>>WELCOME
EVERYONE. IT IS A PLEASURE TO
SEE YOU, ALL BEIT VIRTUALLY.
THANK YOU FOR JOINING THIS ROUND
TABLE, WE COULDN'T DO IT WITHOUT
YOUR PARTICIPATION. AND THESE
MEETINGS ARE VERY IMPORTANT TO
NIAMS AS WE LEARN ABOUT EMERGING
AREAS IN THE FIELD AND HOW WE
MIGHT MAKE A DIFFERENCE. I WILL
NOW TURN THE MEETING OVER TO THE
NIAMS DIRECTOR DR. LINDSEY
CRISWELL FOR OPENING REMAR REMA.
DR. CRISWELL.
>>THANK YOU, JONELLE. GOOD
MORNING EVERYONE, I'M DR. LINDS
SHY CRISWELL, DIRECTOR NATIONAL
INSTITUTE OF ARTHRITIS AND
MUSCULOSKELETAL AND SKIN
DISEASES. WELCOME Y'ALL TO OUR
ROUND TABLE ON CARTILAGE
PRESERVATION AND RESTORATION IN
KNEE OSTEOARTHRITIS. WE ARE
HOPING TODAY'S MEETING WILL HELP
TO GENERATE ADDITIONAL INTEREST
IN THE TOPIC OF CARTILAGE
PRESERVATION RESTORATION AMONG
THE NIAMS COMMUNITY AND TO THAT
END THE MEETING IS BEING
VIDEOCAST AND RECORDED AND WILL
BE AVAILABLE FOR VIEWING ON THE
NIH VIDEOCAST ARCHIVE. SO WE
GREATLY APPRECIATE YOUR
ATTENDANCE TODAY AS WELL AS --
AS YOUR EFFORTS TO GATHER
FEEDBACK FROM YOUR COLLEAGUES.
THE INFORMATION YOU PROVIDED IN
PREPARATION FOR THE ROUND TABLE
HELPED TO SHAPE OUR AGENDA, AND
WILL SUPPLEMENT TODAY'S
DISCUSSION. I WANTED TO THANK
DR. TED XANG FOR AGREEING TO
LEAD THIS MEETING AND ORGANIZING
THE ROUND TABLE HAS BEEN A TEAM
EFFORT INVOLVING IN MEMBERS OF
OUR INSTITUTE. SO OUR DIVISION
OF EXTRAMURAL RESEARCH I WOULD
LIKE TO ESPECIALLY RECOGNIZE DR.
GAIL LESTER WHO SERVES AS
DIRECTOR OF THE DIVISION, DR.
PAE, ANALYST RESPONSIBLE FOR
MUCH OF THE BEHIND THE SCENES
WORK AND PROGRAM DIRECTORS,
INCLUDING DR. LEXI BELGUN, DR.
ANTHONY, DR. MARKWITS AND DR.
CHUCK WASHABAU. I WOULD ALSO
LIKE TO RECOGNIZE STAFF FROM
ANALYSIS POLICY PLANNING BRANCH
WHO PLAYED KEY ROLES PUTTING
THIS ROUND TABLE TOGETHER. DR.
STEPHANIE BURRO, CHIEF OF THE
BRANCH, DR. JONELLE DRUGAN, DR.
VAN NGUYNEY AND DR. THOMAS
JACKSON. BEFORE I GO OVER -- I
WOULD LIKE TO PROCEED WITH
INTRODUCTIONS BY THE GROUP.
FIRST DR. BOB CARTER WHO SERVES
AS DEPUTY DIRECTOR OF THE
INSTITUTE. I WANTED TO INVITE
DR. CARTER TO SAY A FEW WORDS AT
THIS TIME. BOB.
>>GOOD MORNING. DELIGHTED TO BE
HERE WITH Y'ALL, PARTICULARLY
OLD FRIENDS AND HOPEFULLY NEW
FRIENDS. THIS HAS BEEN A LEONG
TIME BIRTHING. WE HAVE BEEN
WORKING ON THIS GOOD YEAR AND A
HALF AT LEAST AND TED HAS BEEN
IN THE MIDDLE AND APPRECIATE HIS
WILLINGNESS TO WORK WITH US AND
BE FLEXIBLE AND WORK WITH WHAT
WE THINK IS AN EXCITING AGENDA.
THERE'S AN AWFUL LOT TO TALK
ABOUT WHEN IT COMES TO
REGENERATIVE MEDICINE APPROACHES
OR HOW TO PRESERVE CARTILAGE IN
PATIENTS WITH OA. IT IS A HUGE
AREA IT IS DIFFICULT AND FRAUGHT
WITH PROBLEMS PARTICULARLY LOT
OF THINGS GOING ON WHICH THERE
IS NOT MUCH DATA ALSO ALL SORTS
OF DIFFERENT THINGS BEING TRIED
WITHOUT MUCH DOCUMENTATION WHAT
THEY ARE. BUT I WANT TO INSTEAD
OF FOCUSING ON THOSE PROBLEMS I
HOPE WE CAN FOCUS TODAY ON WHAT
THE HOPE IS. WHERE IS THE
PROMISE, THE LIGHT THAT WE CAN
SEE COMING? WHERE IS THE HOPE?
WE THINK WE HAVE TO CHANGE HOW
WE TREAT OA. WE CAN'T REPLACE
THE KNEES AND ALL THE PEOPLE
THAT NEED IT IN ANOTHER 10, 20
YEARS, WE DESPERATELY NEED NEW
WAYS TO REVERSE AND PREVENT
REGRESSION OF OA. WHAT WE ARE
DOING TODAY IS WHERE ARE THE
POSSIBILITIES, HOW CAN WE --
WHAT SHOULD WE THINK OF THE
TERMS OF HOW WE ARE GOING TO GET
THERE. SO HOPE WITH THAT FOCUS
REALLY LOOKING FORWARD TO SOME
LEARNING A LOT AND GOOD
DISCUSSION AND THANK YOU FOR ALL
FOR PARTICIPATING.
>>THANKS, BOB. IT IS ALSO
IMPORTANT FOR YOU TO KNOW THAT
NOT ONLY ARE THE LEADERSHIP AND
STAFF OF THE NIAMS PARTICIPATING
IN THIS ROUND TABLE, BUT SINCE
TODAY'S DISCUSSION INTERSECTS
WITH THE PORTFOLIOS OF OTHER NIH
AND HHS COMPONENTS, WE ASKED OUR
COLLEAGUES TO JOIN US HERE
TODAY. THUS WE ARE FORTUNATE TO
HAVE REPRESENTATIVES FROM THE
NATIONAL HEART LUNG AND BLOOD
INSTITUTE. THE NATIONAL
INSTITUTE OF DENTAL AND
CRANIOFACIAL RESEARCH AND THE
U.S. FOOD AND DRUG
ADMINISTRATION. THEIR
INFORMATION IS LISTED IN THE
ROSTER AND THEY WILL INTRODUCE
THEMSELVES SOON. NEXT I WILL ASK
EACH PARTICIPANT IN THE MEETING
TO INTRODUCE YOURSELF TO PROVIDE
A SENSE OF THE BREADTH OF THIS
GROUP THAT WE HAVE ASSEMBLED
TODAY. IN THE INTEREST OF TIME,
WE WON'T HAVE OTHER NIAMS STAFF
LISTED ON THE ROASTER INTRODUCE
THEMSELVES AT THIS TIME BUT ASK
THEY INTRODUCE THEMSELVES WHEN
SPEAKING. NOW WHEN DR. XING
CALLS YOUR NAME UNMUTE AND SHARE
YOUR NAME, INSTITUTION AND THE
EXPERTISE RELEVANT TO TODAY'S
DISCUSSION. TED.
>>GOOD MORNING, EVERYONE. MY
NAME IS TED, TED ZHENG, PROGRAM
DIRECTOR OF NIAMS AND MY
RESEARCH PORTFOLIO IS CLINICAL
OSTEOARTHRITIS AND DIAGNOSTIC
TOOLS. OVER THE LAST YEAR I
WOULD LIKE TO TAKE THIS LEAD AND
BEEN HAS BEEN PLEASURE TO WORK
WITH EACH OF YOU TO PREPARE THIS
ROUND TABLE MEETING. THANK YOU.
I WANT TO THANK EVERY ONE OF YOU
FOR PARTICIPATING TODAY'S
MEETING. I'M GOING TO CALL YOUR
NAME LIKE DR. CRISWELL SAID,
JUST BRIEFLY STATE YOUR NAME,
INSTITUTE AND AFFILIATION, ONE
OR TWO SENTENCE TO HIGHLIGHT
YOUR AREA OF EXPERTISE RELATED
TO THE ROUND TABLE. I WILL START
WITH CO-CHAIRS AND GO BY THE
LIST. BASED ON ALPHABETIC ORDER
OF YOUR LAST NAME. DR. CONSTANCE
CHU PLEASE.
>>HI, GOOD MORNING. I'M CONNIE
CHU, VICE CHAIR OF RESEARCH
STANFORD UNIVERSITY. I'M
ORTHOPEDIC MEDICINE SPORTS
MEDICINE AND ARTHROSCOPY. ACTIVE
RESEARCH IN NIH FUNDED WHERE I
GOT MY START WITH NIH, FOR MORE
THAN 20 YEARS IN JOINT
PRESERVATION AND PREVENTION OF
OSTEOARTHRITIS.
>>THANK YOU. DR. SCOTT RODEO.
>>GOOD MORNING, FIRST GOOD
MORNING TO CONNI CONNIE. I'M SCT
RODEO, ORTHOPEDIC SURGEON
SPECIAL SURGERY NEW YORK CITY I
COME AT THIS AS CLINICIAN AND
SCIENTIST. I TAKE CARE OFFER
ATHLETES IN GIANTS FOOTBALL
TEAM, RESEARCH SIDE WE USE
NUMBER OF ANIMAL MODELS TO STUDY
POST TRAUMATIC OA TENDON
LIGAMENT REPAIR, IS AS VICE
CHAIR AT HHS SO I COME AS
CLINICIAN AND SCIENTIST.
>>THANK YOU, SCOTT.
>>DR. DR. AMBIKP BAJPAYEE.
>>I HEAD THE MOLECULAR
BIOELECTROSTATICS AND DRUG
DEVELOPMENT WE ARE INTERESTED IN
DESIGNING ELECTRICALLY CHARGED
BIOMATERIALS FOR APPLICATIONS IN
DRUG DELIVERY AND IMAGING OF
NEGATIVELY CHARGED AVASCULAR
TISSUES HARD TO PENETRATE. SO WE
HAVE A SPECIAL FOCUS HERE ON
CARTILAGE REPAIR AND TREATING
OSTEOARTHRITIS FOR WHICH WE
DESIGN SUSTAINED RELEASE
THERAPIES USING CATIONIC
PEPTIDES PROTEINS AND EXOSOMES.
HAPPY TO BE HERE. THANK YOU FOR
INVITING ME. DR. BAJPAYEE.
>>DR. FRANKS BARRY.
>>I'M FRANK BARRY, MY CURRENT
AFFILIATION IS AS DIRECTOR OF
THE TRANSLATIONAL MEDICINE
INSTITUTE AT COLORADO STATE
UNIVERSITY. MY AREA OF RESEARCH
FOCUS IS MESENCHYMAL STROME A.M.
CELL THERAPY DEVELOPMENT INST
OWE ARTHRITIS AND CARTILAGE
REPAIR. VERY MUCH WITH
TRANSLATIONAL INTEREST AND VERY
HAPPY TO BE PART OF THE
DISCUSSION TODAY.
>>THANK YOU. DR. STEPHANIE
BRYANT.
>>GOOD MORNING. EVERYONE. MY
NAME IS STEPHANIE BRYANT, I'M
HERE AT THE UNIVERSITY OF
COLORADO BOULDER. I'M IN THE
DEPARTMENT OF CHEMICAL AND
BIOLOGICAL ENGINEERING AS WELL
AS MATERIAL SCIENCE AND
ENGINEERING. I'M AN HE CAN
ENGINEER BY TRAINING. AND MY
RESEARCH REALLY FOCUSES ON
DESIGNING HYDRO GELS FOR
PROMOTING CARTILAGE
REGENERATION. I'M LOOKING
FORWARD TO BEING PART OF THIS.
THANK YOU SO MUCH.
>>THANK YOU. OUR HEART LUNG AND
POLLUTE. DR. DENIS BUXTON
PLEASE.
>>GOOD MORNING, I'M DENII
BUXTON, DIVISION OF
CARDIOVASCULAR SCIENCE. I LEAD
THE NHLBI PROGENITOR CELL
BIOLOGY TRANSLATIONAL CONSOR
CONSORTIUM. AND ALSO MUCH --
SOME OF THE CLINICAL TRIALS IN
CELL THERAPY FOR NHLBI.
>>THANK YOU. SO DR. JENNIFER
ELISSEEFF. MY NAME IS JENNIFER
ELISSEEFF, BIOMEDICAL
ENGINEERING JOHNS HOPKINS AND
WORK ON STEM CELLS AN HYDRO GELS
FOR CARTILAGE REPAIR AND NOW
MOVING TO SENESCENCE AND
INFLAMMATION PATHWAYS ASSOCIATED
WITH OSTEOARTHRITIS AND
CARTILAGE DAMAGE. NICE TO BE
HERE. THANK YOU.
>>DR. ANDREAS GOMOLL.
LOOKS LIKE WE ARE MISSING HIM.
>>I DON'T THINK HE'S ON.
>>DR. DANIEL GRANDE.
>>GOOD MORNING, EVERYONE. I'M
DANIEL GRANDE, SCIENTIST, I'M AT
NORTH WELL HEALTH NEW YORK,
DEPARTMENT OF ORTHOPEDIC
SURGERY. I'M INTERESTED IN MANY
CARTILAGE REPAIR FOR A LEONG
TIME AT THIS POINT. ALSO WE HAVE
A ACTIVE PROGRAM IN REGENERATIVE
MEDICINE HERE. THANK YOU.
>>THANK YOU.
>>DR. FARSHID GUILAK.
>>I'M FARSHID GUILAK.
WASHINGTON UNIVERSITY ST. LOUIS
AND SHRINERS HOSPITALS FOR
CHILDREN IN ST. LOUIS AND MY
RESEARCH IS FOCUSED ON MOSTLY
OSTOSTEOARTHRITIS,S AND RHEUMATD
ARTHRITIS AND DEVELOPING
CELLULAR TISSUE ENGINEERING
THERAPIES TO TREAT THEM AND MOST
RECENTLY I'LL PRESENT TODAY ON
THE APPLICATION OF SYNTHETIC
BIOLOGY TO REPROGRAM STEM CELLS
AS DRUG DELIVERY VEHICLES FOR
ARTHRITIS.
>>THANK YOU. DR. MARK HOCHBERG
>>GOOD MORNING. I'M PROFESSOR
OF MEDICINE EPIDEMIOLOGY PUBLIC
HEALTH UNIVERSITY OF MARYLAND
SCHOOL OF MEDICINE IN BALTIMORE
AND DIRECTOR OF THE MEDICAL CARE
CLINICAL CENTER FOR THE VA
MARYLAND HEALTHCARE SYSTEM. AND
YOU SEE THE BALTIMORE VA MEDICAL
CENTER BEHIND ME ME. I WORKED IN
THE FIELD OF OSTEOARTHRITIS
CLINICAL EPIDEMIOLOGIC RESEARCH
FOR ABOUT 40 YEARS. AND I WILL
BE TALKING ON SMALL MOLECULES
FOR CARTILAGE REGENERATION,
SOMETHING FOR WHICH I HAVE NO
PERSONAL EXPERIENCE.
>>THANK YOU, MARK. DR. JOHNNY
HUARD.
>>I'M JOHNNY HUARD, CHIEF
OFFICER OF THE STEADMAN
PHILIPPON RESEARCH INSTITUTE AND
DIRECTOR OF MEDICINE PROGRAM
HERE IN VAIL, COLORADO. I HAVE
BEEN WORKING ON STEM CELL
THERAPY FOR OSTEOARTHRITIS FOR A
WHILE NOW AND I'M ALSO INVOLVED
IN BIOLOGICAL APPROACH TO REDUCE
INFLAMMATION TO ALIENATION OF
SENESCENCE CELLS AND DEVELOPING
BLOOD FIBROSIS APPROACH. THANK
YOU FOR HAVING ME.
>>AND OUR FROM FDA. DR. LARISSA
LAPTEVA,
>>TISSUES ADVANCED THERAPIES IN
THE CENTER FOR BIOLOGICS
EVALUATION RESEARCH AT THE FOOD
AND DRUG ADMINISTRATION. IN
ADDITION TO THAT MAYBE MORE
IMPORTANTLY I'M ALSO
RHEUMATOLOGIST, BORN AND RAISED
IN NIAMS, MORE THAN 20 YEARS AGO
WHERE I FINISHED FELLOWSHIP AND
WORKED AS A CLINICAL
INVESTIGATOR FOR A WHILE AND
THEN MOVED TO FDA. I'M ALSO
COMBINING MY WORK AT THE AGENCY
WITH THE CLINICAL CARE IN THE
RHEUMATOLOGY CLINIC IN NIAMS UP
UNTIL THIS DAY. LOOKING FORWARD
TO THE DISCUSSION. THANK YOU FOR
INVITING ME.
>>GLAD TO HAVE YOU BACK,
LARISSA. DR. CHRISTIAN
LATTERMANN PLEASE.
>>AMYE LEONG. YOU ARE NEXT.
>>GOOD MORNING, EVERYONE. AMYE
LEONG FROM SANTA BARBARA,
CALIFORNIA PRESIDENT AND CEO OF
HEALTHY MOTIVATION. MY CHARGE IS
TO BRING TO YOU AND OTHERS
PATIENT PERSPECTIVE, A PATIENT
PERSPECTIVE ON THIS. IT HAS
STARTED LIKE SOME OTHERS, BORN
OUT OF NIAMS EARLY, EARLY ON AT
THE START OF NIAMS ACTUALLY. DR.
STEVEN KATZ AND I STARTED
TOGETHER, THE SAME YEAR HE AS
DIRECTOR AND MYSELF AS APPOINTED
TO THIS NIAMS STEERING COMMITTEE
ADVISORY COMMITTEE. DELIGHTED TO
BE HERE. I BRING THE PERSPECTIVE
OF A LIFE LIVED FOR A LEONG,
LEONG TIME WITH VARIOUS FORMS OF
ARTHRITIS, ULTIMATELY
CULMINATING IN OA. I FIND IT
VERY INTERESTING THESE GROUPS OF
MEDICINE OR DISEASES ARE CLUMPED
SO CLOSELY TOGETHER THAT WE
PATIENTS AND THE PATIENT WORLD,
PUBLIC WORLD OF IT IS SO
CONFUSED BY THAT. SO I'M LOOKING
FORWARD TO BRINGING THIS
MESSAGE, MY BUSINESS BACKGROUND
IS IN ORGANIZATIONAL DEVELOPMENT
STRUCTURE ADVOCACY
COMMUNICATIONS, PROCESSES AND I
HOPE THAT CAN BE HELPFUL TO
Y'ALL. THANK YOU.
>>THANK YOU, AMYE.
>>DR. CAROLYN LUTZKO. I SAW
YOUR NAMES HERE. DR. MICHAEL
MONT.
>>OKAY. THANK YOU, TED AND
THANK YOU, EVERYONE, CERTAINLY
AN HONOR TO BE HERE. SO I'M AN
ORTHOPEDIC SURGEON AT SINAI
HOSPITAL AT BALTIMORE, WHERE I
DO MY CLINICAL WORK. I'M ALSO
THE DIRECTOR OF CLINICAL STUDIES
AT NORTH WELL IN THE SAME SYSTEM
AS DANIEL GRANDE WHO JUST
PRESENTED HIMSELF. I'M WELL
KNOWN FOR -- I HAVE ONE OR TWO
NIH GRANTS ON THE FIELD OF
AVASCULAR NECROSIS OR OSTEO
NECROSIS CO-HEADS WITH STANFORD
AND HOPKINS BUT WE ARE FROM MY
WHOLE CAREER WE HAVE BEEN DOING
CLINICAL STUDIES OF VARIOUS
INJEINJECTABLES FOR TREATMENT OF
KNEE OSTEOARTHRITIS. WE HAVE
FOUR OR FIVE CLINICAL STUDIES
ONGOING RIGHT NOW. SO REALLY
LOOKING FORWARD TO THIS PROGRAM,
I LIKE DOING HIP AND KNEE
REPLACEMENTS BUT IT IS MY LIFE
LEONG PASSION TO SAVE PEOPLE
FROM NEEDING THOSE PROCEDURES.
WELCOME, EVERYONE. THANK YOU.
>>THANK YOU. DR. GEORGE
MUSCHLER,
>>PLEASURE TO JOIN TODAY I'M
GEORGE MUSCHLER, ORTHOPEDIC
SURGEON AND BIOPROFESSIONAL
ENGINEER AT CLEVELAND CLINIC. MY
CLINICAL PRAXIS IS ONCOLOGY BUT
HOW HIP AND KNEE ARTHROPLASTY
AND RUN THE JOINT RESERVATION
CENTER WHERE WE HAVE ONGOING
CLINICAL TRIALS AND REGISTRY TO
LOOK AT EFFICACY OF BIOLOGICS.
