ARE ON THE WAIT
TO KIDNEY FAILURE AND DIALYSIS,
HOPEFULLY WE CAN ADVANCE TO
OTHER POPULATION AREAS.
>> LAST QUESTION, VERY
INTERESTING.
I WONDER IF YOU WOULD DISCUSS
ONE OR TWO OF THE MOST
SIGNIFICANT REGULATORY
CHALLENGES THAT UP HAD WITHIN
THESE CLINICAL TRIALS.
>> WE WERE WAY TOO EARLY.
YOU KNOW, THE FDA KEPT CHANGING
THE NEEDLE.
THEY KEPT CHANGING THE GOAL
LINE.
I'LL NEVER FORGET, WHEN WE
IMPLANTED THE BLADDER, I GOT A
PHONE CALL FROM PHIL, THE HEAD
OF THE FDA.
IS CELIA HERE IN THE AUDIENCE?
RICHARD IS HERE.
YOU KNEW -- YOU WERE BACK IN
THOSE DAYS.
I GET A PHONE CALL.
OH MY GOSH, WHAT DID I -- WHEN
WE PUT IN THE BLADDER IT WAS NOT
BEING REGULATED.
THERE WAS NO REGULATIONS BECAUSE
THERE WAS NO SUCH THING.
SO THERE WERE NO REGULATIONS
WHATSOEVER.
AND SO I GOT A CALL FROM HIM IN
MY OFFICE.
I WAS STILL IN BOSTON.
I ANSWERED THE PHONE.
NICE OF HE SAID NICE PAPER, WE
DON'T REGULAR IT, SO YOU'RE
OKAY.
BUT WHY ARE YOU CALLING ME?
I'D LOVE FOR YOU TO VISIT ME.
NEXT TIME YOU'RE IN D.C.
I HAD A STUDY SECTION THE MONTH
LATER, CAME TO D.C.
WENT TO SEE PHIL.
AND, YOU KNOW, PHIL SAID HELLO.
I WANT YOU TO KNOW WE WANT TO
START LOOKING AT THIS AND
REGULATING THIS.
WE'RE THE GOVERNMENT, HERE TO
HELP YOU.
HE MEANT IT.
HE REALLY MEANT IT.
AND SO THEN HE INTRODUCED ME TO
SOMEONE IN THE ROOM, AND HE SAID
BY THE WAY, THIS IS THE
INDIVIDUAL WHO IS GOING TO BE
LOOKING AT THIS EXTENSIVELY.
AND THAT INDIVIDUAL IS ACTUALLY
STEVE BAUER.
AND SO STEVE BAUER WAS RIGHT
THERE ACROSS FROM THE LINE,
THAT'S WHEN I MET STEVE.
STEVE WAS AT THE FDA FOR 31
YEARS, AND HE WAS BRANCH CHIEF
OF CELL AND TISSUE THERAPY FOR
THE LAST 16 YEARS.
HE RETIRED IN NOVEMBER.
AND I TELL YOU THE SMARTEST
THING WE EVER DID WAS RECRUIT
STEVE.
HE'S ALSO WITH US AT THE REGEN
MED, TRYING TO HELP COMPANIES
REGULATE.
HE WILL BE THE FIRST TO TELL YOU
THE REASON THE GOAL LINE KEPT
MOVING WE WERE LEARNING MORE AS
WE WENT ALONG, VERY IMPORTANT
NOT TO HURT PATIENTS, THE NUMBER
ONE DIRECTIVE.
s I THINK THE FDA HAS BEEN
EXTREMELY GOOD.
I REALLY HAVE TO SIT HERE AND
SAY THAT THE FDA HAS DONE IT THE
RIGHT WAY EVERY SINGLE STEP.
THEY ALWAYS HAVE HAD PATIENT --
YOU KNOW, PATIENT WELL-BEING IN
FRONT OF THEM.
SO I THINK THAT, YOU KNOW, IS
THIS BLACK BOX WHEN YOU FIRST
START INTERACTING WITH THE FDA?