MY RESEARCH BACKGROUND IS
STARTED IN HARVEST AND ISOLATION
AND QUANTITATIVE METRICS TO
MEASURE PERFORMANCE OF CELL
POPULATIONS AVAILABLE TO US FROM
BONE MARROW AND BONE. HELPING
WITH STANDARDS DEVELOPMENT IN
THAT AREA. AND RECENTLY
DEVELOPING A PLATFORM FOR
AUTOMATION OF IMAGE PROCESSING
AND CELL PROCESSING FOR MSC AND
IPS CELLS AS SOURCE FOR
CARTILAGE. '
>>THANK YOU. OUR COLLEAGUE FROM
NIDCR.
>>HELLO. THANK YOU FOR THE
INVITATION TO PARTICIPATE IN
THIS ROUND TABLE DISCUSSION. I'M
SENIOR INVESTIGATOR AT THE NIDCR
ON THE NIH CAMPUS AND I WORK ON
SKELETAL STEM CELLS. MY LAB
FOCUSES ON CHARACTERIZING THESE
CELLS. DETERMINING THE ROLE THEY
PLAY IN DISEASE, IN PARTICULAR
HOW TO USE NECESSARY CELLS IN
SKELETAL REGENERATION.
>>THANK YOU. DR. DANIEL SARIS.
>>GOOD MORNING, EVERYBODY.
THANK YOU FOR THE INVITATION AND
I FEEL HONORED AND EXCITED TO BE
PART OF THIS ROUND TABLE. MY
NAME IS DANIEL SARIS, ORTHOPEDIC
SURGEON IN ROCHESTER, MINNESOTA
MAYO CLINIC. THE LARGER PART WAS
IN THE NETHERLANDS WHERE WE RAN
THE TRIALS THAT LED TO CELL
THERAPY REGISTRATION IN THE EMA
AND THE FDA SPACE FOR CARTILAGE
REPAIR. I MOVE TO MINNESOTA IN
2018 AND BECAME PROFESSOR OF
REGENERATIVE MEDICINE AT MAYO
CLINIC. I RUN THE ORTHOPEDIC
SPORTS MEDICINE RESEARCH AND
CARTILAGE BIOLOGY TRANSLATIONAL
LAB AND WE ARE FORTUNATE TO HAVE
INDs OPEN FOR CELL BASED JOINT
PRESERVATION I FEEL STRONGLY
ABOUT FROM A PERSONAL, FROM
PROFESSIONAL PERSPECTIVE AND
HAVING BEEN PAST PRESIDENT OF
THE INTERNATIONAL CARTILAGE
REPAIR AND JOINT PRESERVATION
SOCIETY. LOOK FORWARD TO TODAY,
THANKS FOR THE INVITE.
>>THANK YOU. DR. SHANE SHAPIRO.
>>I'M SHANE SHAPIRO, I WORK AT
MAYO CLINIC SOUTHERN CAMPUS IN
FLORIDA. I'M CLINICIAN AND
SCIENTIST, A MEDICAL ORTHOPEDIST
IN SPORTS MEDICINE PHYSICIAN,
HAVE BEEN USING INJECTABLE
BIOLOGICS AND NON-CELLULAR
REGENERATIVE THERAPIES FOR A
NUMBER OF YEARS AND CONDUCTING
TRANSLATIONAL STUDIES, SOME
RANDOMIZED CLINICAL TRIALS, AND
ALSO DISCOVERY SCIENCE WHERE WE
PARTNERED WITH COLLEAGUES IN
MULTIPLE DISCIPLINES LOOKING AT
EXTRA CELLULAR VESICALES. AS
SUCH I HAVE FILED EIGHT FDA
INDs FOR NOVEL REGENERATIVE
THERAPIES, AND LOOKING FORWARD
TO THIS GREAT DISCUSSION, THANK
YOU FOR HAVING ME. I TOO GOT MY
START AT THE NIH AS AN
INTRAMURAL RESEARCH TRAINEE AT
NHGRI AS PART OF THE HUMAN
GENOME PROJECT. COUPLE OF
DECADES AGO. SO NICE TO BE BACK
AND PARTICIPATING.
>>THANK YOU. DR. DAN WHITE.
>>GOOD MORNING. CERTAINLY AN
HONOR TO BE HERE. I AM A
PHYSICAL THERAPIST AND ASSOCIATE
PROFESSOR AT THE UNIVERSITY OF
DELAWADELAWARE. MY MANGER OF STS
PHYSICAL ACTIVITY IN SEDENTARY
BEHAVIOR USING MONITORING
DEVICES AND WE DO THESE STUDIES
TYPICALLY IN LARGE COHORT
STUDIES AND WE HAVE AS WELL AS
CLINICAL TRIALS AND CURRENTLY I
HAVE A FDA ASKED ME TO DO AN IDE
WHICH WE GOT APPROVED TO LOOK AT
STEM CELLS, MESENCHYMAL STEM
CELLS FROM BONE MARROW ASPIRATE
AND LOOKING AT CHANGES IN
PHYSICAL ACTIVITY FROM THIS IN
PEOPLE WITH KNEE OSTEOARTHRITIS.
ALSO LIKE TO CONGRATULATE SCOTT
RODEO WITH THE TWO AND 0 GIANTS
START FIRST FILE IN A LEONG TIME
SO THANK YOU FOR HELPING THE
TEAM WITH THAT.
>>LEONG SEASON.
>>DR. LATTERMANN JOIN US.
>>HELLO, GOOD MORNING.
APOLOGIZE FOR THE DELAY. I HAD
TO GET MY POWERPOINT. MY NAME IS
CHRISTIAN LATTERMANN CHIEF OF
SPORTS BRIGHAM WOMEN'S HOSPITAL
IN BOSTON AND DIRECTOR FOR MASS
GENERAL BRIGHAM. MY RESEARCH
INTERESTS ARE IN CLINICAL TRIALS
IN CARTILAGE REPAIR AND ORTHO
BIOLOGICS AS WELL AS IN BASIC
SCIENCE. THE ETIOLOGY OF POST
TRAUMATIC OSTEOARTHRITIS,
PARTICULARLY WITH FOCUS ON
INFLAMMATION. GOOD MORNING. GLAD
TO BE PART OF THIS.
>>THANK YOU FOR JOINING US.
ALSO CAROLYN LUTZKO.
>>GOOD MORNING. I APOLOGIZE,
HAVING SOME TECHNICAL TROUBLE
HERE. BUT I AM A PROFESSOR
PEDIATRICS AT UNIVERSITY OF
CINCINNATI, IN CINCINNATI
CHILDREN'S HOSPITAL. MY AREA OF
RESEARCH IS CELL AN GENE
THERAPY. FOCUSED ON
MANUFACTURING AND PREPARATION OF
CELL PRODUCTS EXVIVO FOR PHASE 1
AND 2 CLINICAL TRIALS.
>>THANK YOU, CAROLYN. DR.
CRISWELL, HAPPY TO REPORT ALL
PARTICIPANTS EXCEPT DR. GOMOLL
PRESENT. BACK TO YOU.
>>I'M BLOWN AWAY BY THE
INCREDIBLE EXPERTISE WE
ASSEMBLED HERE. THANK YOU ALL,
REALLY EXCITED TO HAVE YOU
JOINING US. T BEFORE WE BEGIN
OUR SUBSTANTIVE DISCUSSION I
WOULD LIKE TO PROVIDE CONTEXT
FOR THE ROUND TABLE. AS YOU KNOW
KNEE OSTEOARTHRITIS IS A
DEGENERATIVE CONDITION
CHARACTERIZED BY WEARING AWAY OF
CARTILAGE IN THE KNEE. AND THIS
GRADUAL WE ARE AND TEAR
PROGRESSION OF KNEE
OSTEOARTHRITIS LEADS TO
DEVELOPMENT OF BONE SPURS AND
WORSENING PAIN. THUS, IT IS A
VERY IMPORTANT AREA FOCUS FOR
NIAMS AND FOR OUR PUBLIC HEALTH
MISSION. REGENERATIVE MEDICINE
HAS BROUGHT HEALTH APPLICATIONS
IN KNEE OSTEOARTHRITIS, USED FOR
DEVELOPING METHODS TO REGROW,
REPAIR OR REPLACE DAMAGED
CARTILAGE. SO THE GOAL OF THIS
PARTICULAR MEETING IS TO DISCUSS
THE CHALLENGES, THE GAPS AND THE
OPPORTUNITIES FACING THE FIELDS
OF REGENERATIVE MEDS SIN AS
RELATES TO CARTILAGE
PRESERVATION AND RESTORATION IN
KNEE OSTEOARTHRITIS. OVER THE
LEONG TERM DISCUSSIONS OF THESE
ROUND TABLES HAVE HELPED SHAPE
THE INSTITUTE THINKING ABOUT
AREAS TO PURSUE ACROSS OUR BASIC
TRANSLATIONAL AND CLINICAL
PORTFOLIOS. I'M PARTICULARLY
INTERESTED IN LEARNING ABOUT
WAYS WHICH NIAMS CAN FURTHER
ENGAGE WITH RESEARCHERS TO
SUPPORT THIS CRITICAL WORK AND
CONTRIBUTE TO THE ADVANCEMENTED
OF REGENERATIVE MEDICINE. NOW TO
SET A FEW QUICK GROUND RULES. WE
WANT TO LEARN FROM YOU, THE
EXPERTS ABOUT THE BROAD
LANDSCAPE OF REGENERATIVE
MEDICINE AND IMPLICATIONS FOR
KNEE OSTEOARTHRITIS. THUS WE
DON'T WANT THE PRODUCTIVITY OF
THIS ROUND TABLE TO BE LIMITED
BY FOCUSING ON FUNDING AND
DEVELOPMENT OF SPECIFIC FUNDING
OPPORTUNITY ANNOUNCEMENT. NIAMS
RECOGNIZES TODAY'S TOPIC
PRESENTS MANY EXCITING AND
INNOVATIVE OPPORTUNITIES FOR
DISCOVERING AND WILL BE CALLING
ON EACH OF YOU FOR YOUR INPUT
OVER THE COURSE OF THE ROUND
TABLE TO SHARE YOUR EXPERIENCES
ABOUT CARTILAGE PRESERVATION AND
RESTORATION RESEARCH TODAY AS
WELL AS FOO UTURE OPPORTUNITIES
AS YOU SEE THEM. WE WILL ALSO
POST SUMMARY OF TODAY'S
DELIBERATIONS ALEONG WITH LINK
TO RECORDING THE VIDEOCAST ON
THE NIAMS WEBSITE. WE WILL LET
YOU KNOW WHEN SUMMARY IS
AVAILABLE AND ENCOURAGE YOU TO
SHARE WITH THOSE CANVAS FOR
INPUT IN ADVANCE OF THE MEETING.
SOME FINAL QUICK REMINDERS
BEFORE I TURN THINGS TO OUR
CHAIR, DR. DRUGAN. SHE HAS A FEW
THINGS TO SHARE ABOUT LOGISTICS.
JONELLE.
>>THANK YOU, DR. CRISWELL. A
QUICK REMINDER THIS MEETING IS
VIDEOCAST AND I JUST LEARNED
FROM SOME OF MY COLLEAGUES WE
HAVE 70 VIEWERS SO FAR. AND THAT
NUMBER WILL ONLY GROW BASED ON
EXPERIENCE THAT PEOPLE WILL TUNE
IN THROUGH THE DAY, PROMISE
THESE 70 OSTEOARTHRITIS ARE NOT
ALL MY FRIENDS AND FAMILY SO
THERE'S CLEARLY PEOPLE OUT THERE
WHO ARE IN SCIENTIFIC COMMUNITY
WHO ARE INTERESTED IN WHAT WE
ARE TALKING ABOUT TODAY. WE ASK
OUR INVITED PARTICIPANTS TO
PLEASE KEEP YOUR VIDEO ON FOR
THE DISCUSSION PORTION OF THE
MEETING TO HELP DISCUSSION
CO-CHAIRS TO KNOW WHO IS ON
DURING THE DISCUSSION. STAFF
KEEP YOUR CAMERAS OFF P UNLESS
YOU ARE SPEAKING AND IF YOU ARE
SPEAKING INTRODUCE YOURSELF
SINCE YOU WERE NOT INTRODUCE
WHEN DID DID AS ROLL CALL. TO
EVERYONE, PLEASE MUTE YOUR
MICROPHONE UNLESS SPEAKING. IF
YOU WOULD LIKE TO SPEAK DURING
THE DISCUSSION RAISE YOUR HAND
BY CLICKING ON THE PARTICIPANT
ICON AT THE BOTTOM OF THE
SCREEN. AT THE BOTTOM OF THE
PARTICIPANT WINDOW YOU WILL SEE
AN OPTION TO RAISE YOUR HAND.
THE CO-CHAIR WILL CALL ON YOU TO
SPEAK, NIAMS PROGRAM STAFF AND
TED MAINLY WILL LOOK FOR
CO-CHAIRS TO LOOK FOR RAISED
HANDS AND HE WILL MONITOR THE
CHAT FOR COMMENTS. WE HAVE JUST
LEARNED FROM EXPERIENCE THAT WE
PREFER FOR YOU TO MAKE YOUR
COMMENTS VERBALLY BECAUSE THAT
LEADS TO A MORE ROBUST
DISCUSSION. PLEASE REMEMBER TO
LOWER YOUR HANDS WHILE SPEAKING.
DAVE IS GOING TO BE DOING TIME
KEEPING. I'M RUSHING THROUGH
THESE REMARKS SO WE CAN STAY ON
TIME. ONE OTHER THING YOU WILL
SEE ON THE AGENDA WE HAVE A
PHOTO FOR A GROUP LUNCH, COUPLE
OF PEOPLE ASKED ABOUT THAT, IT
IS NOT A TYPO. WE WILL TAKE A
SCREEN SHOT OF OUR GROUP. IT IS
A TRADITION AS WE HAVE TAKEN
PHOTOS AT ALMOST EVERY NIAMS
ROUND TABLE AND THIS IS
SOMETHING WE DIDN'T WANT TO GIVE
UP DURING THIS PERIOD OF VIRTUAL
MEETINGS. DR. CRISWELL, GIVE YOU
AN OPPORTUNITY TO TAKE QUESTIONS
BEFORE TURNING THE MEETING OVER
TO OUR CO-CHAIRS. THANK YOU.
>>THANK YOU FOR YOUR
PARTICIPATION, LOOKING FORWARD
TO A PRODUCTIVE DISCUSSION.
BEFORE WE BEGIN, ARE THERE ANY
QUESTIONS?
>>HEARING UP IN I WILL TURN IT
TO DR. ZHENG.
>>WE WILL STAR START. DR. ROAD,
DR. CHU, YOU ARE ON.
>>THANK YOU, EVERYBODY. IT
GIVES ME GREAT PLEASURE TO
INTRODUCE THE FIRST SPEAKER. SO
AMYE LEONG WILL TALK TO US ABOUT
THE PATIENT PERSPECTIVE. I WANT
TO HIGHLIGHT MORE ABOUT HER
BACKGROUND. SO SHE WAS 18 YEARS
OLD WHEN SHE RECEIVED THE
DIAGNOSIS OF RHEUMATOID
ARTHRITIS. THIS WAS FOLLOWED BY
OSTEOPOROSIS DIAGNOSIS. SHE WAS
WHEELCHAIR BOUND IN SIX YEARS
AND SHE SPENT FIVE YEARS IN A
WHEELCHAIR. SHE HAD MORE THAN 22
SURGERIES AND 20 JOINT
REPLACEMENTS OVER THE SUBSEQUENT
YEARS. DURING THIS TIME SHE
DEVELOPED AMERICA'S LARGEST
NETWORK OF YOUNG ADULT EDUCATION
AND ADVOCACY PROGRAMS. SHE
STARTED A CONSULTING FIRM AND
DECIDED THAT SHE WAS GOING TO
GET OFF OF DISABILITY AND SHE
HAS REALLY BROUGHT THE PATIENT
PERSPECTIVE TO BARE OVER NUMBER
OF YEARS WORKING WITH NOT JUST
NIAMS BUT PCORI AHRQ, AND IS
RECOGNIZED BY PRESIDENT BUSH FOR
HER CONTRIBUTIONS, SO WE ARE
REALLY THRILLED THAT SHE IS ABLE
TO KICK OFF OUR MEETING. PLEASE
JOIN ME TO WELCOME AMYE LEONG.
>>THANK YOU, DR. CHU. I AM
DELIGHTED TO BE HERE FIRST OF
ALL, THANK YOU SO MUCH, DR.
CRISWELL AND GREAT, GREAT NIAMS
TEAM. AS SOMEONE PREVIOUSLY
SAID, THEY GREW UP IN NIAMS. AND
I AM ONE OF THOSE PEOPLE NOT WHO
GREW UP WITHIN THE SYSTEM BUT
GREW UP ALONGSIDE THE SYSTEM.
WHO ASKED TO JUMP THE RIVER AND
COME OVER ON OCCASIONAL BASIS.
MY INVOLVEMENT STARTED WITH ARE
YOU SURE YOU WANT TO INVITE A
PATIENT TO THIS RESEARCH ROUND
TABLE? TO WHY DON'T WE INVITE
PATIENTS IN AN OPPORTUNITY TO
BRING ALL STAKEHOLDERS TOGETHER.
YOU CAN SEE THE TRAJECTORY.
TODAY WE AND THE FIELD OF
MEDICINE IF YOU WILL, IN THE
FIELD OF STRUCTURAL MEDICINE,
CALL THIS PATIENT ENGAGEMENT.
I'M SO EXCITED TO HAVE BEEN A
PART OF THIS IN THE VERY
BEGINNING. THOUGH WE DIDN'T KNOW
WHAT NAME IT WAS. SO THE KINDS
OF THINGS WE WILL TALK ABOUT IN
THE VERY BRIEF TIME I HAVE WITH
YOU AND SOMETIMES I WILL SPEAK
VERY FAST, I ASK YOU TO BEAR
WITH ME, 30 YEARS AGO A LOT OF
THESE ORGANIZATIONS DID NOT
EXIST. HOWEVER BECAUSE OF THESE
ORGANIZATIONS OBVIOUSLY THE
NATIONAL INSTITUTE OF ARTHRITIS
MUSCULOSKELETAL AND SKIN
DISEASES, THE NIH DIRECTORS
OFFICE, ABSOLUTELY. U.S. BONE
AND JOINT DECADE, ABSOLUTELY. AT
THE GLOBAL LEVEL I HAVE SERVED
FOR 15 YEARS AS THEIR
INTERNATIONAL SPOKESPERSON. THE
ARTHRITIS FOUNDATION HERE IN THE
UNITED STATES BECAME MY HOME
BASE. I WANT TO THANK DR. JASON
KIM FOR HELPING THE SLIDES,
BECAUSE IT IS NOT JUST MY
PERSPECTIVE, IT IS A PERSPECTIVE
THAT WE ARE SEEING IN THE PUBLIC
HEARING FROM THE PUBLIC AND WANT
TO SHARE THAT WITH YOU A GREAT
DEAL. THE GLOBAL ALLIANCE FOR
MUSCULOSKELETAL HEALTH, NAMES,
NIH, PCORI AND THE FDA
A. CXFC DISCROW SURE I SERVE AS
FOUNDING MEMBER OF PATIENT --
DISCLOSURE I SERVE AS PATIENT
ENGAGEMENT ADVISORY COMMITTEE
OUT OF CDRH AT THE FDA. SO
ANOTHER GREAT HOME FOR AND
OPPORTUNITY FOR PATIENTS TO
ENGAGE. NEXT SLIDE. SO VERY
QUICK VISION STATEMENT OF THE
ARTHRITIS FOUNDATION, IN TERMS
OF SCIENCE, BUT DON'T LOOK AT IT
AS JUST THAT OWNED BY THE AF, IT
IS A STATEMENT THAT ACTUALLY
BINDS US ALL TOGETHER TO RELIEVE
THE BURDENS OF OSTEOARTHRITIS
PATIENTS THROUGH SCIENCE.
CRITICAL PIECE. IN THIS DAY AND
AGE, LET ME GO ON, IN THIS DAY
AND AGE, GIVING IDEA THE
ARTHRITIS FOUNDATION IS CON VIE
NOR IN IMPORTANT MEET --
CONVENER IN IMPORTANT MEETINGS.
YOU CAN SEE OUR FDA PERSON
THERE, MARK HOPBURG IS
REPRESENTED, MANY OF YOU IN THE
AUDIENCE NOW HAVE PARTICIPATED.
MOVING ONWARD. YOU CAN SEE THAT
DR. RODEO, DR. BROADER, MANY
OTHERS HAVE BEEN PART OF THIS.
DR. MUSCHLER ALSO VERY MUCH
LEADERS IN THIS AREA. SO IT IS
NOT JUST ARTHRITIS FOUNDATION
THING, BUT IT IS AN OPPORTUNITY
THROUGH OTHER CONNECTED ENTITIES
TO BEGIN TO WORK TOGETHER TO
SHARE THE WEALTH TO MOVE FORWARD
TOGETHER. I WANT TO ADDRESS FEW
PUBLIC MISCONCEPTIONS, THE LIST
IS TEN TIMES BIGGER THAN THIS
BUT CERTAINLY AS YOU GO THROUGH
AND READ IT YOU CAN COME BACK TO
THE SLIDE AT YOUR OWN WILL BUT
THERE IS A LOT OF
MISCONCEPTIONS. THE FIRST THING
IS THE FIRST IS EVERYBODY SAYS
IT, NOTHING CAN BE DONE. FOR MY
OA AND MY OA ARM OR KNEE OR OA
ELBOW. WHATEVER THAT BODY PART
IS, AND I KNOW FOCUS IS ON
CARTILAGE TODAY, THE KNEE IN
PARTICULAR BUT THE WIDER
PERCEPTION OF THE PUBLIC IS THAT
WHEN THERE IS A PERCEPTION OF A
HITCH IN THE GET ALEONG, THAT'S
A COLLOQUIAL WAY OF SAYING ITS
HURTS, I CAN'T FUNCTION WIT, I
CAN'T DO WHAT I NORMALLY DO WITH
IT. WHAT HELP CAN I GET? IF YOU
HAVE DONE A SEARCH ON THE
INTERNET YOU SEE THE PUBLIC
MISCONCEPTIONS ARE RAMPANT.
THEREFORE IS THAT RIGHT TANS,
UNPROVEN REMEDIES THOSE KINDS OF
THINGS OCCUR. BUT THERE IS HIGH
INTEREST. TO GET FROM THIS SLIDE
IS THE LITTLE SQUIGGLY LINES
THAT REPRESENT THE BLUE KNEE
PAIN AND THE GREEN SHOULDER
PAIN, THESE ARE THE KINDS OF
SEARCH WEB SEARCH TRENDS THAT
HAVE BEEN GOING ON AND PRODUCED
BY GOOGLE FOR OUR REVIEW WHICH
IS VERY INTERESTING SO THE TOP
TWO IN TERMS OF WHERE PEOPLE ARE
TRYING TO GO TO SEARCH ARE KNEE
AND SHOULDER. BUT THERE IS A
CLOSE ALIGNMENT WITH HIP AS
WELL. SO THERE IS A LOT OF
DESIRE OUT THERE. THESE ARE --
THE NUMBERS ARE IN THE MILLIONS
HERE IS ANOTHER THAT SAYS NOT
JUST ABOUT THE KNEE, IT IS
BEYONDS THE KNEE, THE KNEE IS
THE MOST RESEARCHED JOINT IN OA
BUT NOT ALL PATIENTS ARE
AFFECTED IN KNEE AS YOU KNOW.
TOTAL JOINT REPLACEMENTS ARE A
GOOD OPTION BUT AS DR. CRISWELL
SAID WE CAN'T KEEP DOING THIS.
THERE ARE TOO MANY PEOPLE
GETTING THEM. HI MYSELF AM OWNER
OF 20. SUCCESSFULLY OVER THE
PAST LAST YOU WERE TEEN YEARS
BUT NEWEST IS NOT DOING SO WELL.
AND ALSO LOOKING AT KNEE OA AND
HIP OA, IN THE MILLIONS HIGHER
UP IN TERMS OF WHAT PEOPLE ARE
SEEKING, WHAT THEY WANT TO DO
ABOUT IT, THEN WHEN YOU LOOK AT
THIS IS NUMBER OF PUBMED RESULTS
THAT OSTEOARTHRITIS AND
RHEUMATOID ARTHRITIS ARE THE
LOWEST WHEN COMPARED TO
ALZHEIMER'S DIABETES AND CANCER
LOT OF INTEREST BY PATIENTS BUT
THE DIVERSITY PIECE IS
INTERESTING. SO THE KNEE OA,
THERE IS AGAIN HIGH, HIGH
INTEREST THERE IS MORE INTEREST
WHEN COMPARED IN OTHER DISEASE
SPECIFIC AREAS, CANCER DIABETES,
ALZHEIMERS HIGH INTEREST AREAS.
BUT RHEUMATOID ARTHRITIS AND
OSTEOARTHRITIS ARE VERY, VERY
LITTLE. THIS IS FACTORED IN THE
MILLIONS. I PUT THIS RESEARCH
STUDY UP ABOUT DIVERSITY LOOKING
AT OA IN CHINA FOR THE FIRST
TIME. WHAT THEY FOUND WAS
CHINESE MEN FROM CHINA ACTUALLY
HAD AN 80 TO 90% LESS INCIDENCE
OF OA THAN MEN. IN THE UNITED
STATES. THE ARTICLE WAS QUICK TO
SAY THERE WERE WHITE MEN IN THE
UNITED STATES. SO I THINK THAT
IS A VERY INTERESTING POINT
ABOUT DIVERSITY. I THINK IT WAS
MAYO CLINIC, ONE CLINIC
ANNOUNCED TODAY THAT THEY ARE
STARTING TO APPEAR A DIFFERENCE
BETWEEN RACIAL CONFIGURATIONS IN
SOME OF THE EARLY WORK. SO THOSE
ARE KINDS OF THINGS WE NEED AND
WANT AS PATIENTS TO CONSIDER.
SOMETHING THAT HELPS US FOR US
BUT IS MORE LIKE US. KNEE, VERY
CLEARLY WE NEED MORE CLINICAL
TRIALS. WE NEED MORE CHALLENGING
RESEARCH QUESTIONS. I'M SO
DELIGHTED TO BE PART OF NIAMS
RESEARCH ROUNDS TABLES. THIS IS
THE TIME WHEN WE ARE ROLLING UP
OUR SLEEVES AND SAYING HEY, HOW
ABOUT IF I TALK TO YOU ABOUT
THIS AND THIS, HOW ABOUT IF WE
SIT DOWN AND MAP THIS THING OUT
TOGETHER, IN WAYS YOU HAD NOT
DONE BEFORE. SO THINKING OUTSIDE
OF YOUR BOX. OUTSIDE YOUR
INSTITUTION, YOUR DISTINCT AREAS
OF SPECIALTY, BUT DOING WHAT I
CALL THE JEFF BEZOS APPROACH.
YOU BRING IN ALL THE APPROPRIATE
PEOPLE YOU NEED TO BRING IN AND
YOU SIT THEM DOWN AND YOU GIVE
THEM ALL KINDS OF FOOD BUT YOU
LOCK THE DOOR. YOU SAY PLEASE
COME UP WITH IDEAS AND PRIORITY,
LET'S MOVE IT FROM HERE.ED THE A
FOUNDATION IS INTERESTED IN
MOVING TO RESEARCH PHASE
THEMSELVES. SO THE ARTHRITIS
FOUNDATION MOST KNOW IS A
PATIENT ADVOCACY PATIENT
EDUCATION ORGANIZATION. HOWEVER,
RECENTLY THEY ARE ANNOUNCING
STILL ANNOUNCING TWO PARTICULAR
THINGS, ONE THAT WAS ANNOUNCED
YET AND ONE ANNOUNCED TWO MONTHS
AGO. THE ONE ANNOUNCED TWO
MONTHS AGO IS THE PIKASO
PROJECT. SO THEY POOLED TOGETHER
EIGHT INSTITUTIONS AND
UNFORTUNATELY I CANNOT TELL YOU
WHAT THEY ARE, OTHERWISE THEY
WILL KILL ME BECAUSE IT IS
PREMATURE, GETTING AN EARLY IN
ON THIS. 50 PLUS WORLD CLASS
SCIENTISTS, HUNDREDS OF PEOPLE
WITH HIGH RISK OA AND TESTING
EXCITING LOW COST DRUGS
COMPARATIVE EFFECTIVENESS
RESEARCH. SO THEY WILL BE
EMBARKING ON THAT VENTURE
STARTING IN 2023. THE MORE
RECENT ONE WHICH WAS ANNOUNCED
YESTERDAY, AT THE ANNUAL MEETING
OF THE AMERICAN ORTHOPEDIC FOOT
AND ANKLE SOCIETY IS A RESEARCH
PARTNERSHIP WITH THE ARTHRITIS
FOUNDATION AND AOFAS THAT WILL
ESTABLISH SEVERAL MERITS. SO
THIS IS WHAT IS HAPPENING, IT IS
NOT GOING AWAY, THERE IS MORE OF
IT. I WANT TO LAST LEND ON THIS
IF YOU GIVE ME THREE MORE
MINUTES I APPRECIATE IT. THE
PICTURE ON THE RIGHT IS THE
LOWER HALF OF ME TODAY. YOU ARE
SEEING THE SHOULDERS AND UP PART
OF AMYE. THE SHOULDERS AND BELOW
IS WHAT YOU ARE SEEING ON THIS
PICTURE. MY LEG IS IN A FULL LEG
VERY BRIGHT PINK CAST. WHY?
BECAUSE I HAVE A TIBIA THAT DOES
NOT SUPPORT THE TOTAL KNEE JOINT
REPLACEMENT THAT WAS PUT IN. A
YEAR AND A HALF AGO. THIS IS A
NEW SCENARIO. IT IS ABOUT
QUALITY OF BONE. SO WHEN I THINK
ABOUT ANYTHING, I ALWAYS THINK
ABOUT QUALITY. QUALITY OF THE
FOOD, FRESHNESS OF THE FOOD,
QUALITY OF THE BONE THAT WILL BE
HOLDING A PROSTHESIS. AND HOW
LONG CANNA HAPPEN? HOW LONG CAN
I DO THAT? IN THE MEANTIME,
BEFORE WE CAN COME UP WITH A
SOLUTION WHICH IS THIS PICTURE
GETTING ME BACK INTO WHAT I USED
TO DO, YOGA, WALKING, THOSE
KINDS OF THINGS, IS A LONG HAUL
SO PERSONALLY QUITE EFFECTIVELY
PATIENTS WANT ANSWERS NOW. NOT
TEN YEARS FROM NOW, NOT FIVE
YEARS FROM NOW. THEY WANT TO BE
ABLE TO HOLD THEIR BABY, THEY
WANT TO PICK UP THEIR BABY, PICK
UP THEIR CHILD, THEY WANT TO
WORK BECAUSE AS YOU KNOW,
DISABILITY FROM ARTHRITIS IS
AMONG THE TOP DISABLING
CONDITIONS IN THE UNITED STATES
AS WE KNOW TO BE COUNTING IT SO
THESE ARE BIG, BIG PROBLEMS. WE
NEED YOU, I NEED YOU. THAT IS
WHY I'M SO EXCITED TO BE HERE TO
BEGIN TO SEE MORE A BROADER
PERSPECTIVE ABOUT WHAT IT IS
THAT YOU DO, WHAT IT IS YOUR
EXPERTISE IS AND HOW WE CAN WORK
TOGETHER TO MOVE THIS ALONG
FASTER BETTER MORE EFFICIENTLY.
AND TO REALLY ADDRESS THE
PATIENTS' NEEDS. APPRECIATE YOUR
HELP. AS YOU CAN SEE THIS -- I
LIKE MOSAIC AND THAT IS WHAT I
WANT TO TALK ABOUT. I WANT YOU
TO ALWAYS THINK ABOUT THE BONES
AND CARTILAGE AND JOINTS WHAT
YOU TALK ABOUT AND WORKING ON
BUT TO ME IT IS HOW I FUNCTION.
THIS IS A BIG REQUEST. AND THE
REQUEST IS AS YOU GO BACK TO
YOUR RESEARCH LAB TO YOUR PETRI,
TO YOUR DESIGNS AND GENETIC
STUDIES THINK ABOUT EVERY ONE OF
THOSE CELLS REPRESENTING AMYE.
ME. ACTUALLY REPRESENTING ONES
YOU LOVE. THESE ARE REAL PEOPLE.
REAL LIVES. THAT CAN BE HELPED
BY YOUR IDEAS AND YOUR
CONNECTEDNESS. I LOOK FORWARD TO
TODAY. LET'S GO ABOUT IT AND DO
SOME GREAT STUFF. THANK YOU SO
MUCH.
>>THANK YOU SO MUCH FOR THOSE
COMPELLING WORDS.
>>WHAT DO YOU SEE AS MOST
IMPORTANT BARRIERS TO PATIENTS
ENROLLING IN CLINICAL TRIALS?
>>ACTUALLY WORKING ON THAT NOW,
PATIENT ENGAGEMENT. LACK OF
INFORMATION, KNOWLEDGE AND LACK
OF PEOPLE WHO LOOK LIKE
THEMSELVES, LEADING THE CHARGE.
SOING THE IMPORTANT YOUR NAME IS
ON IT AND YOUR EXPERTISE IS
DRIVING IT BUT BEFORE YOU IS
SOMEBODY LIKE ME. DOESN'T HAVE
TO BE ME BUT LIKE ME WHO SAYS
THIS IS GOOD FOR ALL OF US. THIS
IS GOING TO ADVANCE. THE MORE
YOU ARE GIVING OF YOUR -- WHAT
YOU KNOW ABOUT THE DISEASE, WHAT
YOU KNOW ABOUT THE PAIN, WHAT
YOU KNOW IN TERMS OF FUNCTION.
THESE ARE IMPORTANT CONCEPTS.
EXAMPLE, POST TRAUMATIC STRESS.
MANY OF YOU KNOW I LIVE IN SANTA
BARBARA, CALIFORNIA, I USED TO
LIVE IN MOTESETO AND OUR FAMILY
WAS AFFECTED BY THE FIRES AND
MUD SLIDES, WE LOST OUR HOUSE
AND ALMOST LOST OURSELVES IN ALL
OF THAT. IN THE BEGINNING OF
2018 AND IT HAS TAKEN US TWO
YEARS TO RECOVER JUST HAVING A
HOUSE. WE LOST EVERYTHING. I
LOST CHINA THAT GOES BACK FOUR
GENERATIONS IN MY FAMILY IN
CHINA. I LOST SO MANY WONDERFUL
PICTURES. BUT THE STRESS FROM
ALL THAT, NOT ONLY THE STRESS OF
THE TRAUMA BUT THE STRESS OF THE
BUILDING BACK PART HAS
INTRODUCED A WHOLE DIFFERENT
FOUNDATION FROM WHICH WHICH
IMMUNE SYSTEM NOW MORE CONGESTED
QUITE FRANKLY, TO TRY AND WORK
AND TO BE ON MY SIDE, THAT
HELPS. HAS. THANKS FOR THE QU.
>>AMYE, WE ALL WANT TO DO THESE
CLINICAL TRIALS BECAUSE THAT IS
HOW WE WILL GET SOME ANSWERS BUT
I THINK MOST OF US FIND THE
BIGGEST OBSTACLE IS THE PATIENTS
DON'T WANT TO BE RANDOMIZE, THEY
HEAR THIS 50/50, MAYBE TRY TO
GET LESS THAN 50/50 FOR THE --
SO DO YOU HAVE ANY HINTS FOR US
THAT THAT IS WHAT I FIND MOST OF
US FIND IS BIGGEST OBSTACLE FOR
ADVANCING --
>>THAT IS A WEBINAR OF A WHOLE
DIFFERENT NATURE. YES, THERE ARE
THINGS YOU CAN DO. T YOU HAVE TO
REMEMBER WE DO NOT HAVE YOUR
EDUCATIONAL BACKGROUND. WE DON'T
HAVE A SCIENCE MINDED APPROACH
TO DRAWING CONCLUSIONS. MUCH OF
THE PUBLIC I SAY IN A BROAD
FASHION, THERE IS A RANGE EVEN
IN THAT. ARE BASED ON YOUR
PERCEPTIONS. WHO YOU KNOW, WHAT
YOU KNOW, YOUR ACCESS EVEN DOWN
TO ETHNICITY OF HOW YOUR PARENTS
RAISE YOU IN TERMS OF PROBLEM
SOLVING. IS THERE A LOCAL
PATIENT GROUP ORGANIZATION
PREFERABLY, NOT JUST A GROUP
MEETING, AN ORGANIZATION THAT
CAN BE HELPFUL BUT THERE ARE
WAYS THAT CAN BE DONE. QUITE
HONESTLY, THE FACT IS, IN THE
THE RHEUMATOLOGY COMMUNITY, THAT
IS LARGER COMMUNITY RESEARCH
COMMUNITY, THAT WE BELONG TO,
THAT IS NOT REALLY AN ACTIVE
TOPIC. IT SHOULD BE. ABSOLUTELY
SHOULD BE. SO WE CAN BEGIN
PROCESS. IS THAT YOUR
RESPONSIBILITY? PROBABLY NOT BUT
I WILL TALK TO ARTHRITIS
FOUNDATION, I WILL TALK TO THE
ALLIANCE FOR GLOBAL
MUSCULOSKELETAL ACTION. I WILL
TALK TO A LOT -- PCORI DOES
DIFFERENT KINDS OF OPPORTUNITIES
THAT HELPS PEOPLE UNDERSTAND THE
SCIENTIFIC METHODOLOGY, THAT IS
REALLY IMPORTANT.
ONCE THEY UNDERSTAND THAT, OK O.
SO THEY MAY NOT LIKE IT, THEY
MAY NOT KNOW, THEY SHOULDN'T
EVEN KNOW BUT THE FACT IS YOU
HAVE TO TELL THEM A LITTLE BIT
BUT THEN SCOOT OVER IT. BUT
THAT IS ANOTHER CONVERSATION SO
BE HAPPY TO ENTERTAIN THAT
LATER.
>>I WILL TAKE THE MIC AS
PREROGATIVE TO STAY NEAR ON
TIME. MY PLEASURE TO INTRODUCE
CONNIE CHU WHO INTRODUCED
HERSELF EARLIER BUT BRIEFLY
PROFESSOR AND VICE CHAIR OF
RESEARCH AT STAN -- ALSO DIRECTS
THE JOINT PRESERVATION CENTER
AND CHIEF OF SPORTS MEDICINE AT
THE VA NEAR STANFO STANFORD.
ACCOMPLISHED SCIENTIST,
EXTENSIVE FUNDING, HER WORK IS
FOCUSED ON CARTILAGE REPAIR
REGENERATION AND CARTILAGE
IMAGING WHERE SHE PUBLISHED
EXTENSIVE WILL I SO SHE WILL
TALK ON BLOOD DERIVED THERAPIES
FOR OA.
>>U THAT, SCOTT. AMYE, ALSO,
THANK YOU FOR INTRODUCING WHAT
WILL BE THE PRIMARY THING OF MY
TOPIC, THAT IT IS NOT CARTILAGE
OF BONE CHANGES IN ISOLATION BUT
RATHER BLACKING AT PEOPLE AS --
LOOKING AT PEOPLE AS
INDIVIDUALS, AND TAKING A MORE
SYSTEMS BASED APPROACH TO
OSTEOARTHRITIS. SO I AM THANKFUL
FOR THIS OPPORTUNITY TO TOUCH ON
THIS ASPECT OF OSTEOARTHRITIS BY
TALKING ABOUT BLOOD DERIVED
BIOLOGIC THERAPIES FOR
OSTEOARTHRITIS. SO MY APPROACH
TO OSTEOARTHRITIS HAS BEEN EARLY
DIAGNOSIS AND EARLY TREATMENT TO
PREVENTED OR DELAY ONSET OF
OSTEOARTHRITIS. SO REALLY THE
GOAL IS TO TRANSFORM OUR
CLINICAL APPROACH FROM SAYING
OH, THERE IS NOTHING WE CAN DO
OR PALIATION, TOWARDS PREVENES
AND TOWARDS EARLY TREATMENT
THERAPIES. SO BLOOD REALLY
REFLECTS WHAT IS GOING ON IN THE
HUMAN BODY. AND I AM IN SPORTS
MEDICINE, AND THE PUBLIC, THE
AMERICAN PUBLIC LOVES SPORTS.
AND SO I WAS IN PITTSBURGH AT
THE TIME WHEN WE WERE BATTLING
FOR ONE OF OUR SUPERBOWL
CHAMPIONSHIPS, AND THE ANC
CHAMPIONSHIP FINALS, TOURISM CL
AND THE SUPERBOWL WAS TWO WEEKS
AWAY. SO AT THAT TIME HE
RECEIVED A NEW TREATMENT A NEW
TREATMENT. NOT ONLY WAS HE BACK
ON THE FIELD BUT HE CAUGHT TWO
INNING TOUCHDOWNS AND NAMED
SUPERMVP. THE LITERATURE OF
ASTHMA EXPLODED AND IS MOST
PEOPLE KNOW ERP IS TOUTED AS
BEING USEFUL FOR EVERYTHING FROM
TREATING BALDNESS TO ALL ACHES
AND PAINS SO OF COURSE IT HAS
BEEN EVALUATED AND USED IN THE
TREATMENT OF OSTEOARTHRITIS. I
JUST WANT TO HIGHLIGHT SOME OF
THE EARLIER ARTICLES GOT IT
RIGHT. HE GOT NOT JUST
PLATELETS BUT HE GOT PLASMA AND
IT IS A PROMISING TREATMENT FOR
ATHLETES IN BLOOD AND ALSO THERE
IS INCLUDING TIGER WOODS HAVE
PUBLICLY RECEIVED PRP TREATMENT
THE PUBLIC INTEREST HAS GROWN
FROM THERE. PRP IS ILL DEFINED
GENERALLY, HOWEVER, IT IS A
BLOOD PRODUCT AND REGULATED AS A
BLOOD PRODUCT. THE USE GOES BACK
DECADES. WE HAVE HEARD MANY
DEFINITIONS, BUT ESSENTIALLY IN
THE CODES OF FEDERAL REGULATIONS
IT STATES CLEARLY IN 640.34, PRP
PRODUCTS SHOULD HAVE AT LEAST
250,000 PLATELETS PER
MICROLITER. SO THOSE WHO
MEASURED THE PLATELET COUNTS
KNOW SOME HAVE THAT, ALREADY IN
THEIR PLASMA. AND OTHERS HAVE
LEVELS BELOW THIS. SO IN THE USE
FOR OSTEOARTHRITIS, THE QUESTION
IS, DOES THIS WORK? I THINK THAT
IS VERY DIFFICULT TO ANSWER FOR
VARIETY OF REASONS, LOOK AT
STUDIES OVER THE YEARS DOING
SOME OF MY OWN RESEARCH AND ALSO
READING STUDIES OF OTHERS, IT
BILLS DOWN TO IT DEPENDS,
DEPENDS ON THE QUALITY OF
PATIENT HEALTH AND THEIR BLOOD
AT THE TIME THE AUTOLOGOUS PRP
IS PREPARED. A RECENT STUDY,
HAVING TROUBLE ADVANCING. VERY
WELL DONE STUFF OUT OF VAILIA, A
RANDOMIZED PLACEBO CONTROLLED
CLINICAL TRIAL. THEY LOOKED AT A
RELATIVELY EARLY OA POPULATION.