OF COURSE WE INTERACTED WITH
THEM A LOT WITH A LOT OF OUR
TECHNOLOGIES OVER THE YEARS.
THEY WERE ALWAYS HELPFUL.
THEY ALWAYS WANT YOU TO SUCCEED.
YOU HAVE TO GO IN KNOWING THE
RIGHT QUESTIONS.
I THINK THE NUMBER ONE CHALLENGE
IS KNOWING WHAT YOUR QUESTION
NEEDS TO BE, THAT YOU NEED TO
ANSWER.
AND THAT YOU'RE WELL PREPARED
WITH THE SCIENCE AND RELEASE
CRITERIA FOR TECHNOLOGIES BEFORE
YOU TAKE THEM THERE SO YOU DON'T
HAVE TO REINVENT THE WHEEL AND
FAIL.
SO TALK TO THEM EARLY.
TALK TO THEM OFTEN.
INTERACT WITH THEM.
THAT'S MY ADVICE.
THEY HAVE BEEN A GREAT PARTNER
AND GREAT RESOURCE FOR US.
>> GREAT.
LET ME THANK YOU FOR THE GREAT
TALKS.
>> WE'LL TAKE A 15-MINUTE BREAK
AND START AT 4:00, GO TO 4:30 AT
PLANNED.
I THINK WE'VE COVERED A LOT OF
WHAT WE WANTED TO GET OUT OF THE
NEXT SESSION, WHICH IS A SUMMARY
OF BRINK THE TOPICS TOGETHER
INTO FOCUS, WE'LL SPEND 30
MINUTES ON THAT STARTING AT 4:00.
SO WHEN EVERYBODY IS READY.
I THINK WHAT I WILL DO IS SORT
OF GO OVER WHAT THE AIM, WHAT
THE PURPOSE OF THIS WAS.
AND THEN TURN IT OVER TO JOHNNY
TO MODERATE.
SO, WHAT WE -- THE WAY WE
PLANNED THESE COUPLE SESSIONS,
THE ONE THIS AFTERNOON AND THEN
TOMORROW MORNING, WAS TO TAKE
TWO TOPICS THAT WE THOUGHT WOULD
BE SORT OF THE PLATFORMS THAT
MIGHT APPROPRIATE FOR CELL-BASED
THERAPIES CONSORTIUM.
WE'VE HEARD ABOUT DIFFERENT
POSSIBILITIES AND INCLUDING SUCH
THINGS AS ORGANOIDS AND
EXTRACELLULAR VESICLES.
BUT A LITTLE HARDER TO GET
ALIGNMENT ON THOSE, WHO AREAS WE
COULD LIKELY GET ALIGNMENT BOTH
ACROSS NIH INSTITUTES, FEDERAL
AGENCIES WITH PRIEF SECTORS,
REGENERATIVE MEDICINE AND
iPSCs, COALESCE AND DRAW
BOUNDARY THAT COULD BE REFINED,
AND PERHAPS BY GROUPS OF
INTERNAL GROUP, TAKEN TO
INDUSTRY FOR INPUT WHAT THEY
MIGHT BE INTERESTED IN,
INCLUDING SUCH THINGS AS
POSSIBLE TRIALS.
SO, THIS SESSION WE HAD TODAY WE
HEARD FANTASTIC TALKS, EXCITING
THINGS, SHOWING POTENTIAL OF
WHAT REGENERATIVE MEDICINE COULD
BE.
BUT IT WASN'T QUITE ON TOPIC.
IT WASN'T QUITE ON STEM CELLS.
IT WAS BROADER THAN THAT.
WE HEARD A LOT OF INTERESTING
THINGS, BUT WHAT WE WANT TO DO
IN THIS SESSION NOW IS TO TAKE
THE FOCUS OF TISSUE-SPECIFIC
STEM CELLS AND THINK ABOUT WHAT
IS A SORT OF FOCUS, AN AREA OF
RESEARCH, THAT COULD BE DONE AS
CONSORTIUM THAT WOULD PRODUCE
DATA THAT WOULD BE OF INTEREST
BOTH TO US AS RESEARCHERS AND
INDIVIDUAL LABS AND NIH FUNDERS
AND TO NIH.