SO AMYE SHOWED EMAILS AND I KNOW
MY OWN INBOX IS FLOODED WITH
EMAILS FROM PEOPLE WHO ARE
LOOKING FOR THIS TREATMENT AS
ALTERNATIVE TO JOINT
REPLACEMENT. IN THIS STUDY THAT
THEY LOOKED AT EARLIER GRADES OF
OSTEOARTHRITIS AND REALLY SHOWED
THAT THERE WAS NO DIFFERENCE
MANY THE MAIN OUTCOMES BETWEEN
PLATELET RICH PLASMA AND SALINE.
THEIR MAIN PLATELET COUNT DID
MEET FDA ROLES. SO I KNOW THEIR
CRITICISMS OF THIS STUDY, I
WOULD ENCOURAGE EVERYONE WHO IS
INTERESTED TO READ IT THOROUGHLY
INCLUDING THE ADVANCE PLEASE,
THE APPENDICES, BECAUSE I -- THE
QUALITY OF THIS STUDY IS QUITE
GOOD IN MY OPINION. MY OWN WORK,
THIS IS STILL ONGOING, AT SIX
MONTH FOLLOW-UP WED 100%
FOLLOW-UP IN THE PATIENT
REPORTED OUTCOMES. ESSENTIALLY
THE MEAN OUTCOMES DO SHOW
IMPROVEMENT IN PAIN STIFFNESS
AND FUNCTION. THOSE WHO NOW
REACHED TWO YEARS, FOLLOW-UP, I
EVALUATED SOME IN CLINIC, AFTER
THEY FILLED OUT THEIR PATIENT
REPORTED OUTCOMES. WHAT I CAN
SAY IS WE DO SEE SYMPTOMATIC
FUNCTIONAL IMPROVEMENT, I WILL
SHOW YOU THE GATE STUDIES. CAN
WE GO BACK PLEASE. WE ARE DOING
GATE STUDIES AND LOOK AT
PROTEOMIC PROFILES OF INJECTED
PRP. WHAT THIS SHOWS IS THAT
PATIENTS WHO REPORT PAIN RELIEF,
THEY VISIBLY WALK BETTER. IF WE
CRITICALLY ROOK AT OUR DATA, IT
IS LESS THAN HALF OF PATIENTS
WHO HAVE THIS SUSTAINED
IMPROVEMENT THROUGH SIX MONTHS,
NOW THROUGH TWO YEARS. THOSE
PATIENTS RAVE ABOUT THE
TREATMENT. BUT I CAN GO NEXT
DOOR INTO THE NEXT PATIENT ROOM
AND FIND ANOTHER PATIENT WHO IS
NOT AS HAPPY M. SO YOU CAN SEE
WHERE THE IDEA THAT PRP WORKS
FOR KNEE OA CONTINUES TO
PERPETUATE ITSELF BECAUSE SOME
PATIENTS AFTER RECEIVING THIS
TREATMENT DO HAVE SUSS
SANESYMPTOMATIC AND FUNCTIONAL
RELIEF. IF WE -- SUSTAINED
SIMILAR TO MADIC RELIEF. IF WE
DRAW DOWN AND LOOK AT PREDICTORS
OF RESPONSE I COME UP EMPTY.
THESE ARE OUR PROPOSED OUTCOMES.
AND THE ONLY THROUGH PCA
ANALYSIS, WE DID FIND A FEW
CYTOKINES THAT DID NEGATIVELY
RELATE, THE HIGHER LEVELS OF
CYTOKINES, THE MORE PAIN
PATIENTS REPORTED AT BASELINE
BUT THESE DIDN'T PREDICT HOW
WELL THE PATIENT WOULD RESPOND.
SO SEVERAL YEARS AGO WE LOOKED
AT THE PRP AND COMPARED THE PRP
FROM OLDER MALES WITH KNEE
OSTEOARTHRITIS AND THAT OF YOUNG
HEALTHY PRIMARILY MEDICAL
STUDENTS. WE FOUND THE PRP FROM
OLDER MALES DEPRESSED
CHONDROCYTE METABOLISM AND
UPREGULATED INFLAMMATION. SO I
HOPE THE MOVIES IN THE NEXT
SLIDE WILL WORK. WHAT I AM
SHOWING HERE IS GIVING THE THE
PRP TO MONOCYTE CULTURES AND
FINDING THAT THE PRP FROM THE
YOUNG HEALTHY MOUSE INDUCED THE
FORMATION OF THE M 2 MACROPHAGE
PHENOTYPE. WHEREAS IF WE GAVE
THE PRP THE OLDER MALES, IT
INDUCED THE M 1 PHENOTYPE. O SO
I WANT TO TAKE US BACK TO SOME
OF THE PARABAYOUSIS STUDIES DONE
BY TOM RANDO NOW PUBLISHED IN
2004, 2005 WHERE THEY CONNECTED
THE BLOOD SUPPLY OF YOUNG MICE,
REALLY THESE STUDIES SHOULD GIVE
A LOT OF HOPE. THE OLDER MICE
WITH AGED STEM CELLS IN AGED
SYSTEM, ACTUALLY WHEN CONNECTED
TO BLOOD SUPPLY AND ALSO THE
MILIEU OF YOUNGER MICE, STEM
CELLS SHOWED GREATER
REGENERATIVE CAPACITY. OTHERS
HAVE SHOWN HEALTHIER HEARTS, IN
WYSS COREY, BETTER MEMORY. THESE
STUDIES ILLUSTRATE THERE ARE
CIRCULATING FACTORS IN THE BLOOD
THAT HELP TO PROMOTE AND CAN
KICK START AND JUMP START
REGENERATION IN OLDER
INDIVIDUALS AND EVEN PEOPLE WHO
HAVE DISEASE. BUT THE FLIP SIDE
IS, IF YOU LOOK AT THE ACTUAL
DATA THE YOUNG MICE WHO WERE
CONNECTED TO THE OLDER MICE,
THEIR PROLIFERATIVE STATUS,
INFLAMMATORY STATUS WAS LORE
THAN THAT OF YOUNGER MICE
CONNECTED TO OTHER YOUNG MICE.
SO WHAT THIS MYLIGHTS IS THERE
IS GOOD BLOOD AND BAD BLOOD.
THERE ARE ANYTHINGTIVE INHIBITOR
FACTORS IN BLOOD OF OLDER MICE.
THIS IS AN AREA PRIMED FOR
RESEARCH. WYSS COREY WENT TO
SHOW YOU CAN GIVE INJECTIONS OF
FRESH YOUNG PLASMA AND SEE
IMPROVED LEARNING MEMORY IN AGED
MICE AND THEY HAVE DONE CLINICAL
TRIALS IN THIS AREA. MORE
RECENTLY, CONVOY'S GROUP HAS
SHOWN PLASMA DILUTION WILL
ATTENUATE NEUROINFLAMMATION IN
OLDS MICE SO THIS TO ME IS VERY
EXCITING. THEY FURTHER SHOWED --
THEY ALSO LOOK AT USE OF
ANTI-SINOLITIC AGENT, A
PERIPHERALLY ACTIVE AGENT AND
THEY FOUND THE PLASMA DILUTION
HAD GREATER ANTI-INFLAMMATORY
AND REJUVENATIVE EFFECTS BEEN
THE ANTI-SINOLITIC AGENTS, WE
HAVE IN OUR GROUP TODAY JOHNNY
HUARD, JENNY ELISSEEFF AND
OTHERS WHO ARE ACTIVELY WORKING
ON ANTI-S XENOLYTICS SO GREAT TO
HEAR THEIR PERSPECTIVES. BACK TO
WHAT WE CAN DO TODA TODAY. THISS
AMYE'S QUESTION, WHAT PATIENTS
ARE IS INTERESTED IN. THE YOUNG
PRP SHOWED LOWER LEVELS OF
INFLAMMATION WITH RED IN OUR
SCALE REFLECTING HIGHER LEVELS
OF INFLAMMATION. BUT I WANT TO
POINT OUT IT WASN'T EVERYONE,
THIS YOUNG MAN CERTAINLY SHOWED
HIGH LEVELS OF INFLAMMATION.
AND I LATER LEARN HE FREQUENTED
MCDONALDS. SO THINGS WE CAN
THINK OF HEALTH PROMOTION, LIFE
SPAN PROMOTION IS THINGS WE READ
ABOUT. AFTER EATING A FAST FOOD
BURGER NEGATIVE THINGS HAPPEN
AND PROMOTION AND INFLAMMATION
HAS BEEN FOUND SO PROFOUND IT IS
LIKENED TO HAVING A BACTERIAL
INFECTION. SO WHAT I REALLY LIKE
TO HIGHLIGHT IS THAT BLOOD
TREATMENTS PARTICULARLY IN OUR
ATHLETICALLY GIFTED YOUNG ACTIVE
ATHLETES, THEIR BLOOD LIKELY HAS
MORE REGENERATIVE FACTORS THAN
WHAT IS IN OUR OLDER PATIENTS
WITH OSTEOARTHRITIS WHO AREN'T
ABLE TO EXERCISE, EXERCISE IS
SHOWN TO ENHANCE THE QUALITIES
AND THE PLATELET RICH PLASMA AND
ALSO STEM CELL FACTORS THERE IS
AN EMERGING LITERATURE ON THE
GUT MICROBIOME JOINT CONNECTION
AND AMYE ALREADY TOLD US THE
STRESS OF LOSING HER HOME REALLY
CHANGED THE INFLAMMATORY
ENVIRONMENT. SO THESE ARE
SYSTEMIC FACTORS AND I WANT TO
HIGHLIGHT WE NEED TO TAKE THIS
AS A SYSTEMS BASED APPROACH AND
THINK HOW WE CAN OPTIMIZE
SYSTEMIC BIOLOGY FOR JOINT
HEALTH. I BELIEVE THIS WILL BE
REFLECTED IN THE BLOOD WHICH
CIRCUMSTANCE RATES THROUGHOUT
THE SYSTEM. AND PRP IF USING AS
TREATMENT FOR OUR BONE MARROW SO
PREPARATIONS WILL LIKELY BE
ENHANCED IN REGION OPERATIVE
CAPACITY. THIS IS OPINION RIGHT
NOW. BUT THESE ARE THE STUDIES,
THAT CAN REALLY HIGHLIGHT
WHETHER DIET AND LIFESTYLE
IMPROVEMENT TODAY CAN IMPROVE
SYMPTOMS. THESE ARE AREAS WHERE
PATIENTS CAN ALREADY START
FOLLOWING GUIDELINES SHOWN TO BE
HEART HEALTHY FOR THE BRAIN AND
OVERALL HEALTH IN GENERAL. THANK
YOU FOR YOUR ATTENTION. HAPPY TO
TAKE QUESTIONS OR TO DONATE TIME
BACK TO THE PROGRAM.
>>TWO QUESTIONS, WE HAVE BEEN
CHATTING BEHIND THE SCENES AND
WE ARE GOING TO TAKE TEN MINUTES
OUT OF THE LUNCH AND FIVE
MINUTES OUTS OF THE BREAK TO GET
US CAUGHT UP SO IT IS MORE
IMPORTANT WE HAVE A DISCUSSION.
>>I HAVE A QUESTION.
>>YES.
>>GREAT TALK. THANK YOU. THE
AUSTRALIAN STUDY YOU MENTIONED
WAS PRP CONCENTRATION THAT WAS
FAIRLY LOW BY OTHER TYPES OF
PRP. DEVICES. SO IN YOUR STUDY
WHICH YOU DID SHOW SOME POSITIVE
RESULTS, WHAT WAS YOUR PERCENT
-- CONCENTRATION ABOVE BASELINE,
HOW DID IT COMPARE WITH THAT
STUDY?
>>YES. SO MINE WAS SIMILAR TO
THAT STUDY. SO REALLY FOR US TO
DO THIS TRIAL, THIS IS AT THE
VETERANS HOSPITAL, WE WEREN'T
ABLE TO MAKE OUR OWN PRP OR HAVE
DEFINED CONCENTRATIONS IN THESE
COMMERCIALLY AVAILABLE SYSTEM,
IT WAS THE OLD SYSTEM AND WE
HAVE BEEN ABLE TO HAVE A WORK
AROUND, AND CONTINUE WITH THAT.
I HEAR WHAT YOU ARE SAYING,
OTHERS DO AND STUDIES SHOW IS IT
5X BASELINE, 3X BASELINE. WE
WERE RIGHT AROUND CLOSE TO WHERE
THE AUSTRALIAN STUDY WAS.
>>OKAY. THANK YOU.
>>YES.
>>I THINK WE C WE CAN GET CUSTD
PRP TO SAY THIS IS IS A GOOD
SPECIMEN, CAN WE USE THIS DATA
TO IDENTIFY CHARACTERIZE PRP.
>>YES. I THINK MANY IN THIS
ROOM ARE IS LOOKING INTO THOSE
QUESTIONS, AND REALLY ONE OF THE
FIRST STEPS IS THE PARABAYOUSIS
STUDIES AND EARLIER IN VITRO
STUDY, FOR SOME PEOPLE,
PARTICULARLY HOLDER PEOPLE WITH
MORE SEVERE DISEASE, THERE ARE
LIKELY FACTORS IN THEIR BLOOD WE
DON'T WANT TO CONCENTRATE WITH
PRP TYPICALLY YOU ARE
CONCENTRATING A LITTLE BIT. SO
POTENTIALLY THINGS LIKE IF YOU
CAN IDENTIFY WHAT THE BAD
FACTORS ARE, THEY CAN BE REMO
REMOVED. AND I KNOW OTHERS WILL
SPEAK ON SMALL PROTEINS OR
EXOSOMES. WE CAN SHOW SOME
THINGS TO BE BENEFICIAL, THOSE
CAN POTENTIALLY BE ENHANCED OR
PATIENTS EVALUATED TO SEE
WHETHER THEY FALL INTO A
REGENERATIVE PHENOTYPE AND WOULD
BE CANDIDATES FOR USE OF THEIR
OWN BLOOD OR NEED SOME OTHER
FORMULATION.
>>DR. HOCHBERG HAS A QUESTION.
>>I JUST UNMUTED MYSELF. SO THE
PREPONDERANCE OF EVIDENCE FOR
PRP, DOES NOT SUPPORT ITS USE.
DESPITE THE FACT IT IS
EXTENSIVELY USED, PARTICULARLY
IN PRACTICE OF SPORTS MEDICINE,
P FOCI TRY ORTHOPEDIC SURGERY,
THE RECOMMENDATIONS OF THE
ARTHRITIS FOUNDATION AND THE
AMERICAN COLLEGE OF
RHEUMATOLOGY, AMERICAN ACADEMY
OF ORTHOPEDIC SURGEON, THE VA
DEPARTMENT OF DEFENSE, THESE
RECOMMENDATIONS FOR THE
NON-SURGICAL MANAGEMENT OF KNEE
OSTEOARTHRITIS,S DO NOT
RECOMMEND USE OF PRP.
>>I THINK THAT -- I USE IT IN
MY PRACTICE AT THE VA AND I
THINK THE WAY I THINK ABOUT IT
IS WE ARE USING IT IN YOUNGER
PATIENTS WITH LESS SEVERE
DISEASE, I TELL ALL MY PATIENTS
THAT IT DOESN'T WORK WITH
EVERYONE. MY OPINION BASED ON
EARLY STUDIES IS HEALTHIER THEY
CAN GET THEMSELVES THE MORE
LIKELY IT IS THEIR BLOOD, SO
THIS IS ESSENTIALLY WHAT I HAVE
TALKED ABOUT. WHAT WILL BE USED
BLOOD AND PLATELETS WHICH IS
REALLY THERAPY WE ARE USING BE
MORE LIKELY TO HAVE BENEFICIAL
EFFECTS IN THAT IN SOME INSTA
INSTANCES, THE BLOOD SHOULDN'T
BE CONCENTRATED AND USED. I
DON'T THINK WE HAVE THE ANSWER.
THE AMOUNT OF INJECTIONS THAT
HAVE BEEN GIVEN WOULD
SUBSTANTIATE NO SIGNIFICANT
SAFETY CONCERNS, REALLY THE
QUESTION IS EFFICACY AND THE
QUANTITATIVE MR WORK HAS NOT
SHOWN REGENERATIVE CAPACITY.
>>SO THE QUESTION IS WHETHER TO
RECOMMEND OR PROVIDE A TREATMENT
WHICH WHILE SAFE HAS NOT BEEN
SHOWN EFFICACIOUS IN CONTROLLED
CLINICAL TRIALS. I WOULD SAY MY
COLLEAGUES HERE AT THE VA IN
MARYLAND WHO ARE IN POSIATRY AND
ORTHOPEDICS ALSO USE PRP
INJECTIONSS. MY FELLOWS REFER
PATIENTS FOR PRP INJECTIONS. BUT
THE ISSUE WOULD BE WHAT ABOUT
FOR SYMPTOMATIC THERAPY, ONE CAN
CONSIDER SALIENT INJECTIONS SO
THE ISSUE IS WHETHER THERE IS
EVIDENCE OF REGENERATIVE
CAPACITY UNQUOTE. IN THE
PATIENT WITH NIKOS ARTHRITIS.
WHO IS DIFFERENT FROM THE YOUNG
ATHLETE WITH A ISOLATED
CARTILAGE DEFECT IS WE WILL
DISCUSS DURING THE DAY TODAY. I
WILL GO BACK ON MUTE.
>>TWO MORE QUESTIONS, DR.
WHITE.
>>THANK YOU FOR THAT WONDERFUL
PRESENTATION DR. CHU. IT IS
INTRIGUING WITH HEALTHY
LIFESTYLE ASSOCIATED RESPONSE
SEEMS TO PRP OR AT LEAST THAT IS
HYPOTHESIZED. ANYONE DELVED INTO
THAT LOOKING AT OBJECTIVELY
MEASURE HOW ACTIVE SOMEBODY
ACTUALLY IS, MAYBE IN ADDITION
TO THEIR DIET AND QUALITIES OF
HEALTHY LIFESTYLE AND RESPONSE
TO PRP INJECTION?
I HAVEN'T COME ACROSS THAT AT
ALL BUT INTRIGUED BY YOUR
STATEMENT WITH REGARDS TO THAT.
>>I THINK YOUR BACKGROUNDS
CERTAINLY WITH WEARABLES AND
MEASURING THINGS, LEFT TO HAVE
FURTHER DISCUSSIONS WHERE WE ARE
WORKING TO IMPLEMENT THOSE TYPES
OF PROGRAMS INTO ACTUALLY
CLINICAL PRACTICE. AT THE
VETERANS HOSPITAL HERE. THESE
ARE ALL THINGS THAT I THINK NEED
TO BE LOOKED AT. THANK YOU FOR
BRINGING THAT UP.
>>GREAT. THANKS.
>>ONE LAST QUICK QUESTION. WE
TRY TO STAY ON PROGRAM LALE BIT
HERE.
>>I HAD A COMMENT REGARDING
CUSTOMIZATION OF PRP. SOME OF US
HAVE SHOWN IF YOU WANT TO USE
PRP FOR SKELETAL MUSCLE, AND IF
YOU BLOCK TGF BETA 1 YOU GET
BLOOD FIBROSIS AND IMPROVE
BENEFIT OF PRP. WE DID THE SAME
FOR CARTILAGE WITH VGF AND
ANGIOGENESIS FOR PFP WITH
CARTILAGE REPAIR. I BELIEVE
CUSTOMIZATION OF PRP MAYBE MORE
THAN MINIMAL MANIPULATION OF
THIS PRODUCT SO I WOULD LIKE TO
ASK CONNIE, WHAT HAPPENED IF YOU
INJECT PRP BUT TREAT PATIENT
WITH FIBROTIC DRUG, LOSARTIN OR
KOZAR OR BLOOD VEGF THAT PREVENT
CUSTOMIZATION OF PRP BUT THE
SAME BENEFIT ON CARTILAGE.