WITHIN THAT SPHERE OF TISSUE
CELLS, TISSUE-SPECIFIC STEM
CELLS.
AND JOHNNY AND I DISCUSSED A
COUPLE IDEAS, BUT THE POINT HERE
IS THIS IS NOT NIH TALKING TO
YOU ALL AND TELLING US WHAT WE
WANT TO DO.
THIS IS YOUR CHANCE FOR YOU ALL
TO DEFINE THIS SORT OF
CONSORTIUM-TYPE PROJECT.
WE WANT TO SEE HOW YOU DEVELOP
IT, WHAT ARE YOUR IDEAS.
WITH THAT, JOHNNY?
>> YES, I THINK, YOU KNOW, WHAT
WE HEARD ABOUT, A LOT OF
DIFFERENT THINGS.
WE LEARNED ABOUT iPS CELLS,
SMART STEM CELLS,
TISSUE-SPECIFIC STEM CELLS,
FULLY DIFFERENTIATED CELLS.
AND ONE THING I TRIED TO GATHER,
YOU KNOW, CROSS-CUTTING RESEARCH
NEEDS, AN EXAMPLE.
AS PART OF THE RMIP PROJECT, THE
CATALYST PROGRAM ALLOWS YOU LIKE
ME IN VAIL, CANNOT DO PROTEIN OR
RNAseq, I SEND THE CELLS TO
THEM, THEY DO ANALYSIS, THAT'S
ONE AREA THAT I THINK IF WE WERE
ALL DOING THIS THEN WE WOULD
KNOW WHICH WE'RE TALKING ABOUT.
I WANT TO TELL YOU IN THE
CLINICAL TRIALS I TALKED ABOUT
THIS MORNING, WE HAVE VERY FEW
STEM CELLS IN THE BONE MARROW
WE'VE INJECTED.
WE'RE TALKING ABOUT THOUSANDS OF
STEM CELLS.
THAT IS VERY IMPORTANT BECAUSE
WHEN I TALKED TO CHRIS, SEND ME
THE CELLS IN GEORGIA TECH OR
WHEREVER, I DON'T HAVE A LOT OF
CELLS.
I DON'T WANT TO GIVE IT TO YOU
BECAUSE I NEED IT BECAUSE NOW I
FEEL THE EXOSOME IS PROBABLY
VERY IMPORTANT.
I FOUND THOUSAND OF STEM CELLS
IN BONE MARROW, BILLIONS IN THE
EXOSOME.
ONE AREA TO DISCUSS AFTER THAT
IS THE FACT THAT WE TALKED A LOT
TODAY ABOUT IF I GROW THE STEM
CELLS ARE THEY AS POTENT BEFORE
STARTING TO DO THE EXPANSION AND
WITHOUT CLONAL ANALYSIS, I'VE
BEEN DOING CELLS A LONG TIME.
ONE THING IF YOU LOOK AT A
PATIENT, WHAT DO YOU DO, THE
STEM CELLS, EXPANDED, FULL BODY
RADIATION TO THE PATIENT, AND
AFTER THIS REINJECT
HEMATOPOIETIC STEM CELLS BANKED
TWO WEEKS BEFORE, THEY DON'T DO
AN EXPANSION.
THEY SAVE LIFE EVERY SINGLE DAY
WITH THIS TREATMENT SOAP THE
QUESTION THAT I -- SO THE
QUESTION I WOULD LIKE TO ASK THE
GROUP FOR SOME APPLICATION DO WE
NEED BILLIONS OF STEM CELLS?
IF THEY CAN RECONSTITUTE LITERS
OF BONE MARROW WITH A FEW
HEMATOPOIETIC STEM CELLS, WHY WE
CANNOT USE THEM TO INJECT INTO
THE KNEE JOINT OF THE PATIENT,
AND THE INJECTION, ONE THING I
KNOW, I DON'T KNOW IF IT'S
WORKING BECAUSE THE CLINICAL
TRIALS IS ON THEIR WAY NOW, WE
HAVE THE PLACEBO GLOBE, DOING
ALL THIS WORK, I CAN TELL YOU
SOMETHING, THERE IS NOT A LOT OF
STEM CELL TO START WITH AND
THOSE PATIENTS ARE GETTING
OLDER.
CLEARLY I THINK IS THERE A PLACE
SOMEWHERE, WHERE WE CAN TALK
ABOUT NOT EXPANDING THOSE STEM
CELLS, DO WE HAVE ANY
APPLICATION TO THINK OF, AND CAN
WE START TO COLLABORATE ON
SOMETHING LIKE THIS, OR MAYBE
IT'S A CRAZY IDEA BUT I REALLY
BELIEVE THIS IS SOMETHING WE
NEED TO PAY ATTENTION BECAUSE
FACE IT, IF YOU PUT THEM IN
PETRI DISHES, REMOVE THEM, CELLS
BECOME SENESCENT, NOW WE HAVE
PAPER SHOWN CLEARLY, WHEN YOU
GROW THEM, WE KNOW THE GROWING
THE STEM CELLS HAS A NEGATIVE
IMPACT ON THEIR FUNCTION.
THAT HAS BEEN PUBLISHED FOR MANY
YEARS.
WOULD LIKE TO OPEN UP WITH THIS
IF THERE'S ANY COMMENTS TO THIS.
I'M SURE THERE IS A LOT.
>> YOUR TALK WAS STRIKING YOU'RE
MAKING CARTILAGE THE SAME WAY
I'M MAKING A BLOOD VESSEL, USING
BONE MARROW MONO NUCLEAR CELLS,
YOU'RE USING DERIVED CELLS,
WE'RE CREATING TISSUES.
I TOO DID THE BACK OF THE NAPKIN
CALCULATION, SAW VERY FEW STEM
CELLS AND THEN SHOWED THE SEEDED
CELLS PLAY NO ROLE IN TISSUE
FORMATION.
I.
I THINK IT GOES BACK TO THE
NOTION OF STEM CELLS, BASICALLY
A CONCEPT THAT WAS DEVELOPED AS
PART OF DEVELOPMENTAL BIOLOGY.
I THINK WE'RE TALKING ABOUT
REGENERATIVE MEDICINE, WITH THE
SORT OF THERAPIES DISCUSSED
TODAY, WE'RE NOT TRYING TO MIMIC
DEVELOPMENTAL PATHWAY.
I THINK THERE'S VALUE IN
STUDYING THAT.
WE'VE LEARNED A LOT OF THINGS.
WHAT WE'RE TRYING TO DO IS
REGENERATE.
IF YOU THINK ABOUT REGENERATION
FROM THE EVOLUTIONARY
PERSPECTIVE WE HAVE THE ABILITY
TO REGENERATE AND LOST A LOT OF
IT.
WE STILL POSSESS SOME BUT WHAT'S
STRIKING IS WHEN YOU LOOK AT
ANIMALS THAT CAN REGENERATE,
IT'S INFLAMMATION MEDIATED
PROCESS.
I THINK INFLAMMATION, ITS ROLE
IN REGENERATION IS SOMETHING
THAT NEEDS MORE ATTENTION.
>> I WOULD SAY INFLAMMATION AND
FIBROSIS BECAUSE FIBROSIS IS
ALSO, YOU KNOW, AS TONY WAS
SAYING, ONE OF THE BIGGEST
ENEMIES FOR TISSUE REPAIR.
AND THIS IS WHY WE'RE USING
(INDISCERNIBLE).
IS THERE ANY -- YOU KNOW, PEOPLE
IN THE ROOM THAT DO SOME
INJECTION OF NON-EXPANDED STEM
CELLS?
>> IS THERE NEIGHBOR DO AN
INJECTION OF NON-EXPANDED STEM
CELL THAT HAS NOT BEEN EXPANDED.