>>THANKS, I THINK WHAT YOU ARE
TALKING ABOUT IS COMBINATION
TYPE THERAPY WHERE YOU ARE
LOOKING AT NOT JUST LOOKING AT
WHETHER THIS HAS REGENERATIVE
CAPACITY BUT BLOCKING SOMETHING
THAT MAY BE INHIBITING
REGENERATION. AND YOUR OTHER
WORK WITH ANTI-XENOLYTICS,
TAKING THE APPROACH TO ADDRESS
BOTH SYSTEMIC ASPECT AND ALSO
THE LOCAL JOINT ENVIRONMENT I
THINK THOSE TYPES OF TAKING A
BROADER LOOK BEYOND CARTILAGE
AND BEYOND BONE AND ADDRESSING
THE JOINT ALONG WITH SYSTEMIC
COMPONENTS PARTICULARLY RELATED
TO AGE AND OTHER DISEASE
PROCESSES. CRITICALLY IMPORTANT,
THANK YOU FOR HIGHLIGHTING THAT
>>GEORGE DO YOU WANT TO ASK A
QUICK QUESTION? YOU HAVE YOUR
HAND UP.
>>MY ONE QUESTION IS CONNIE,
YOU POINTED OUT THERE IS A
SIGNIFICANT PART OF SUCCESS OR
FAILURE OF CURRENT TREATMENT
WHICH IS CHOOSING THE RIGHT
PATIENT. THERE ARE PATIENTS WE
CAN GUESS OR LESS LIKELY TO
RESPOND SO VARIOUS AREAS OF
DISEASE OR STABILITY OF THE
JOINT OR PAST HISTORY, WEIGHT
AND AGE. THEN THERE ARE PATIENTS
WHO MAY BE BAD DONORS BECAUSE
BLOOD COMPONENTS AT THE TIME
WHEN WE WANT TO TREAT THEM, ARE
FLAWED. OTHER THAN THE WORK YOU
ARE DOING WHERE WE ARE MEASURING
COMPONENTS IN THE PRP AND
CHARACTERISTICS IN THE PATIENTS
ARE WE DESIGNING STUDIES TO
ALLOW US TO ANSWER THESE TWO
IMPORTANT QUESTIONS WHO TO TREAT
AND WHO NOT TO TREAT.
>>ID THINK THOSE STUDIES A
CRITICALLY IMPORTANT. I HAVE
SOME UPCOMING STUDIES WHERE WE
WILL TRY TO ADDRESS THAT BUT IT
IS NOT -- IT IS SOMETHING THAT I
THINK FOR THE BROADER COMMUNITY,
THIS IS A WAY TO APPROACH THIS,
THAT WE NEED TO DEFINE DIFFERENT
SUB TYPES. I KNOW YOU HAVE DONE
WORK IN THIS AREA. SO DEFINING
STRUCTURAL SUB TYPES, DEFINING
MOLECULAR SUB TYPES. ALSO
LOOKING AT DISEASE PRIOR TO
SYMPTOM ONSET IS CRITICALLY
IMPORTANT. STUDY AFTER STUDY,
HAS SHOWN THAT REALLY IT IS ONLY
ADVANCED BONE ON BONE STRUCTURE
DISEASE OR PATIENT REPORTED
OUTCOMES START TO TRACK. YET ALL
THESE DEVELOP EARLIER LIKE A
HEART ATTACK, YOU DON'T REALLY
KNOW UNTIL EVERYTHING CULMINATES
AND CATASTROPHIC FAILURE AND
PATIENTS ARE IN PAIN ALL THE
TIME AND THEN REALLY IT IS TOO
LATE. BRING IT BACK TO EARLY OA
PRE-OA ARE VERY, VERY IMPORTANT
>>THANK YOU.
>>THANK YOU. SO MUCH. IT GIVES
ME GREAT PLEASURE TO INTRODUCE
MY CO-CHAIR, SCOTT RODEO. WHO
HAS REALLY BEEN DRIVING THOUGHT
LEADER IN THE AREA OF
REGENERATIVE MEDICINE, HE IS
ACCOMPLISHED CLINICIAN SCIENTIST
NIH FUNDED, HE IS VICE CHAIR
RESEARCH HOSPITAL FOR SPECIAL
SURGERY, I KNOW DR. WHITE WAS
ALSO A GIANTS FAN. HE'S BEEN
TEAM PHYSICIAN FOR PRO FOOTBALL
AND OTHER SPORTS FOR MANY, MANY
YEARS. HE'S GOING TO TALK
CONCEPTS UNDER ROLE OF STEM
CELLS IN OSTEOARTHRITIS.
>>THANK YOU, CONNIE. LET'S MOVE
AHEAD. LET'S TALK CELL THERAPY
DISCLOSURES ARE HERE. NOT GOING
DIRECTLY RELEVANT EXCITE
HONESTLY. I WILL START ASKING
THE QUESTION WHAT IS A STEM
CELL? ARE THERE ANY TRUE QUOTE
UNQUOTE STEM CELLS WE CAN USE
TODAY. WE CAN USE CELLS FROM
BONE MARROW ADIPOSE TISSUE,
PERINATAL TISSUE, AMNIOTIC
MEMBRANE, CORED BLOOD AND THINGS
LIKE THAT, UNDERSTAND UNIVERSAL
STEM CELL CRITERIA INCLUDE
UNSPECIALIZED CELLS THAT HAVE
POTENTIAL FOR SELF-RENEWAL, THEY
DIVIDE ASIMILAR METICALLY TO TWO
DAUGHTER CELLS ONE COPY OF
ORIGINAL AND SECOND DAUGHTER
CELL DIFFERENTIATE, THERE'S
MULTI-POTENT DIFFERENTIATION
CAPACITY GIVES YOU A SENSE OF
THE DIFFERENTIATION CAPACITY.
UTILIZED CELL SOURCES CONTAIN
FEW IF ANY STEM CELLS BY FORMAL
CRITERIA. MANY KAPLAN CLASSIC
1991 PAPER FOR DEFINING
MESENCHYMAL STEM CELL BACK IN
THE 1960s AND 70s, SPUE
FRIEDENSTEEN INTRODUCED BONE
MARROW AND KAPLAN INTRODUCED
MESENCHYMAL STEM CELLS IN 1991,
PROGENY BECOME COMMITTED TO
PHENOTYPIC PATHWAY LEADING TO
DIFFERENTIATION. THIS IS A
CONCEPT BACK THROUGH THE '90s,
ORAL CAPLAN AND OTHERS WORK. HE
TALKED ABOUT EXTRINSIC FACTORS
AS WELL AS INTRINSIC FACTORS IN
THE CELLS WITH EACH STEP TO
CONTROL THE CHARACTERISTIC
PHENOTYPE OF CELLS AS THEY GO
THROUGH THE DIFFERENTIATION
PROCESS. HE CONCLUDED THE
ISOLATION MITOTIC EXPANSION AND
SITE DIRECTED DELIVERY OF
AUTOLOGOUS STEM CELLS CAN GOVERN
THE RAPID AND SPECIFIC REPAIR OF
SKELETAL TISSUES. 26 YEARS
LATER, WE RECOGNIZE REVISED
CONCEPT AS FAR AS WHAT IS STEM
CELL, BECAME EVIDENT THAT
BIOLOGIC EFFECT OF EXOGENOUS
CELLS CAN BE DUE TO PRODUCTION
OF ANTI-INFLAMMATORY AND IMMUNE
MODULATING MEDIATORS, PROBABLY
MODIFY LOCAL ENVIRONMENT, AFFECT
LOCAL RESIDENT CELLS. THIS IS A
QUOTE FROM CAPLAN I URGE WE
CHANGE THE NAME TO MEDICINAL
SIGNALING CELLS TO ACTIVELY
REFLECT THE FACT THESE CELLS
HOME IN ON SITES OF INJURY, AND
THEY SECRETE BIOACTIVE FACTORS
THAT BOTH HAVE IMMUNE MODULATING
PROPERTIES, POTENTIALLY
REGENERATIVE. HE QUOTED FURTHER
INDEED PATIENT OWN SITE SPECIFIC
TISSUE SPECIFIC RESIDENT STEM
CELLS CONSTRUCTED NEW TISSUE
STIMULATED BY THESE BIOACTIVE
FACTORS. WE RECOGNIZE EXOGENOUS
CELLS MAY FUNCTION BY MODIFYING
THE INJURY ENVIRONMENT, RATHER
THAN DIRECTLY CONTRIBUTING TO
HEALING. SO AT THE END OF THE
DAY, THIS INTRODUCE CONCEPT OF
STIMULATION OF EXTRINSIC THE
INTRINSIC STEM CELL NICHE THAT
EXISTS AND MAKE TISSUES
PRE-NATAL AS WE GO THROUGH THE
TALK WE UNDERSTAND HOW EXOGENOUS
CELLS WE CAN USE HOW THEY
INTERACT WITH INTRINSIC STEM
CELL NICHE RESIDENT TISSU TISSUR
TALK LATER ON EXOSOMES EXOSOMESL
SKIP THIS IN THE INTEREST OF
TIME, DANIEL WILL TALK ABOUT
EXOSOMES BUT THESE EXTRA
CELLULAR VESICALES RELEASE CELL
CARTILAGE IF YOU WILL AND
PRESENT POTENTIAL TO OBTAIN
BENEFITS OF CELL THERAPY WITHOUT
CELL CULTURING AND EXOSOMES ARE
COMPLEX, ONE OF THE FUNDAMENTAL
MECHANISMS IS INDUCTION OF
POLARIZATION TO MACROPHAGES
CONTRIBUTING TO
ANTI-INFLAMMATORY IMMUNE
MODULATING PROPERTIES OF CELLS.
CELLS WE CAN USE TODAY EXOGENOUS
CELLS MARROW ADIPOSE PERINATAL
TISSUE AND AGAIN INTRINSIC STEM
CELL NICHE. WE WILL COME BACK TO
THIS AS WE GO THROUGH THIS. WE
TALK ABOUT CELLS MSCs, THE S
IS STROMAL CELLS. MESS CHIMAL
STROMAL CELLS AND STANDARD
CRITERIA PUT FORTH BY
INTERNATIONAL SOCIETY FOR
PLASTIC GENE THERAPY, AND
DIFFERENTIATION CAPACITY SO KEEP
THIS IN MINE. THIS IS BASIC
DEFINITION AND THIS IS
IMPORTANTLY BASED ON CELL
BEHAVIOR IN VITRO. IN CULTURE.
GEORGE MADE SOME VERY IMPORTANT
CONTRIBUTIONS IN THIS FIELD AND
INTRODUCED CONCEPT CONNECTIVE
TISSUE PROGENITOR, PROBABLY A
BETTER TERM TO USE, WITH CELLS
WE ARE IMPLANTING IN OUR
CLINICAL APPLICATION
HETEROGENOUS POPULATION OF
TISSUE RESIDENT CELLS AND CAN
PROLIFERATE AND GENERATE PROGENY
WITH CAPACITY TO DIFFERENTIATE
IN ONE OR MORE -- DIFFERENTIATE
TO CONNECTIVE TISSUES, WE CAN
MEASURE PROGENITOR CELLS BY
COUNTING COLONY FORMING UNITS IN
CULTURE, EACH REGENERATIVE CELL
IN CELL FOR COLONY. I WOULD
SUBMIT THE TERM MSC SHOULD BE
USED TO REFER TO CULTURE
EXPANDED POPULATION OF CELLS
THAT MEET THESE CRITERIA,
IMAGING FOR CELL THERAPY AND
SHOULDN'T USE THE TERM TO
DESCRIBE HETEROGENOUS
POPULATIONS OF NATIVE CELLS WITH
UNDEFINED PROPERTIES IN VIVO.
THIS GETS SOME OF THE POINTS
LAST DISCUSSION FROM CONNIE'S
TALK, THE HETEROGENEITY IN
FORMULATIONS AND NEED TO
CHARACTERIZE WHAT WE ARE PUTTING
TO OUR PATIENTS. HOW MIGHT
CELLS WORK? SEEM TORR SYMPTOM
MODIFYING AS FAR AS IMPROVING
SYMPTOMS TYPICALLY PAIN AND
SWELLING IN PATIENTS. AGAIN BACK
TO PARACRINE MECHANISM VIA
ANTI-INFLAMMATORY MEDIATORS AND
VARIOUS IMMUNE MODULATING
FACTORS. THEY WAY ACT ON
SYNOVIAL CELLS IN THE JOINT FOR
IMMUNOMODULATION AND SYMPTOM
MODIFICATION. THINK OF
OSTEOARTHRITIS. OTHER PART OF
THIS IS CAN CELLS STRUCTURE
MODIFYING? CAN THEY INDUCE TRUE
TISSUE GENERATION. TO THAT THEY
NEED TO ACT UPON CHONDROCYTE IN
JOINT, SYNOVIAL CELLS, BOB
MARROW BEREAVED CELLS TO INDUCE
-- BONE MARROW DERIVED CELLS TO
INDUCE TISSUE REGENERATION. THIS
IS A PIE IN THE SKY AS FAR AS
USING CELL THERAPIES TO INDUCE
TWO STRUCTURE MODIFICATION. WITH
THAT BACKGROUND ABOUT CELL
THERAPY WE CAN CONSIDER THE ROLE
IN TREATMENT OF OSTEOARTHRITIS.
INFLAMMATION PLAY AS CRITICAL
ROLE IN PATHOPHYSIOLOGY OF
OSTEOARTHRITIS. THIS IS A GROUP
ON THIS DOPE NEED TO GET INTO
DETAIL BUT IMPORTANT TO POINT
OUT OA IS COMPLEX PROCESS
CHARACTERIZED BY INVOLVEMENT OF
COURSE IN NUMEROUS CELLS AND
TISSUES, CARTILAGE SUBCHONDRAL
BONE, SYNOVIUM. WE KNOW INNATE
IMMUNE CELLS, MACROPHAGES MK
CELLS PLAY IMPORTANT ROLE IN
EARLY INFLAMMATORY RESPONSE AND
ADAPTIVE IMMUNE CELLS, T AND B
CELLS CONTRIBUTE TO DEVELOPMENT
OF CHRONIC RELAPSING SYMPTOMS IN
OUR PATIENTS. OBVIOUSLY
INFLAMMATION I IS A HIGHLY COMPX
PROCESS. ANTI-INFLAMMATORY AND
IMMUNE MODULATING EFFECTS OF
CELLS IS CONTEXT DEPENDENT. THE
DIAGRAM GIVES A SENSE, MSCs,
MESENCHYMAL STROMAL CELLS FROM
MARROW OR ADIPOSE TISSUE,
STANDARD SOURCES, THESE CAN
PROMOTE ENDPLAYMATION WHEN
IMMUNE SEASONAL IS
UNDERACTIVATED. MSCs DECREASE
INFLAMMATION WHEN IMMUNE SYSTEM
IS OVERACTIVATED. SUPPRESS
IMMUNE SUPPRESSERS THAT SWITCH
FROM PRO INFLAMMATORY TO
ANTI-INFLAMMATORY PHENOTYPES,
HOW COMPLEX THESE CELLS ARE.
THEY ARE MEDIATED BY
POLARIZATION OF PROINFLAMMATORY
M 1 TO PANT INFLAMMATORY
PHENOTYPE. SO SUMMARIZED A LOT
OF WORK IN INTEREST OF TIME,
CLEARLY THE CELL THERAPIES
MODULATE INFORMATION AND
UNDERSTANDING IS THESE THERAPIES
WORK VIA PRODUCTION OF HOST OF
ANTI-INFLAMMATORY AND IMMUNE
MODULATING FACTORS AND BIOLOGY
IS COMPLEX, ILLUSTRATED HERE,
JUST GIVE YOU A 30,000-FOOT
VIEW. I WANT TO INTRODUCE THE
CONCEPT THESE IMPORTANT
INTERACTIONS BETWEEN MSCs AND
IMMUNE CELLS SUBTYPES WHETHER
SYSTEMIC OR LOCAL IMMUNE CELLS
IN THE JOINT ENVIRONMENT. WE
KNOW MCs CAN DIRECTLY AFFECT
SYNOVIAL INFLAMMATION. THIS IS
WORK FROM A GROUP IN NETHERLANDS
USING MOUSE MODEL OF
EXPERIMENTAL OA. INDUCED SIGH
EWE VIETIS OR DISSEMINATION OF
MEANIAL ME IN THIS CUSS MODEL.
THEY FIND SYNOVIUM IN ANIMALS.
IF THEY TREAT THE ANIMALS, TREAT
WITH ADIPOSE DERIVED CELLS, THEY
FOUND SUPPRESSION OF ACTIVATED
MACROPHAGES, THEY SEE DOWN
REGULATION OF VARIOUS
PROINFLAMMATORY MEDIATORS.
DECREASE IN OSTEOCYTE FORMATION.
YOU CAN SEE PROACTIVELY SYNOVIAL
ACTIVATION SIGH KNEW VIETIS
SCORES IN THESE ANIMALS SO BASIC
LABORATORY ANIMALS DO
DEMONSTRATE DIRECT EFFECT OF MSC
ON THAT SYNOVIAL INFLAMMATORY
PROCESS. MORE WORK AT MSC AND
HOW MEDIATED BY CELLS IN INNATE
IMMUNE SYSTEM, IMPORTANT FROM
GROUP IN ROT TEARDAM. THEY
REPORT SYSTEMICALLY ADMINISTERED
MSCs ARE PHAGOSIGH THOSED BY
MONOCYTES THAT LEADS TO POLAR --
PHAGOCYTOSED BY THIS PHENOTYPIC
SWITCH. THESE PRIME MONOCYTES
INDUCE UPREGULATION OF T
REGULATORY CELLS TO YOUR
ADAPTIVE IMMUNE RESPONSE, LEADS
TO INDUCTION OF LONG TERM
ADAPTIVE IMMUNE RESPONSE UPON
DIFFERENTIATION OF THESE
AFFECTED MONOCYTESES AFTER THEY
PHAGOCYTOSE CELLS, DIFFERENTIATE
IN IMMUNE MACROPHAGES. THIS IS
INTERESTING BECAUSE THE DATA
SUGGESTS THE BIOLOGICAL ACTIVITY
OF INFUSED CELL MAYBE
INDEPENDENT OF CELLULAR
ACTIVITY. CHALLENGES HYPOTHESIS
THAT AFFECTS OF MSCs ARE
MEDIATED BY THE SECRETOME. THE
ADDITIONAL SIGNALING CELL FROM
CAPLAN YEARS AGO SO IMPORTANT
REARE ACTION BETWEEN CELLS
MSCs AND IMMUNE CELLS WHICH
LEADS TO DISCUSS MORE ABOUT THE
ROLE OF MACROPHAGES IN OA
DEVELOPMENT AND PROGRESSION,
GROUP FROM FRANCE WITH
CHRISTIAN, THEY IMPORTANT POINT
OUT HOW MACROPHAGES ARE
IMPORTANT INFILTRATES IN OA. BUT
MACRO BIOLOGY IS COMPLEX. PEOPLE
DISCUSS TWO POPULATION
MACROPHAGES RESIDENT
MACROPHAGES, PRESENT IN THE
JOINT, AS WELL AS MONOCYTE
DERIVED MACROPHAGES FROM
CIRCULATION IN THE INTERACTION
BETWEEN THESE POPULATIONS IS
CRITICALLY IMPORTANT. MACROPHAGE
BIOLOGY IS VERY COMPLEX WITH
THESE CELLS INFILTRATING ANA
BOLLIC AND CATABOLIC, THERE ARE
PRO INTORY AND ANTI-INFLAMMATORY
MACROPHAGES IN OA SO FOLLOWING
THE THEME ABOUT MACROPHAGES,
OTHER WORK HERE THAT THEY WENT
ON THE SAME GROUP FROM FRANCE,
JUST TO SUMMARIZE THE PATHWAYS
DISCUSSED. THERE IS
INFLAMMATORY SIGNALING PATHWAYS
ACTIVATED IN SETTING OF
OSTEOARTHRITIS. AND THAT DOES
ATTRACT CIRCULATING
PROINFLAMMATORY MONOCYTE DERIVED
MACROPHAGE, THE M 1 POPULATION
WHICH THEN WILL INFILTRATE THE
JOINT, THESE PROINFLAMMATORY
MACROPHAGES DO CARRY OUT
PHAGOSITIC FUNCTION BUT THEN
BEGIN TO SECRETE
ANTI-INFLAMMATORY MEDIATORS.
WHICH CAN ULTIMATELY HAVE ROLE
PERHAPS IN PROMOTING WOUND
REPAIR. THIS LEADS POLARIZATION
FROM THIS M 1 PROINFLAMMATORY TO
THE ANTI-INFLAMMATORY PHENOTYPE.