>> SO, YEAH, WE HAVE A CLINICAL
TRIAL, WE'RE DOING BONE MARROW
AND REINJECTING BACK INTO THE
HEART, INJECTED 130 PATIENTS,
RESULTS ARE NOT FINISHED YET.
WE HAVE THOSE.
WE DO KEEP SOME CELL PRODUCT, IT
HAS A UNIQUE SPIN TO IT THAT
WE'RE TAKING POTENCY-SELECTED
PRODUCTS, SO WE ACTUALLY DO A
SMALL VOLUME BONE MARROW
ASPIRATE IT THE PATIENT, TWO
WEEKS PRIOR TO THE ACTUAL
TREATMENT TO DETERMINE WHETHER
THEY MEET CERTAIN POTENCY
REQUIREMENTS.
IF THEY DO, THEY WILL COME BACK,
INVITED BACK TWO WEEKS LATER, DO
A MUCH LARGER VOLUME BONE MARROW
ASPIRATE AND REINJECT BACK INTO
THE HEART, SO THAT'S BEEN GOING
ON.
SIMILAR TRIALS LIKE THAT IN
CARDIOLOGY HAVE BEEN DONE
BEFORE.
>> ALKALINE BURN IN ONE EYE,
STANDARD CARE TO TRANSPLANT IN
BOTH EYE, NO EXPANSION.
>> I KNEW THERE IS APPLICATION
WE CANNOT DO IT LIKE THE IPS
CELL BUT FOR SOME MAYBE WE NEED
TO LOOK INTO THIS.
>> SO, I HAVE TO TAKE A LITTLE
BIT OF ISSUE WITH SUCH AN
INTENSE FOCUS ON STEM CELLS
BECAUSE THE RMIP PROJECT INDEED
WAS DICTATED BY CONGRESSIONAL
MANDATE REQUIRING CLINICAL FOCUS
USING STEM CELLS.
THAT WAS A CONGRESSIONAL
MANDATE.
BUT THAT DOES NOT MEAN THAT THAT
DEFINES REGENERATIVE MEDICINE.
AND SO I THINK IT'S PROBABLY A
MISTAKE TO PUT SO MUCH FOCUS ON
SOME SORT OF -- IF YOU WANT TO
CALL EIGHT STEM CELL, PRECURSOR
CELL, REGENERATIVE CELL,
WHATEVER YOU WANT TO CALL IT BUT
HAVING AN INTENSE FOCUS ON CELL
BIOLOGY TAKES US AWAY FROM THE
FACT THERE'S A LOT OF NIH MONEY
GOING INTO CELL BIOLOGY, NOT AS
MUCH INTO UNDERSTANDING HOW
CELLS COME TOGETHER AND MAKE A
TISSUE OR ORGAN WHICH IS
ACTUALLY WHAT WE'RE GOING AFTER,
RIGHT?
SO, I THINK TOO MUCH EMPHASIS ON
THE CELL, PER SE, EVENING THOUGH
THAT'S THE FUNCTIONAL UNIT
IGNORES THE FACT THE CELL HAS TO
BE IN AN ENVIRONMENT.
WE TALKED ABOUT FIBROSIS, WE
DON'T KNOW MUCH ABOUT HOW WE GET
PAST THE SCARRING ENVIRONMENT.
BEYOND EVEN JUST THAT FIBROTIC
AND SCARRING ENVIRONMENT THERE'S
A TISSUE MILIEU WHICH SOMETIMES
THERE ARE ACTUALLY THINGS THAT
ARE GOING VERY CLOSE TO THE
CLINIC NOW THAT ARE IN CLINICAL
TRIALS WHERE THERE'S NO CELLS AT
ALL.
IT'S AN EXTRACELLULAR
MATRIX-BASED PRODUCT OF ONE KIND
OR ANOTHER, EITHER DECELLED OR
DE NOVOD OR SOMETHING.
WHAT WE FIND SURPRISINGLY IN
SOME CASES IS THAT AFTER TIME,
THIS THING REMODELS BECAUSE
CELLS IN THE BODY COME IN AND
THAT'S -- IT'S JUST REGENERATION
OCCURS BECAUSE WE PROVIDED THE
RIGHT ENVIRONMENT.
SO, I'M NOT SAYING WE SHOULD
JUST DO THAT, BUT I THINK AT OUR
PERIL DO WE IGNORE THAT BY
PUTTING A LASER-LIKE FOCUS ON
CELLS PER SE.
>> SO, TO FOLLOW UP AND
REINFORCE THAT, THINK ABOUT YOUR
OWN DATA, THINK ABOUT DATA WE'VE
HEARD TODAY.
LET'S USE THE KNEE AND THE
ARTICULAR CARTILAGE AS AN
EXAMPLE.
YOU GO BACK IN, YOU DON'T FIND
THE DONOR CELLS.
YOU FIND THE HOST CELLS THAT
HAVE REGENERATED.
SO, A BIG PART OF THE QUESTION
IS WHAT ARE THE CELLS WE'RE
GIVING ACTUALLY TELLING THE HOST
CELLS, TO USE THAT TERM, RIGHT?
AND IT MAY BE -- ENVIRONMENT IS
EVERYTHING.
MATRIX IS EVERYTHING, AGREED.
BUT MAYBE WORKING ON THE
SECRETOME, THE EVASE IS ONE
EXAMPLE, A HUGE OPPORTUNITY
HERE.
THIS WOULD POTENTIALLY SIMPLIFY
LOGISTICS, EASIER TO UNDERSTAND
SECRETOME AND PERHAPS MIMIC THE
SECRETOME, IT'S ANOTHER THING TO
TAKE ALL THE MANUFACTURING
LESSONS FOR THE CELLS AND APPLY
THEM TO PRODUCTION OF EVS.
THAT'S BOTH AN OPPORTUNITY AND
NIGHTMARE ACTUALLY.
BUT, AGAIN, I THINK AS WE THINK
FURTHER, THIS COULD BE A WAY TO
GO.
WITH RESPECT TO THE
iPS-DERIVED CELLS WE'RE LOOKING
AT TWO THINGS, RIGHT?
SO ENGRAFTMENT VERSUS
NON-ENGRAFT ITS.
EPITHELIAL PIG THE OR OTHERWISE,
HOW MANY REPLICATION OF INJECTED
CELLS IS THERE?
OR IS IT A COUPLE CELLS SENDING
OUT SMOKE SIGNALS TO CAUSE THE
HOST RETINAL PIGMENT EPITHELIAL
CELLS TO REPAIR THEMSELVES OR
WHAT HAVE YOU?
THAT IS WHERE THE SCIENCE OF
THIS CONSORTIUM COULD HELP OUT
WITH.
>> I TOTALLY AGREE.
I WANT TO ADD SOMETHING FOR
CARDIAC REPAIR, THEY SHOWED THE
REST OF US IF YOU INJECT STEM
CELLS INTO THE HEART YOU PROMOTE
CELL CELL REPAIR BUT THEY DO NOT
BECOME CARDIOMYOCYTE.
I AGREE A LOT OF US THAT WORK ON
CARTILAGE REPAIR INJECT INTO THE
KNEE JOINT, REPAIR CARTILAGE BUT
WE SEE VERY FEW CELL, IF ANY,
INTO THE REPAIR CARTILAGE.
THE QUESTION COMES UP DO WE NEED
EXPANDED STEM CELLS TO DO THIS?
CAN WE USE NON-EXPANDED STEM
CELLS AND MAYBE THAT'S SOMETHING
WE CAN THINK ABOUT.
>> YEAH, I WANT TO COMMENT
BUILDING ON WHAT WE'VE HEARD, I
THINK YOU'RE POSING THE QUESTION
FROM VIEW OF HEMATOPOIETIC STEM
CELL EXPERT, THAT'S REALLY
IMPORTANT.