FAILURE OF THIS ORCHESTRATED
MACROPHAGE RESPONSE FROM
SYNOVIAL MEMBRANE OR FAILURE OF
RESOLUTION LEADS TO CHRONIC
INFLAMMATION, CONTRIBUTING TO
PERSISTENT SYMPTOMS. WHAT ABOUT
USING MSDs TO TARGET THESE
MACROPHAGES? SINCE THEY HAVE
SUCH A CRITICALLY IMPORTANT ROLE
AND CLEARLY MSCs INTERACT WITH
IMMUNE CELLS, HOW CAN MSCs
HAVE THERAPEUTIC IN THE JOINT
HERE? SO AGAIN MSC ENABLE SWITCH
FROM PROINFLAMMATORY TO
ANTI-INFLAMMATORY SUB SETS.
MOLECULAR MECHANISM ARE COMPLEX
BUT NUMEROUS FACTORS INCLUDING
TNF ALPHA, PBE 2, EXTRA CELLULAR
VESICLES PLAY A ROLE. SO WE HAVE
THE DAMAGE JOINT, AGAIN
PROINFLAMMATORY MACROPHAGES
INFILTRATE AND NOW MSCs ARE
SUPPLIED TO THAT PATIENT, DOSED
IN THE KNEE EXOGENOUSLY. THAT
CAN AFFECT THE MACROPHAGE
POPULATIONS AND POTENTIALLY LEAD
TO ANTI-INFLAMMATORY PHENOTYPE.
WE KNOW MSC DERIVED EXTRA
CELLULAR VESICALES TRANSPORT
MOLECULES, THAT CAN'T BE
SECRETED INCLUDING PROTEINS
ENZYMES, AND OTHER FACTORS, YOU
WILL HEAR MORE ABOUT THIS IN THE
TALK FROM DANIEL SARIS. MSC
DERIVED VESICALES ARE SHOWN TO
PROMOTE ANTI-INFLAMMATORY
MACROPHAGE PHENOTYPE, AN
IMPORTANT PRINCIPAL IN OUR
DISCUSSIONS LATER ON. SO THAT
BACKDROP, WHAT DOES THIS MEAN AS
TREATING OUR PATIENT?
THEY AFFECT QUALITY SYMPTOMS
FROM KNEE OA. 12 PATIENTS WITH
KNEE OA TREATED WITH SINGLE
INTRAARTICULAR INJECTION OF 1,
10, OR 50 MILLION BONE DERIVED
CELLS, NO ADVERSE EVENT, THEY
DID REPORT SIGNIFICANT
IMPROVEMENT IN OUTCOME MEASURES
YOU CAN SEE THE SYMPTOM SCALE ON
THE RIGHT SID SIDE. YOU DO SEE
IMPROVEMENT IN PATIENT SYMPTOMS
AND THEY HAVE THE MOST RELEVANT
IMPROVEMENTS IN OUTCOME
MEASURES. THIS GROUP WENT TO USE
MRI TO LOOK AT CARTILAGE
MORPHOLOGY AND COLLAGEN CONTENT
USING RELAXATION TIME
MEASUREMENTS. THIS SCORE DIDN'T
CHANGE SO THOUGH SYMPTOM
MODIFYING MAYBE NOT STRUCTURE
MODIFYING IN JOINTS. THEY DID
FIND CARTILAGE CATABOLIC
BIOMARKER AND MRI SCORE LOWER
DOSE, SYNOVIAL SCORE IN THE
RIGHT, HIGH DOSE RED LINE, LOWER
SINUVITIS SCORE. THEY FIND
PROPORTION OF PRO-INFLAMMATORY
MONOCYTES AND MACROPHAGES
DECREASED IN H JOINTS TREAT WITH
MSC. THEY HAD A PANEL OF
ANTI-INFLAMMATORY MARKERS THEY
SURVEYED IN MSC SAMPLES, THEY
FOUND THIS PANEL WAS PREDICTIVE
OF PATIENT OUTCOME MEASURES OVER
12 MONTHS. THIS DATA PROVIDE
PREDICTIVE SELECTION CRITERIA WE
CAN USE IN STUDIES OF CELL
THERAPY IN PATIENTS. IN
SYMPTOMATIC IMPROVEMENT, BRIEFLY
META ANALYSES, HERE IS ONE THAT
RANDOMIZED TRIALS RETROSPECTIVE
STUDIES OVER 500 PATIENTS REPORT
IMPROVEMENTS IN ANALOG SCORES,
NO ADVERSE EVENTS IN PATIENTS.
META ANALYSIS, VISUAL
IMPROVEMENTS, YOU CAN SEE IN THE
FOREST PLOT HERE, THERE ARE
STUDIES THAT DEMONSTRATE
IMPROVEMENT WITH CELL THERAPY.
THE NEXT QUESTION, ARE THESE
CELLS STRUCTURE MODIFYING? CAN
WE REGENERATE TISSUE? LITERAL
STEM CELLS FOR PATIENT IS
POTENTIAL FOR REGENERATION OF
STRUCTURALLY FUNCTIONALLY NORMAL
TISSUE, BASED ON DEMONSTRATED
MULTI-LINEAGE DIFFERENTIATION
POTENTIAL CELLS WHICH IS SHOWN
IN VITRO. THERE IS LIMITED
EVIDENCE FOR TRUE TISSUE
REGENERATION BY IMPLANTED CELLS,
LIMITED BY NOW EXOGENOUS CELLS
WILL INT INTERCO-TO HOST TISSUED
DIFFERIATE TO HUMAN -- INTER
COLLATE TO HOST TISSUES. TO
UNDERSTAND REGENERATION WE NEED
TO KNOW IMPORTANT TO UNDERSTAND
HOW TISSUE GENERATION OCCURS. IT
IS FELT TISSUE GENERATION IN
ADULT MAMMALIAN TISSUE IN ORGANS
IS ORCHESTRATED BY IMMUNE
RESPONSE H COMPLEX BIOLOGY BUT
PLAY CRITICAL ROLE IN TISSUE
REGENERATION. NEUTROPHILS IN PRO
INFLAMMATORY MACROPHAGES
INFILTRATE THE JOINTS. WE HAVE
INJURED JOINT ARTHRITIC JOINT,
PTOA B JOINT, M 1 MA CASH FLOW
PHAGOINFILTRATE THE JOINT IN
RESPONSEOBTAINFLAMTORY MEDIATORH
POLARIZED PHENOTYPE BUT THE
PROLONGED DAMAGE CAN LEAD TO
UNRESOLVED INFLAMMATION THAT
LEADS TO FIBROSIS RATHER THAN
TRUE TISSUE REGENERATION. THIS
IS IMPORTANT BIOLOGIC CHALLENGE
HERE. THIS GETS BACK TO THE
INTRINSIC STEM CELL NICHE, WE
ARE TALKING POTENTIAL TO
REGENERATE TISSUE. MANY HARBOR A
POPULATION OF INTRINSIC
REGENERATIVE CELLS, THESE ARE
LOCALIZED TO WALLS OF BLOOD
VESSELS, PICTURE BOTTOM RIGHT
IMPORTANT PAPER FROM BACK IN
2008, DEMONSTRATING THE PRESENCE
OF THESE CELLS. WE KNOW
EXOGENOUS CELLS PRODUCE
SIGNALING MOLECULES THAT
STIMULATE THESE INTRINSIC
PROGENITOR CELLS. THIS IS
PROBABLY THESE INTRINSIC CELLS
THAT INITIATE TISSUE HEALING AND
REGENERATION. SO POTENTIAL TO
INDUCE REGENERATION LIKELY DUE
TO STIMULATION OF INTRINSIC STEM
OR PROGENITOR CELLS THAT
RESIDENT IN MANY TISSUES USE THE
TERM CONNECTIVE TISSUE
REGENERATIVE BACK TO GEORGE
MUSCHLER'S WORK AS WELL. OUR
STUDY ANIMAL MODEL, POTENTIAL
FOR CELLS TO REGENERATE TISSUE
IN THE OA JOINT. THIS GROUP FROM
CHINA USE RAT KNEE OA MODEL. ACL
TRANSSECTION MODEL, ANIMALS
TREAT WITH BONE MARROW DERIVED
MANY,SC OR THE EXOSOMES AND
FOUND BONE MARROW DERIVED AN
EXOSOMES ALLEVIATED THE
CARTILAGE DESTRUCTION AND SOME
BONE REMODELING IN THIS RAT
MODEL. YOU CAN SEE OA SCORE
DIFFERENT IN THOSE ANIMALS WITH
EXOSOMES OR BONE MARROW DERIVED
CELLS. FOUND REDUCED JOINT
DAMAGE AND CHANGES IN SUB --
MICROCT TO MEASURE
MICROSTRUCTURAL PROPERTIES IN
BONE. SO THEY FELT THESE BONE
MARROW DERIVED CELLS OBSERVED
BENEFICIAL EFFECT BY REDUCING
CELL SENESCENCE AND APOPTOSIS OF
CHONDROCYTES. SO IMPORTANT
DISCUSSION LATER TODAY. WE ARE
NOT HUMAN CLINICAL STUDIES, ANY
EVIDENCE CELLS STRUCTURE MODIFY,
THERE'S EARLY EVIDENCE, CHRIS IN
KOREA, GROUP OF PATIENTS TREATED
WITH INTERARTICULAR INJECTION OF
OUTGAS ADIPOSE DERIVED MSC SO
THEY OBTAINED CELLS AND CULTURE
THE CELLS, SO THIS IS IN KOREA,
THE CELLS REJECT AFTER THREE
WEEKS CULTURE, THEY EXTENSIVELY
TESTED CELLS FOR CELL NUMBER,
VIABILITY, PURITY, IDENTITY, SO
DO THE APPROPRIATE ANALYSES ON
THEIR CELLS, PRIOR TO
IMPLANTATION. STUDIES THREE
DOSES IN A SMALL GROUP OF
PATIENTS. THEY FOUND
IMPROVEMENTS IN THEIR PATIENT
OUTCOME MEASURE BUT IMPORTANTLY
REJECTED EVALUATION WITH MRI AND
ARTHROSCOPY DID FIND THE SIZE OF
CARTILAGE DEFECT DECREASED IN
THE VOLUME OF CARTILAGE
INCREASED IN THE COMPARTMENT
SEEN GRAPHICALLY HERE. THEY
FOUND BIOPSY GENERATED HIGHLIGHT
CARTILAGE EARLY EVIDENCE HERE
CULTURE EXPANDED CELLS MAY IN
FACT BE STRUCTURE MODIFYING.
SIMILAR STUDY FROM PAIN,
RANDOMIZE TRIAL ALLOGENEIC,
CULTURE EXPANDED MARROW CELLS,
INTRAARTICULAR INJECTION IN
JOINTS OF KNEE OA PATIENTS
CONTROLLED WITH HYALURONIC ACID
INJECTION. AND THE CELL TREATED
PATIENTS HAD IMPROVEMENTS IN
THEIR PATIENT OUTCOME MEASURE
BUT IMPORTANTLY ON MRI USING
RELAXATION TIME MEASUREMENTS OF
CARTILAGE FOUND IMPROVEMENT IN
CARTILAGE QUALITY AND THOSE
PATIENTS TREATED WITH CELLS.
CULTURE EXPANDED CELLS. SO
POTENTIAL FOR CELL TO INDUCE
TISSUE REGENERATION. SO TO
CONCLUDE, I WOULD SUBMIT WE
CURRENTLY HAVE LITTLE ABILITY TO
USE TRUE STEM CELLS DEFINED BY
ANY FORMAL CELLULAR OR MOLECULAR
CRITERIA. BUT THERE IS DATA TO
SUGGEST SYMPTOM MODIFICATION.
CELL THERAPY HOLDS POTENTIAL FOR
SYMPTOMS IN KNEE OA. THIS
PARACRINE AFFECT AFFECTING LOCAL
TISSUE MICROENVIRONMENT BY
PRODUCTION OF ANTI-INFLAMMATORY
AND IMMUNE MODULATING FACTORS,
CLEARLY ERR ACT WITH LOCAL AND
SYSTEMIC IMMUNE CELL SUBTYPES IN
KNEE OA JOINT. PLAY A CRITICAL
ROLE IN MACROPHAGE POLARIZATION.
THE OTHER SIDE OF THE COIN TO
ABILITY TO MODIFY STRUCTURE AND
REGENERATE TISSUE THERE'S
POTENTIAL. WHAT WE NEED IS MOVE
TO ABILITY TO PICK OUT CELL
SORTING TO ALLOW SELECTION OF
DESIRED CELL POPULATIONS,
FOLLOWED BY CULTURE EXPANSION OF
THOSE CELLS AND MAYBE
IMPORTANTLY ELIMINATION OF THE
UNDESIRED CELLS. THIS SUGGESTS
NIEDERHUBER TO IDENTIFY MARKERS
OF PURITY POTENCY AND BIOLOGIC
ACTIVITY SO WE CAN AFFECT
CHARACTERIZE AND SELECT OPTIMAL
CELL POPULATION. I RECOGNIZE
TISSUE REGENERATION MAY OCCUR
VIA STIMULATION OF INTRINSIC
PROGENITOR CELLS RESIDENT IN
TISSUE. I WILL STOP THERE. THANK
YOU.
>>THANK YOU, SCOTT. THIS IS
OPEN FOR QUESTIONS. I HAVE A
QUICK QUESTION REGARDING -- SO
MANY ANIMAL STUDIES IN
PARTICULAR USE YOUNG ANIMALS.
ARE THERE STUDIES SHOWING
WHETHER MACROPHAGE POLARIZATION
AFFECTS FROM CELLS FROM OLDER
INDIVIDUALS OR INDIVIDUALS WITH
DISEASE STATES, DO THEY
SIMILARLY INDUCE M 2
POLARIZATION?
>>NOT SEEING MUCH, VERY GOOD
QUESTION, IN THE ANIMAL STUDIES
LARGELY BEEN EXPERIMENTAL OA S
NEXTUVITIS, D, MANYM MOLDS LIKE
THAT WE NEED CLINICAL STUDIES IN
OUR PATIENTS AND THAT IS WHY IN
OUR CLINICAL STUDIES WE NEED TO
REALLY CHARACTERIZE PHENOTYPE OF
PATIENTS SO I DON'T -- HAVE NOT
SEEN MUCH EXAMINED THAT
IMPORTANT QUESTION.
>>SO DAN GRANDE.
>>APPRECIATE -- HI. SCOTT,
APPRECIATE YOUR WONDERFUL TALK.
I WANTED TO YOU TO PERHAPS
FOLLOW-UP WITH RESPECT TO DO YOU
THINK THAT SOME OF THE STUDIES
ARE ALLO GENIC, SOME ARE
AUTOLOGOUS, WHAT ARE YOU THINK
IS THE DIFFERENCE, IS THERE AN
IMPORTANT DIFFERENCE BETWEEN
CULTURED MSCs VERSUS USING SAY
BMAP WHERE YOU HAVE THE
INTERACTION OF THE OTHER CELLS
AND THE CROSS SIGNALING, VERSUS
PURE COB CENTRATION OF CULTURED
MSCs?
>>HUGE DIFFERENCE. THE POORLY
CHARACTERIZED NATIVE CELL
PREPARATION, WE USE WITH BONE
(INAUDIBLE) THESE UNCULTURED
CELLS, HETEROGENOUS POPULATIONS,
VERY VARIOUS POPULATION CULTURE
OF CELLS, CULTURE CERTAIN CELL
DOMINATE THE CULTURE SO THEY ARE
VERY DIFFERENT. SO ALLOGENEIC,
IF WE USE THAT PREPARATION IT
GIVES THE POTENTIAL TO
CHARACTERIZE THOSE CELLS
PRE-OPERATIVE SO WE HAVE SOME
IDEA OF THE PROFILE OF THOSE
CELLS. SO THOSE WILL BE VERY
DIFFERENT POPULATIONS AND IF WE
MOVE TO ALLOGENEIC CELL SOURCES
THEN WE CAN DO APPROPRIATE CELL
SORTING, CULTURE EXPANSION OF
THE DESIRED CELLS IN THOSE
PREPARATIONS. THEY CHARACTERIZE
WHAT WE ARE PUTTING IN PATIENTS.
I SUBMIT TO ALL OF US CLINICIANS
IS USING ALL THESE THERAPIES,
WHETHER CELL THERAPY OR PRP
QUESTION, WE NEED AN ALLOQUAT OF
THAT MATERIAL AND CARRY OUT OUR
LABORATORY, WHATEVER TESTS WE
CAN DO TO CHARACTERIZE THE
PURITY, POTENCY, ACTIVE WHATEVER
IT IS, WE IDENTIFY THE SENTINEL
MARKERS THAT ARE PRACTICAL AND
CORRELATE PATIENT OUTCOMES.
CLINICAL OUTCOMES IMAGING
OUTCOMES WITH OUR CELL
CHARACTERIZATION.
>>THANK YOU.
>>PAM ROBEY HAS A QUESTION.
>>THANK YOU FOR THAT OVERVIEW,
SUCH A WONDERFUL OVERVIEW. THIS
IS MORE OF A QUESTION GENERALLY
TO THE FIELD. THAT IS, DON'T YOU
THINK IT IS TIME TO ACTUALLY
START USING NAMES THAT ARE MORE
DEFINED IN MANY THE CELL
POPULATIONS WE ARE USING? YOU
REVIEWED NICELY THE HISTORY
BLIND THE TERM MESENCHYMAL STEM
CELL, I THINK GIVEN THE FACT
THAT WE NOW KNOW THAT THINGS
TOSSED TO THAT BUCKET ARE QUITE
DIFFERENT, THAT WE NEED TO START
GIVING CELLS SPECIFIC NAMES,
BONE MARROW DERIVED ADIPOSE
DERIVED. THERE'S MANY TIMES
PEOPLE DON'T IDENTIFY THEIR CELL
SOURCE. WE KNOW THESE CELLS ARE
INTRINSICALLY DIFFERENT. THIS IS
VERY IMPORTANT IN TERMS OF
CLINICAL APPLICATION, THAT
DEFINING THE CRITICAL QUALITY
ATTRIBUTES DEPENDS ON THE CELL
SOURCE. DIFFERENT CELL SOURCES
MAY HAVE VERY DIFFERENT AFFECTS.
SO IF WE WANT TO TRY TO COMPARE
ONE STUDY TO ANOTHER, WE NEED TO
KNOW MORE ABOUT THE TISSUE
SOURCE AND WHAT THE CRITICAL
QUALITY CHARACTERISTICS ARE, OF
THAT POPULATION. WANT YOUR
THOUGHTS ON THAT SUBJECT AND
SURE GEORGE PROBABLY HAS
THOUGHTS TO.
>>MY RESPONSE IS AMEN. YOU SAY
THE PROBLEM WELL AND EXPERTS IN
THE FIELD HELP US, COULDN'T
AGREE MORE. GOES WITHOUT
SAYING, YOU STATED THAT WELL. WE
NEED TO DO THAT. CLEARLY WE NEED
TO CHARACTERIZE WHAT WE ARE
PUTTING IN THE PATIENT.
>>THANK YOU, CHRISTIAN
LATTERMANN.
>>SCOTT, THANK YOU VERY MUCH
FOR THAT OVERVIEW. THAT WAS
BEAUTIFUL. ONE OF THE QUESTIONS
THAT I WRESTLE WITH LOOKING AT
CHRONIC INFLAMMATION IN THE
CONTEXT OF PTOA AND TRY TO
COMPARE TO CHRONIC INFLAMMATORY
CONDITIONS, WE COME BACK TO THIS
CONCEPT OF RESOLUTION OF
INFLAMMATION. YOU HAVE MENTIONED
THAT ALSO YOU TOLD US VERY MUCH
ABOUT THE M 1 M 2 MACROPHAGE
SWITCH THAT STILL CELLS ARE
ACTING ON. ONE OF THE CLINICAL
QUESTIONS I ASK MYSELF AND I
WANT YOUR OPINION, DO WE DEAL
WITH THE SITUATION WHERE WE HAVE
TOO LITTLE INTRAVESICULAR
RESPONSE TO THE INJURY OR DO WE
DEAL WITH SITUATION WHERE WE
HAVE TOO MANY FACTORS THAT ARE
PREVENTING AN APPROPRIATE
RESPONSE? BECAUSE WE DO HAVE AN
INTRINSIC HEALING RESPONSE THAT
STARTS BUT SOMEHOW IT FAILS. I'M
TRYING TO FIGURE OUT BASICALLY
WHAT DO YOU THINK IS HAPPENING
HERE?
>>MY SIMPLE ANSWER OR CONCEPT
IS THAT CLEARLY RIGHT. THERE IS
INJURY INDUCE TRAUMA INDUCES
INFLAMMATION. INFLAMMATION TURNS
ON INTRINSIC HEALING RESPONSE,
GOOD THING. PROBLEM IS IT IS
CHRONIC UNRESOLVED INFLAMMATION
THAT YOU TAKE A LEFT TURN GO
DOWN THE WRONG PATHWAY SO MAYBE
WITH INJURY YOU -- THE INTRINSIC
INNATE SYSTEMS ARE FOR TISSUE
GENERATION ARE HEALING ARE
STIMULATED BUT CHRONIC
INFLAMMATION THEY LEAD YOU THE
WRONG PATHWAY IF YOU WILL, THAT
IS INSTEAD OF REGENERATIVE
TISSUE YOU GO TO FIBROSIS
PATHWAY. INFLAMMATION IS HIGHLY
COMPLEX BUT IN MY MIND CHRONIC
UNRESOLVED INFLAMMATION IS
PRIMARY FACTOR. AS PROBLEM WITH
ANY DISEASE STATES.