I WANT TO CONGRATULATE YOU AND
THE ENTIRE FIELD, FOUNDATIONAL
WORK IN STEM CELLS, BUT IF YOU
THINK ABOUT THE HUMAN BODY,
BLOOD IS ONE OF MANY ORGANS,
WITH A HUGE CONTRAST BETWEEN
BLOOD VERSUS A SOLID ORGAN.
I THINK IN THINKING ABOUT WAYS
WE COULD RALLY TOGETHER AROUND
YOUR QUESTION, LET'S TRY CATCH
UP SOLID ORGAN BIOLOGY TO WHERE
ARE YOU IN THE BLOOD.
WE HEARD ABOUT THIS A SECOND
AGO.
A HUGE QUESTION OF THE NICHE
THAT'S MORE PALPABLE, HOW YOU
CLEAR CELLS IN EACH THESE
TISSUES, WHAT'S THE ANALOGY OF
RADIATION, CHEMOTHERAPY FOR
HEMATOPOIETIC STEM CELL
TRANSPLANT.
WE TALK ABOUT A DIFFERENT ORGAN
WITH NON-HEMATOPOIETIC CELLS, WE
NEED TO THINK ABOUT THAT
CONTRAST.
>> JUST AGAIN TO PUSH BACK AND
CONTINUE WHAT WAS SAID, FOR THIS
COMMON FOCUS CONSORTIUM FOR
REGENERATIVE MEDICINE CELL-BASED
THERAPIES WHAT ARE RELATIVELY
STABLE TYPES OF VARIABLES IN THE
REGENERATIVE MEDICINE PROGRAM
THAT CAN BE QUANTIFIED AND
UNDERSTOOD ACROSS PLATFORMS?
AND SO THAT I WOULD ARGUE THAT
WOULD BE A STABLE CELL TYPE
LIKE iPS, DIFFERENTIATED CELLS
UPON WHICH WE CAN LOOK AT
ENVIRONMENTAL INFLUENCES,
EXOSOME EFFECTS, TISSUE
INTERACTION, QUANTIFIED WITH
MODERN GENOMIC TOOLS AND THEN
THOSE GENOMIC TOOLS, EPIGENETIC
TOOLS CAN BE USED ACROSS
PLATFORMS AND ALSO THEN IS A
REUSABLE AND PORTABLE SET OF
INFORMATION TO GO FORWARD,
WHEREAS SOME OF THE MORE OTHER
TYPE OF APPROACHES ARE LESS
DEFINABLE AT LEAST AT CURRENT
STAGE IN TERMS OF INTERACTION IN
AND OUT AND CAN BE PORTED ACROSS
TISSUE TYPES.
>> YEAH.
>> WE HAVE TIME FOR ONE MORE
QUESTION OR COMMENT.
>> RIGHT.
>> NOT A QUESTION BUT AN ANSWER
TO YOUR QUESTION ABOUT THE RPE.
ENGRAFTMENT OF TRANSPLANTED
CELLS OCCURS AND SURVIVES FOR
THE LIFE OF THE ANIMAL.
THAT'S FOR TRANSPLANT OF RPE
CELLS.
THERE'S BEEN TRANSPLANT OF
NEURAL PROGENITOR CELLS UNDER
THE RETINA THAT STIMULATES RPE
PROLIFERATION.
I THINK BOTH ANSWERS ARE
CORRECT.
AND THEN EXOSOMES YOU MENTIONED
BUT I'LL SKIP OVER AND SAY WE
MAKE BEADS OF GROWTH FACTORS
THAT CAN STIMULATE THE RPE.
THE RPE NICHE IS TIED WITH THE
BROOKS MEMBRANE ON ONE SIDE,
PHOTORECEPTORS ON THE OTHER,
HEXAGONAL, VERY LITTLE
PROLIFERATION OCCURS NORMALLY
CAN BE STIMULATED WITH GROWTH
FACTORS OR PERHAPS WITH
EXOSOMES, WE HAVEN'T LOOKED AT
THAT YET.
BACK TO YOUR QUESTION, INCLUDING
TISSUE ITSELF, BUT HOW MUCH
TISSUE REGENERATION HAS NOT
INVOLVED STEM CELLS?