>>SO THE QUESTION THAT I'M
TRYING TO GET AT IS WE CAN SHUT
DOWN INFLAMMATION RELATIVELY
QUICKLY EVEN IN A KNEE JOINT. WE
HAVE DONE THAT IN CLINICAL
TRIALS WE HAVE DONE WITH
CORTISOL FOR EXAMPLE BUT
QUESTION, IS THAT A GOOD THING,
JUST TIMING ISSUE? OR IS IT JUST
SOMETHING THAT IS TOO TEMPORARY
AND BASICALLY WILL GO DOWN THE
WRONG PATH BECAUSE SYSTEM IS
OVERCOME BY FACTORS THAT WILL
OVERWHELM ANY RESTORATION OF
HOMEOSTASIS SO TO SPEAK NO
MATTER WHAT.
SPEAKER5: COMPLEX BECAUSE I
THINK WE NEED A MORE NUANCED
APPROACH, IF YOU HIT WITH
CORTICOSTEROID, NICE WORK BUT
MAYBE INFLAMMATION IS VERY
COMPLEX, THERE ARE MEDIATORS,
CYTOKINES MAYBE BLOCK OTHERS WE
DON'T AND THEN YOU HAVE TIMING
ISSUES. SO WE ARE TIP OF THE
ICEBERG AS FAR AS UNDERSTANDING
HOW WE AS CLINICIANS MODULATE
INFLAMMATION. THAT IS OUR
CHALLENGE. YOU HAVE PATIENTS IN
THE OFFICE IN CLINIC, SWOLLEN
KNEE, I CAN PUT A STEROID IN BUT
SO VARIABLE, TIMING OF INJURY,
OTHER FACTORS IN THAT PATIENT'S
KNEE. DO I NEED TO REPEAT THIS
THERAPY. I THINK WE NEED A MUCH
MORE REFINED APPROACH TO
MANAGING INFLAMMATION.
>>DANIEL WHITE.
>>THANK YOU FOR THE WONDERFUL
PRESENTATION, DR. RODEO.
WONDERING IF YOU CAN COMMENT ON
THE QUALITY OF THE CLINICAL
TRIALS THAT HAD CLINICAL
OUTCOMES IN PARTICULARLY
INTERESTED IN WHETHER BLINDING
WAS DONE, WAS THERE A PLACEBO IN
ADDITION TO STEM CELL? WHAT
PEAKS MY QUESTION ABOUT THIS IN
OTHER PRP STUDIES THERE'S
VARIABLE AND QUALITY AND WE MOW
PLACEBO MAKES A DIFFERENCE WITH
CLINICAL OUTCOMES AND GIVEN NO
BENEFICIAL EFFECTS STRUCTURAL SO
FAR, I UNDERSTAND PRELIMINARY
STUDIES BASIC QUESTION HOW MUCH
IS THIS PLACEBO EFFECT?
>>GREAT QUESTION. OVERALL STUDY
METHODOLOGY,S MODERATE TO POOR
IN A LOT OF STUDIES WHAT YOU CAN
SAY ABOUT A LOT OF LITERATURE,
THE ISSUE TO CHARACTERIZE TWO
THINGS, DR. ROBEY BROUGHT ONE,
CHARACTERIZE WHAT WE ARE PUTTING
IN PATIENT, SO CALLED ME MEBO
INFORMATION. MINIMAL, BIOLOG
BIOLOGICAL, WHAT CELLS ARE USING
PRP HOW WOULD -- IT WAS OBTAINED
PREPARED ET CETERA, WE NEED TO
CHARACTERIZE WHAT IS PUT IN THE
PATIENT AND OTHER SIDE THE
PATIENT PHENOTYPE BACK TO
CONNIE'S EARLIER QUESTION.
PATIENT AGE GENDER MEDICAL
CO-MORBIDITIES. ALL THESE
ISSUES. STUDIES OFTEN DON'T HAVE
ALL THAT INFORMAT INFORMATION. S
COMMENT, WE FOOD THAT DATA IN
OUR CLINICAL STUDIES. BE
IMPORTANCE OF NIGH FOR WELL
DESIGNED CLINICAL TRIALS WHICH
ARE CHALLENGING. THAT IS IS WHAE
NEED IN THIS FIELD.
>>REALLY GREAT TALK. ENJOYED
THAT. I WAS PART OF THE ACADEMY
PANEL, ABOUT TEN PEOPLE, WE HAD
TO PUT SOME TREATIES TOGETHER ON
ALL THE HIGH LEVEL STUDIES FOR
TREATING THE OA MESENCHYMAL
CELLS, IT ENDED UP BEING EXACTLY
WHAT YOU SAID, VERY INCLUSIVE
AND EVERYBODY USING DIFFERENT
CONCENTRATIONS OF CELLS WITH
DIFFERENT PROCUREMENT TECHNI
TECHNIQUES. DO YOU THINK IT IS
POSSIBLE THIS GROUP COULD PUT
TOGETHER A TREATISE FOR GOING
FORWARD ON THIS IS THE MINIMAL
-- MAYBE THIS IS MINIMAL
INFORMATION YOU SHOULD TRY TO
COLLECT ON YOUR TAKING -- THIS
IS THE WAY TO CONDUCT SOME OF
THE STUDIES SO WE HAVE A LITTLE
MORE STAND STANDARDIZATION SO WE
DO IT AGAIN MANY FIVE YEARS WE
HAVE A BETTER HANDLE ON THIS
FIELD? COULD THAT BE A RESULT OF
THIS MEETING?
>>LOOK AT PAPER FROM BOB LAPROD
2017 IAN MURRAY, TOOK US DOWN
DOING THIS, SUGGESTING THE FACT
THAT WE SHOULD CHARACTERIZE,
MAYBE WE NEED TO REVISIT THAT
AND WE HAVE A MORE REFINED
ABILITY OR ABILITY TO HAVE A
MORE REFINED ANALYSIS BUT
CLEARLY POINTS OUT IMPORTANCE OF
CHARACTERIZING FORMULATION OF
PATIENTS IN ADDITION TO
CHARACTERIZING THE PATIENT,
RECIPIENT.
>>DAN YOU HAD YOUR HAND UP A
WHILE, DID YOU STILL HAVE A
QUESTION?
>>THANKS CONNIE. THANK YOU VERY
MUCH, SCOTT. IT WAS MORE
REFLECTION, QUESTION TO SCOTT
AND MAYBE INFO FOR THE GROUP.
SCOTT WHERE DO YOU SEE ROOM FOR
MAKING BETTER STEPS IN USING
STEM CELL BASED THERAPIES AND I
WILL OPEN TO CARTILAGE REPAIR
AND OSTEOARTHRITIS. I LIKE
TREATING SOONER RATHER THAN
LATER SO AFTER REVIEWING THIS
AND SHARING THAT BE US WHERE YOU
TAKE IT WHETHER YOU SEE RESEARCH
HAS BEEN ALREADY. FOR GROUP
LARGER INFORMATION, IMPORTANT TO
KNOW WE HAVE BEEN DOING THESE
ALLOGENEIC MSC WORK, TREATING
PATIENTS WITH ALLOGENEIC MSC,
FOR THE REASON DR. ELISSEEFF
SAID AND DR. LATTERMANN REFERRED
TO, MSCs ARE BETTER GAUGING
THE JOINT AND PROVIDING
APPROPRIATE IMMUNE MODULATION
THAT ARE INJECTION OF
CORTICOSTEROIDS ARE. SO MY
FEELING IS THAT WE SHOULD TREAT
BLACK BOX OF MSCs BECAUSE WE
DON'T UNDERSTAND THEM FULLY AS A
BENEFICIAL ASPECT AS PART OF OUR
THERAPY BEING SMARTER THAN WHEN
WE USE AUTOLOGOUS OR WHEN WE USE
EXTERNALLY APPLIED CHEMICALS BUT
MY QUESTION IS, WHERE DO YOU
THINK US TAKING MSCs AS PART
OF THERAPEUTICS SHOULD GO FROM
RESEARCH PERSPECTIVE?
>>CHARACTERIZING THE CELL
FORMULATION, I THINK IDENTIFYING
THE OPTIMAL CELL FORMULATION FOR
DIFFERENT TISSUE, ONE SIZE
DOESN'T FIT ALL, ONE FOR TENDON
DIFFERENT THAN CARTILAGE
DIFFERENT FOR MUSCLE AND BONE.
CHARACTERIZE WHAT WE NEED TO
TREAT SPECIFIC TISSUE PATHOLOGY
AND CHARACTERIZE CELL POPULATION
AS PAM ROBEY ARTICULATED.
ANOTHER AREA IS INTERACTION WITH
INTRINSIC STEM CELL, PROGENITOR
CELL POPULATION IN TISSUES AND
IMPORTANT ROLE OF IMMUNE CELLS
IN THAT PROCESS. THE PARACRINE
EFFECT OF THESE MATERIAL YOUR
EXOSOME WORK WILL GET TO THAT.
THESE MOLECULES FROM CELLS, HOW
DOES THAT AFFECT INTRINSIC
PROGENITOR CELLS IN TISSUES?
>>FULLY AGREE BUT ALSO WHAT
THAT MEANS IS INTERESTING FOR
OUR FIELD TO RESPONDS TO THAT
YOU HAVE TO GO ALLOGENEIC IF
CHARACTERIZIZATION AND
RELIABILITY EVAPORABILITY IS A
BIG THING AND COLLEAGUES FIND IT
CONSIDERABLE CHALLENGE BECAUSE
REGULATORY BURDEN ON ALLOGENEIC
WORK. HOW DO YOU SEE THAT
HAPPEN?
>>THOSE ARE CHALLENGES FOR US,
THAT'S THE REGULATORY SIDE OF
THINGS AND THE NEED TO CONTINUE
TO RELATIONLATORY ENVIRONMENT
LANDSCAPE INVOLVES.
>>MOVING ON, THEY ASKED US TO
DO SO. WITH THAT I WILL -- WE
WILL MOVE TO DR. MARK HOCHBERG,
PLEASURE, PROFESSOR MEDICINE
EPIDEMIOLOGY AND PUBLIC HEALTH
UNIVERSITY OF MARYLAND. HE IS
HEAD OF DIVISION OF RHEUMATOLOGY
AND CLINICAL IMMUNOLOGY AS WELL
AS VICE CHAIR IN THE DEPARTMENT
OF MEDICINE, AT UNIVERSITY OF
MARYLAND. BRIEFLY MENTION VERY
DISTINGUISHED AWARDS FROM DR.
HOCHBERG OVER THE YEARS FROM THE
DISTINGUISHED CLINICAL
INVESTIGATOR WORK, AMERICAN
COLLEGE OF RHEUMATOLOGY,
LIFETIME ACHIEVEMENT AWARD FROM
ORSE, PAST PRESIDENT OF THE U.S.
BONE AND JOINT INITIATIVE. VERY
ACCOMPLISHED IN HIS FIELD. HE IS
CURRENTLY PI BALTIMORE CLINICAL
SECTOR FOR THE OA INITIATIVE. HE
WILL TALK TO US ON THE ROLE OF
CHONDROGENNIC SMALL MOLECULES.
THANK YOU, DR. HOCKBU HOCK BERG.
>>THANK YOU DR. RODEO AND DR.
CHU. I WAS TASKED TO SPEAK ON
CARTILAGE REGENERATION BY
CHONDROGENNIC SMALL MOLECULES.
AS I MENTIONED DURING THE
INITIAL PART OF THIS MEETING I
HAVE NO PERSONAL EXPERIENCE IN
THIS. LET ME MOVE FORWARD I
GUESS. I'M SHOWING DISCLOSURES
FOR THE REASON THERE'S TWO
COMPANIES WHICH ARE IN IN BOLD
PRESENTING TATTED FROM BOTH
COMPANIES IN TERMS OF SMALL
MOLECULES. WE ARE TALKING
OSTEOARTHRITIS THERE IS ONE USE
OF THE TERM DEGENERATIVE DURING
THE FIRST TWO HOURS OF THIS
MEETING. AND BUT MAJORITY OF
PEOPLE HAVE USED DEGRADATION. .
SO AS DR. RODEO JUST POINTED
OUT, THIS IS AN IMMUNE MEDIATED
INFLAMMATORY CONDITION. WE HAVE
ACTIVATION OF THE CHONDROCYTE,
INITIALLY IN SO CALLED
IDIOPATHIC OSTEOARTHRITIS,
PRESUMABLY STIMULATED BY
ABNORMAL BIOMECHANICAL LOAD
WHICH LEADS CHONDROCYTE TO
GENERATE INFLAMMATORY CYTOKINES
INFLAMMATORY CYTOKINES
SIMPLISTICALLY WILL LEAD TO
DEGRADATION OF THE CARTILAGE
MATRIX MEDIATED BY ENZYMES
PRODUCED BY THE CHONDROCYTE WITH
THE ASSOCIATED SUBCHONDRAL BONE
CHANGES. PEOPLE IDENTIFIED ROLES
FOR BONEMORPHO GENIC PROTEIN,
TGF BETA AND WINT PATHWAY
LIGANDS WITH REGARD TO
SUBCHONDRAL BONE CHANGES. I
WON'T TALK ABOUT THAT VASCULAR
ENVATION OF THE ARTICULAR
CARTILAGE, ET CETERA. I WILL
FOCUS ON CHONDROCYTE CHANGES
THAT ARE CURRENTLY
OSTEOARTHRITIS AND THESE
SUMMARIZE IN THE UPPER RIGHT
HAND BOX IN THIS SLIDE WHICH
COMES FROM PAPER PUBLISHED TEN
YEARS AGO. SO THERE IS
CHONDROCYTE PROLIFERATION.
INITIALLY INCREASE IN MATRIX
SYNTHESIS. SO WE WANT TO
HARNESS THIS REGENERATIVE
CAPACITY OF THE CHONDROCYTE AS
IT PROLIVE RATES IN CURTILAGE.
WITHOUT PRODUCTION OF
INFLAMMATORY CYTOKINES, WITHOUT
PRODUCTION OF TISSUE DESTRUCTIVE
ENZYMES AND TRYING TO RESTORE
NORMAL PHENOTYPE TO THE CONT
CONTRACYTE. -- CHONDROCYTE. IT'S
BEEN DISCUSSED ABOUT THE ROLE OF
INFLAMMATORY CYTOKINES, AND
IMMUNE SYSTEM IN PATIENTS WITH
OSTEOARTHRITIS AND DEVELOPMENT
OF OSTEOARTHRITIS. I WANT TO
MENTION THERE'S A ROLE FOR
ANTI-INFLAMMATORY CYTOKINES
WHICH ARE PRODUCED BY THE
CHONDROCYTE INCLUDING IL 4 AND
IL 10 AND THERE'S SOME WORK NOW
IN TERMS OF TRYING TO LOOK AT IL
10, PROTEIN NOT SMALL MOLECULE
IN TERMS OF ITS EFFICACY FOR
OSTEOARTHRITIS AND CARTILAGE
REGENERATION. SO THE STRATEGIES
DISCUSSED INCLUDE REPAIR
STRATEGIES, WE HAVEN'T TALKED
MICROFRACTURE OF THE SUBCHONDRAL
BONE, AUTOLOGOUS CHONDROCYTE
TRANSPLANTATION. THE USE OF
MESENCHYMAL STEM CELLS OR
STROMAL CELLS AS WELL AS TISSUE
ENGINEERED CARTILAGE. ALL THESE
HAVE BEEN OR WILL BE DISCUSSED
DURING THE WORKSHOP TODAY. KEY
FOR THIS IS CARTILAGE
REGENERATION. HOW WE STIMULATE
CARTILAGE PROGENITOR CELLS OR
RESIDENT CHONDROCYTES. SO THIS
WILL LEAD ME TO SMALL MOLECULE
COMPOUNDS. I WANT TO SITE THIS
PAPER AND I DON'T KNOW IF YOU
CAN SEE THE CITATION ON THE
BOTTOM OF THE SLIDE. WHICH COMES
FROM -- EXCUSE ME FOR A SECOND.
LEE AND COLLEAGUES FROM CHINA
PUBLISHED IN BIOMEDICINE AND
PHARMACO THERAPY IN 2020. SO
THESE AUTHORS THAT SYSTEMATIC
REVIEW OF BENCH BIOMEDICAL
PRE-CLINICAL OR ANIMAL STUDIES
AS WELL AS HUMAN STUDIES OF
SMALL MOLECULES. WHICH PROMOTE
CHONDROGENNIC DIFFERENTIATION OF
STEM CELLS, SO GOING FROM THE
STEM CELL TO THE CHONDROCYTE,
NOT TO THE OSTEOCYTE OR
OSTEOBLAST OR MUSCLE CELL. OR
CHONDROCYTE PROLIFERATION OF
CHONDROCYTE PROGENITORS
ASSOCIATED WITH MATRIX
SYNTHESIS. BEFORE PRESENTING
THEIR DATA, I WANT TO MENTION A
PAPER BY LEE AND COLLEAGUES THIS
IS A DIFFERENT GROUP. THIS WAS
PUBLISHED IN OPEN LIFE SCIENCES
THIS YEAR 2022 WHERE THEY
IDENTIFIED CHONDROCYTE CELL
RECEPTORS WHICH CAN BE ENGAGED
BY SMALL MOLECULES. THESE
RECEPTORS ALL LEAD TO THE
CHONDROCYTE INCREASING MATRIX
SYNTHESIS, SYNTHESIS OF MATRIX
COMPONENTS. THESE INCLUDE
GROWTH FACTOR ASSOCIATED WITH
RECEPTORS INCLUDING THOSE FROM
THE TGF BETA BMP SUPERFAMILY,
IGF 1, FIBROBLAST GROWTH FACTOR,
AND EPIDERMAL GROWTH FACTORS.
THEY IDENTIFY HORMONES
ASSOCIATED RECEPTORS INCLUDING
ESTROGEN RECEPTOR, PROGESTERONE,
AND RECEPTORS FOR ACTIVE
METABOLITES OF VITAMIN D. THE
PPAR RECEPTORS, ALPHA BETA AND
GAMMA, INTEGRINS WHICH BINDS TO
MOLECULE THE EXTRA CELLULAR
MATRIX. THEN LRP AND FIZZLE
PROTEIN WHICH ACTIVATE THE WINT
BETA CATENIN SIGNALING PATHWAY.
LET'S LOOK AT THIS FIGURE FROM
THE PAPER BY LEE ET AL IN TERMS
OF SMALL MOLECULES PROMOTING
CHONDROGENESIS. THEY THEN
IDENTIFY SEVERAL SMALL
MOLECULES, WHICH CAN BIND CELL
SURFACE RECEPTORS TO PROMOTE
CHONDROGENESIS FROM CHONDROCYTE
PRECURSORS. SO THESE INCLUDE
PROSTAGLANDINS, RESVERETROL, ONE
PRESUMED ACTIVE COMPONENTS, FROM
GRAPES, WHICH CAN ACTIVATE
CIRCULAR PATHWAYS. WE WILL SKIP
AROUND, SYNBA STATIN AND OTHER
STATINS, MELATONIN. STATINS
AGAIN HERE, MELATONIN HERE.
GLUCOCORTICOIDS, AND THEN SMALL
MOLECULES WHICH CAN ACTIVATE
HEDGEHOG SIGNALING PATHWAYS.
AGAIN HERE YOU HAVE STATINS
ACTIVATING WINT SIGNALING,
ACTIVATION OF BMP SIGNALING.
ACTIVATION OF TGF BETA. AND
ACTIVATION OF HORMONE RECEPTORS
SO SMALL MOLECULES WHICH CAN
ACTIVATE CELL SURFACE RECEPTORS
AND LEAD TO CHONDROGENESIS FROM
PRECURSORS. THESE FIGURE
IDENTIFIES SMALL MOLECULES,
WHICH LEAD TO CHONDROCYTE
PROLIFERATION OF EXISTING
CHONDROCYTES AND INCREASE MATRIX
SYNTHESIS. SO HERE WE HAVE WINT
SIGNALING PATHWAY, AND THIS
GROUP IDENTIFIED GLUCOSAMINE FOR
EXAMPLE. SOMETHING IN LABORATORY
AND PRE-CLINICAL MODELS
SUGGESTING IT MAY HAVE STRUCTURE
OR DISEASE MODIFYING EFFECTS.
BUT THERE IS NOT SHOWN TO BE
EFFICACIOUS IN HUMAN STUDIES.
WHEN WELL CONTROLL CONTROLLED. N
BINDING TO RECEPTOR AS WELL AS
AKT TUGNALLING PATHWAYS.
SOLITRASIDE TO TGF SIGNALING IS
SMALL MOLECULE, THE ACTIVATED
FORM OF VITAMIN D 125 HYDROXY
VITAMIN D, GROWTH HORMONE AND
VITAMIN D SIGNALING AS WELL AS
ESTROGEN AND OTHER COMPOUNDS TO
ERK SIGNALING. ALL WITH DOWN
TREATMENT EFFECTS LEADING TO
ANALOG PHENOTYPE OF THE
CHONDROCYTE. ANOTHER GROUP HAS
LOOKED AT NARRATIVE REVIEW OF
SMALL MOLECULES FOR CHONDROCYTE
REGENERATION. THIS IS CHEN AND
COLLEAGUES IN CELLULAR AND
MOLECULAR LIFE SCIENCES IN 2021.