I THINK IT WOULD BE VERY LITTLE.
SO OPENING THE DOOR TO
REGENERATION MIGHT DRAG STEM
CELLS OR CELLS ALONG WITH IT.
>> A REALLY IMPORTANT STATEMENT
AND COMMAND.
THE DEFINITIONS WE'VE ALL THE
BEEN USING ARE DIFFERENT TODAY.
AND THAT'S A HUGE PART OF THE
LACK OF PROBLEM, WE CAN
ACCELERATE.
I DEFINE AS ONE THAT CAN
DIFFERENTIATE INTO AT LEAST ONE
KIND OF PROJECT -- PROGENY.
HOW DO YOU DEFINE?
>> WE NEED VACATE THE ROOM VERY
SHORTLY.
THE QUICK ANSWER IS THAT I
AGREE WITH YOUR DEFINITION OF A
SELF-RENEWING CELL THAT CAN
DIFFERENTIATE INTO SOME OTHER
TARGET TISSUE.
HOWEVER WHEN HE USE THE WORD
STEM CELL SOMETIMES WE'RE
TALKING ABOUT CELLS THAT WE GET
OUT OF THE BONE MARROW THAT ARE
PRECURSOR CELLS FOR
HEMATOPOIETIC STEM CELLS.
SOMETIMES WE GET CELLS THAT ARE
PROFESSIONAL SECRETORY CELLS.
I DON'T KNOW WHAT TO CALL THEM
BUT I KNOW IF YOU MAKE A CULTURE
OF THESE NICE CELLS THAT YOU
ISOLATE THROUGH SOME KIND OF
MARKER AND PUT THEM IN CULTURE,
THEY PEE OUT EXOSOMES LIKE
CRAZY.
SO THAT MUST BE THEIR MAJOR
THING THAT THEY DO.
ARE THEY THE SAME CELLS THAT ARE
THOSE PRECURSOR CELLS THAT MAKE
YOUR TISSUE?
I WONDER, AND I DOUBT IT
ACTUALLY, FRANKLY.
BUT WE DON'T HAVE ENOUGH ASSAYS
TO SHOW THAT, AT LEAST I HAVEN'T
SEEN ENOUGH PAPERS TO
DEMONSTRATE THAT YOU ALWAYS GET
THAT OUTCOME.
I AGREE THAT THERE'S A PRECURSOR
SINGLE-CELL CLONE THAT CAN BE
PUSHED TO MAKE CERTAIN
POPULATIONS THAT ARE
SELF-RENEWABLE BUT ONCE WE PUSH
TO SOME OTHER THING, ARE THEY
SOME OTHER THING?
ARE THEY STILL A STEM CELL?
I THINK WE THROW THIS TERM
AROUND SO MUCH WE'RE CONFUSING
THINGS.
>> IT'S FUNNY, WHEN WE WROTE THE
GRANT I WAS INJECTING BONE
MARROW ASPIRATE, I WANTED TO BE
RESPONSIVE TO THE RFA.
I HEAR THEY HAD VERY FEW STEM
CELLS THERE BUT THE QUESTION IN
THE BACK AND ONE HERE.
THIS IS OUR LAST QUESTION.
ALL THE OF THE MATURE
LINEAGES, I PUT THAT IN A
KIDNEY, WHAT DOES THE CELL DO?
I COULD BE WRONG BUT I DON'T
THINK ANYBODY HAS EXPLORED THAT.
IT GETS TO THE HEART AND SOUL OF
YOUR DEFINITION, BUT WHO CARES.
IT'S THE APPLICATION, RIGHT?
AND SO IF I COULD HARVEST A
WHOLE BUNCH OF SKIN, BASAL
CELLS, WHATEVER, SERVES AS
PROGENITOR CELLS IN THE SKIN.
IF I PUT THOSE INTO A LUNG THEY
WILL TURN INTO LUNG CELLS,
THAT'S A GAME CHANGER TYPE THING.
>> [OFF MICROPHONE].
WELL, TBD, RIGHT?
THANK YOU, GUYS.