THEY PUBLISHED A NARRATIVE
REVIEW ON DEVELOPMENT OF
FUNCTIONAL ARTICULAR
CHONDROCYTES FROM CELLS OR
PROGENITOR CELLS AND CHONDROCYTE
EXPANSION, RELEVANT TO THE WORK
OF IMPLANTATION OR STRUCTURAL
HYDRA GELS FOR IMPLANTATION AS
WELL ASTHMA ANYPLACE RATION
CHONDROCYTE PHENOTYPE INCLUDING
INHIBITION INFLAMMATION AND
REGULATION OF CHONDROCYTE
METABOLISM. THIS FIGURE WHICH
IS TAKEN FROM THEIR PAPER SHOWS
WAYS OF DIFFERENTIATING
PLURIPOTENTIAL STEM CELLS Z,
MESENCHYMAL STEM CELLS, STROMAL
CELLS, TRANSDIFFERENTIATING
FIBROBLASTS IN FUNCTIONAL
CHONDROCYTES WITH SMALL MOLECULE
WHICH IS ARE LISTED ON THE
SLIDE. AS WELL AS POTENTIAL ROLE
OF STAT STATINS FROM ISOLATED
CHONDROCYTES TO CAUSE EXPANSION
FORMING FUNCTIONAL CHONDROCYTES
WHICH CAN BE THEN USED FOR CELL
THERAPY DESCRIBED BY DR. RODEO
AND AS DISCUSSED BY OTHERS
DURING AFTER THE BREAK. THIS
GROUP ALSO IN THE SECOND PART OF
THEIR PAPER, SUMMARIZE DATA ON
MORE THAN 170 COMPOUNDS
PREVIOUSLY OR CURRENTLY UNDER
INVESTIGATION. IN PRE-CLINICAL
MODELS AS ANALGESIC AGENTS OR
POTENTIAL DISEASE MODIFYING
OSTEOARTHRITIS DRUGS DESIGNED TO
INHIBIT STRUCTURAL PROGRESSION
VIA ANTI-CATABOLIC PATHWAYS, OR
ANTI-INFLAMMATORY PATHWAYS.
DISAPPOINTINGLY THESE AUTHORS
CONCLUDED THAT NONE HAVE HAD A
SIGNIFICANT LONG TERM EFFECT IN
PRE-CLINICAL MODELS. NONE
EFFECTIVE IN HUMAN STUDIES. SO
WHERE DOES IT TAKE US? THESE
AUTHORS DESCRIBE WAYS ONE
SCREENS FORMAL MOLECULES AND
THEY DESCRIBING A MOSTIC
METHODOLOGIES OF SCREENING SMALL
MOLECULES TO SEE IF ONE IDENTIFY
SMALL MOLECULES WHICH AFFECT
CHONDROCYTE REPLICATION OR
PROLIFERATION OR LEADING TO THE
DEVELOPMENT OF ANABOLIC
PHENOTYPE. SO SAMIMED, BIOSPLICE
THERAPEUTICS EMPLOYED THIS
TECHNOLOGY TO IDENTIFY POTENTIAL
SMALL MOLECULE WINT SIGNALING
PATHWAY MODULATORS. HIGH
THROUGH PUT SCREENING. IDENTIFY
ONE COMPOUND SM 0690. 03690. NOW
CALLED (INAUDIBLE) ADMINISTERED
AS A SINGULAR INTRAARTICULAR
INJECTION. STUDIED BY
(INAUDIBLE) AND COLLEAGUES IN
OSTEOARTHRITIS CARTILAGE IN 2018
AND 2019 IN PRE-CLINICAL MODELS
SHOW THIS COMPOUND REDUCE
RELEASE MATRIX DEGREE DATING
ENZYMES AND INFLAMMATORY
CYTOKINE PRODUCTION SO IT WAS
ANTI-CATABOLIC AND INCREASED
ANABOLIC TIFTED OF CHONDROCYTES
IN VITRO AND IN VIVO IN
PRE-CLINICAL MODELS OF
OSTEOARTHRITIS. SO IT WAS
ANTI-CATABOLIC AS WELL AS
ANABOLIC AND DEMONSTRATED
MOLECULAR MECHANISMS WHICH HAD
THIS PANT CATABOLIC AND ANABOLIC
EFFECT. SO THIS MOLECULE WAS
SHOWN TO UPREGULATE WNT
SIGNALING OR DOWN REGULATE THE
WNT SIGNALING WHICH CONTRIBUTES
TO OA PROGRESSION. MODULATE WNT
SIGNALING TO ANTI-INFLAMMATORIER
IS SO COLLEAGUES CONDUCTED A
SERIES OF PHASE 1 AND PHASE 2
STUDIES AND INTERIA THE I CAN
LAR INJECTION APPEARED SAFE WELL
TOLERATED ADMINISTERED AS A
SINGLE ARTICULAR INJECTION. THE
PHASE 2 STUDIES DEMONSTRATED
POTENTIAL THERAPEUTIC DOSE AND
TARGET POPULATION WITH
UNILATERAL SYMPTOMATIC KNEE
OSTEOARTHRITIS MEANING THEY HAVE
SINGLE JOINT INVOLVEMENT OR
BILATERAL SYMPTOMATIC KNEE OA
BUT MORE PAIN IN ONE THAN THE
OTHER KNEE WITHOUT BIDE SPREAD
PAIN. INTERARTICULAR INJECTION
WAS NOT ONLY EFFECTIVE
SYMPTOMATICALLY BUT ALSO
UNCREASE THICKNESS BY JOINT
SPACE WITHSTANDING KNEE
RADIOGRAPHS SO THE COMPANY IS
TAKEN THIS INTO PHASE 3 STUDIES
FOR SYMPTOM IMPROVEMENT AS WELL
AS STRUCTURE MODIFICATION. THESE
HAVE BEEN COMPLETED, BUT RESULTS
ARE PENDING. I LOOKED ON
CLINICALTRIALS.GOV AND RESULTS
ARE STILL PENDING. WHAT ABOUT
OTHER SMALL MOLECULE? THIS IS
ADEN SCENE. IT SIGNALS THROUGH
THE 2A RECEPTOR AND ATTENUATES
THE INFLAMMATORY RESPONSE IN
CHONDROCYTES BY LEADING TO
DOWNSTREAM INHIBITION OF NF
KAPPA B AS WELL AS UPREGULATION
AND RELEASE OF THE
ANTI-INFLAMMATORY CYTOKINE THAT
I MENTIONED EARLIER INTERLEUKIN
10. ADMINISTRATION OF LIPOSOMAL
ADEN SCENE WAS FOUND EFFICACIOUS
IN RODENT AS WELL AS MURINE
MODELS. THIS IS SHOWN IN TWO
PAPERS CITED AT THE BOTTOM OF
THE SLIDE. ONE BY BEKISZ, OTHER
BY CAI PUBLISHED IN OBESITY
REVIEWS THIS YEAR. ADENOSENE IS
DEVELOPED AS A TREATMENT FOR
POTENTIAL TREATMENT FOR PATIENTS
WITH OSTEOARTHRITIS. BY
INCORPORATION INTO LIPOSOMES AND
IT IS SHOWN YOU CAN HAVE
ACTIVATION OF A 2A RECEPTOR BY
INTERARTICULAR INJECTION OF
LIPOSOMAL ADENOSINE, IT SLOWED
OA PROGRESSION IN TWO MODELS OF
ESTABLISHED OSTEOARTHRITIS. AS
WELL AS MURINE MODEL OF OBESITY
INDUCED OSTEOARTHRITIS AND RAT
MODEL OF POST TRIAL
OSTEOARTHRITIS. ALTERED TGF B
ACTIVATION AND POST RECEPTOR
SIGNALING FOR A PATHWAY
ASSOCIATED WITH CHONDROCYTE
HYPERTROPHY AND TERMINAL
DIFFERENTIATION AND MODULATEDNA
TO A PATHWAY ASSOCIATED WITH
CHONDROCYTE PROLIFERATION AND
MATRIX PRODUCTION. STUDIES HAVE
BEEN CONDUCTED IN A DOG MODEL OF
OSTEOARTHRITIS AND NOT YET
PUBLISHED SO I WON'T PRESENT
THEM AT THIS FORUM, BUT ANOTHER
POTENTIAL SMALL MOLECULE WHICH
MAYBE EVE DA I SHUTS FOR
CHONDROCYTE PROLIFERATION AND
REGENERATION. BEING COGNIZANT OF
THE TIMELY STOP HERE AND THERE
ARE SMALL NOVEL COMPOUNDS
IDENTIFIED THROUGH HIGH THROUGH
PUT SIGNALING AND KNOWN
MECHANISTIC PATHWAYS WHICH
TARGET CARTILAGE REGENERATION
AND THESE HAVE POTENTIAL FOR
FUNCTION DISEASE MODIFYING DRUGS
IN PATIENTS WITH OSTEOARTHRITIS
THERE IS A LONG WAY TO GO TO
REALIZE THIS AS FUTURE
TREATMENT. SO I WANT TO THANK
YOU FOR YOUR ATTENTION. SHOWING
YOU (INAUDIBLE) HALL HERE FOR
OVER 200 YEARS, USE FOR MEDICAL
EDUCATION. HOPEFULLY BEFORE THE
NEXT CENTURY WE WILL HAVE
EFFECTIVE SMALL MOLECULE
TREATMENTS FOR CARTILAGE
REGENERATION FOR OUR PATIENTS
WITH OSTEOARTHRITIS.
>>WONDERFUL TALK. GREAT I DON'T
HAVE VIEW. I THINK ABOUT
CARTILAGE REGENERATION I THINK
IN THIS WHOLE WEBINAR TODAY OA I
DICHOTOMIES A IN CARTILAGE
REGENERATION, AS A DIFFERENT
GROUP OF PATIENTS, CARTILAGE
CLINICALLY WE DO THERE SINGLE
FOCAL CARTILAGE DEFECTS. EARLY
IN ARTHRITIC KNEE BUT DIFFERENT
THAN CHANGES IN BONE SHAPE, BONE
MORPHOLOGY, SYNOVIUM, CARTILAGE
BONE, NOT AMENABLE TO PER SE
CURRENT TECHNIQUE REGENERATE
CARTILAGE IN THE JOINT, THAT'S
GREAT BUT THINK ABOUT CARTILAGE
REPAIR REGENERATION FOR SMALLER
FOCAL EFFECTS WHICH BRINGS I
THINK THE IMPORTANT NEED FOR
EARLY IDENTIFICATION. CHRONIC
WORK WITH IMAGING WE ALL
RECOGNIZE WE NEED BETTER WAYS TO
IDENTIFY THE PATHOLOGY ONCE
STRUCTURAL CHANGES IN THE JOINT
BIGGER CHALLENGE IS STRUCTURAL
CHANGES CLINICALLY SILENT.
EARLIER EXAMPLE HEART ATTACK, OR
THE DIABETIC PATIENT, THE EARLY
PATHOLOGY IS CLINICALLY SILENT
TIME WE DETECT END STAGE ORGAN
DISEASE, THE COW IS OUT OF THE
BARN. JUST A POINT FOR THE NEED
FOR EARLY DIAGNOSIS. SO
REGENERATE TISSUE.
>>I WOULD FULLY AGREE WITH YOU.
AND I THINK THAT'S WHY WE NEED
TO IDENTIFY PEOPLE WHO DON'T
HAVE ALREADY ESTABLISHED GRADE
3, 4 OR EVEN STAGE 2 DISEASE. WE
NEED TO IDENTIFY PEOPLE WHO HAVE
SYMPTOMS. DON'T AS YET HAVE
RADIOGRAPHIC CHANGE. BUT MAY
HAVE CHANGES ON MAGNETIC
RESONANCE IMAGING. INTERVENING
THERE TO TRY TO PREVENT
DEVELOPMENT OF THE STRUCTURAL
CHANGES WE SEE ON RADIOGRAPHS.
ONCE WE HAVE STRUCTURAL CHANGES
ON RADIOGRAPH, PARTICULARLY ONCE
WE HAVE JOINT SPACE NARROWING ON
THE RADIOGRAPH AND WE HAVE
SUBCHONDRAL BONE CHANGES, I
THINK IT IS GOING TO BE VERY
DIFFICULT UNLESS WE HAVE TWO
STAGE RESPONSE, ONE WHICH IS
ANTI-CATABOLIC RESPONSE IN ORDER
TO PREVENT FURTHER CARTILAGE
DEGRADATION AND THEN COME IN
WITH SOMETHING TO PROMOTE
CARTILAGE REGENERATION. THAT
REQUIRES TWO STAGE RESPONSE OR
TWO STEP RESPONSE UNLIKELY TO
OCCUR WITH SINGLE SMALL
MOLECULE. MAY OCCUR WITH GENE
THERAPY, MAY OCCUR WITH PROTEIN
THERAPY AND MAY OCCUR WITH STEM
CELL THERAPY. OR CELLULAR
THERAPY. BUT IS UNLIKELY I THINK
TO OCCUR WITH SMALL MOLECULE
THERAPY.
>>WHOLE ISSUE I TRIED TO
HIGHLIGHT SYMPTOM MODIFICATION
VERSUS STRUCTURE MODIFICATION.
IMPORTANT GOALS BUT PERHAPS
DIFFERENT.
>>AMBIKA HAS HER HAND UP.
>>THANK YOU FOR THAT TALK DR.
HOCHBERG. HOW MANY HUMAN STUDIES
YOU REFER TO UTILIZE DELIVERY
SYSTEMS FOR DELIVERING THESE
SMALL MOLECULES, I ASK THAT
QUESTION AS SMALL MOLECULES HAVE
SHORT RESIDENCE TIME INOR INSIDE
THE JOINT SO THE THE MODE OF
DELIVERY IS NOT IMPLANTABLE
INJECTION IT IS DIFFICULT TO GET
A LONG TERM RESPONSE WITH THESE
ONE SHOT INJECTIONS
INTRAOCULARLY. SO WHEN YOU SAY
THAT MANY -- INTERARTERIOLY,
WHEN YOU SAW STUDIES DON'T
CORRELATE WITH PRE-CLINICAL, HOW
MANY OF THOSE UTILIZE ANY
DELIVERY SYSTEMS OR WERE THEY
ONLY DIRECT INJECTION OR ORAL
INJECTION?
>>IN THE REVIEW CONDUCTED THAT
I CITED, THE SMALL -- MOST OF
THE SMALL MOLECULE STUDIES WERE
IN HUMANS, ACTUALLY ORAL SMALL
MOLECULES ORALLY ADMINISTERED AS
OPPOSED TO INTERARTICULARLY
ADMINISTERED. ONCE WE
INTERARTICULARLY ADMINISTER VERY
SHORT RESIDENCE TIME AS YOU
MENTIONED SOME OF THE NEWER
STUDIES WHICH ARE NOT CITED IN
THAT PAPER ARE USING FOR
EXAMPLE, LIPOSOMAL
ADMINISTRATION OR TRYING TO
COMBINE THIS WITH HIGH LURE
ONTIC ACID TO -- HYALURONIC ACID
TO TAKE ON THE BINDING OF HA TO
CELL SURFACE RECEPTORS ON THE
CHONDROCYTE TO GET INTERNALIZED
BY ENDOCYTOSIS. YOU BRING UP AN
IMPORTANT POINT ABOUT SHORT
RESIDENCE SMALL MOLECULES WHEN
GIVEN BY THEMSELVES
INTERARTICULARLY. ALSO DELIVERY
INTO CARTILAGE. WE TARGET SITES
OR CHONDROCYTES IF WE ENABLE
LONGER TERM RETENTION THE JOINT
USING HYALURONIC ACID, WE ARE
NOT ENSURING DELIVERY TO TISSUE
TO REACH CHONDROCYTE SO THAT IS
ANOTHER AREA WHERE DELIVERY IS
EXTREMELY IMPORTANT FOR ANY OF
THESE DRUGS TO TRANSLATE.
>>RIGHT BECAUSE YOU HAVE TO GET
DIFFUSION INTO THE MATRIX IN
ORDER TO APPROACH CHONDROCYTE.
>>THANK YOU.
>>I MAY HAVE GOTTEN YOU CLOSER
TO ON TIME.
>>TED YOU WOULD LIKE TO TAKE
OVER AND GIVE INSTRUCTIONS NOW?
>>JONELLE?
>>I CAN DO THAT. THANK YOU,
EVERYBODY, THIS WAS A GREAT
DISCUSSION AND I THINK IT IS
MORE IMPORTANT THAT WE HAD SUCH
ROBUST DISCUSSION THAN THAT WE
STAYED ON TIME. THE DOWN SIDE IS
WE ARE GOING TO HAVE SHORTER
TIME FOR LUNCH. AS I SAID
EARLIER WE WOULD LIKE A GROUP
PHOTO BEFORE WE BREAK FOR LUNCH
SO WE HAVE IT FOR OUR ARCHIVES
AND WHEN WE TALK ABOUT
IMPORTANCE OF OUR ROUND TABLES
WE HAVE A VISUAL RATHER THAN A
TEXT HEAVY SLIDE. IF EVERYBODY
WHO WANTS TO BE IN THE PICTURE
INCLUDING NIAMS STAFF WHO ARE
INVOLVED WOULD LIKE TO TURN ON
THE CAMERAS, I'M GOING TO ASK
DAVE TO TAKE A PICTURE. THEN WE
CAN START THE CLOCK OFF PICTURE
FOR 20 MINUTES FOR LUNCH.
>>OUR NEXT SPEAKER IS
DAN GRANDE.
HE IS DIRECTOR
ORTHOPEDIC RESEARCH AT THE
FEINSTEIN MEDICAL RESEARCH PART
OF THE HOSPITAL SYSTEM IN NEW
YORK. I THINK WE HAVE HEARD OF
AUTOLOGOUS CHONDROCYTE
IMPLANTATION, THE FIRST FDA
APPROVED CELL PER THINK IN
ORTHOPEDICS. DAN DID THE
PRE-CLINICAL STUDY THAT LED TO
THAT BREAK THROUGH. SO WE ARE
PLEASED HE COULD TALK TO US
ABOUT MATRIX BASED THERAPIES IN
TISSUE ENGINEERED CARTILAGE.
>>THANK YOU, EVERYONE. THANK
YOU CONNIE FOR THE KIND
INTRODUCTION. I WILL FOCUS VERY
NARROW AREA WHICH IS THIS
CONCEPT OF MY TRICKS BASED
THERAPIES AND TISSUE ENGINEERED
CARTILAGE. THIS IS A VIN
DIAGRAM WE DID YEARS AGO WITH --
FOR THE NATURE REVIEW
RHEUMATOLOGY ARTICLE THAT I
WROTE WITH MYCOLOGS AND
BASICALLY THIS COMBINATION OF
SCAFFOLDS AND CELLS AND THEIR
INTERACTION WITH TISSUE
ENGINEERING AS YOU CAN SEE,
THESE DIFFERENT CELL DIFFERENT
SCAFFOLD TYPES, ET CETERA. THE
FIRST TISSUE ENGINEERING WAS
DEVELOPED BY LANGER WHERE THEY
USE PGA SUTURES AND CHONDROCYTES
AND YOU CAN SEE ON THE RIGHT A
NICE ME IN THIS CUSS OUT OF
THAT, THAT WAS THE FIRST STEP
TOWARD TISSUE CARTILAGE
ENGINEERING, WE WILL TALK ABOUT
ACI IN A FEW MINUTES BUT THE
UTILITY OF SCAFFOLD TISSUE
ENGINEERING IS THAT IT PROVIDES
A 3-D SPATIAL FILLING SURGEON
FRIENDLY WITH RESPECT TO BEING
ABLE TO IMPLANT CELLS IN A
CONTROLLED FASHION COMPARED TO
THE ORIGINAL AC I. THIS OF
COURSE LED TO MANY STUDIES
LOOKING AT PGA PLA PLGA
CONSTRUCTS, HERE IS SOMETHING
FROM A WORK WITH LISA FRIED
HARVARD YEARS AGO BUT THE
IMPORTANT THINGS IS THAT FORMING
STABLE CARTILAGE HELPS REDUCING
FIBROUS OR VASCULAR INFILTRATION
INTO A CARTILAGE CONSTRUCT. THAT
IS VERY IMPORTANT FOR CONTINUITY
OF CARTILAGE. SOME OF THE
CONCEPTS FOR CELL BASED
THERAPIES INVOLVE IDENTIFYING
SOURCES OF CELLS, WHETHER WE USE
PRIMARY AUTOLOGOUS CHONDROCYTES
SORRY FOR MISSPELLING, BONE
MARROW OR LIPO ASPIRATE STEM
CELLS. THEY REQUIRE EXPANSION, A
METHOD RETAINING IN SITU AND
THEN THE PHENOTYPIC STATE
CHONDROGENNIC EFFECT HOW THEY
FORM OR DIRECT FUNCTIONAL TISSUE
FORMATION. AS CONNIE MENTIONED
HEARSAY THE ORIGINAL WORK THAT
WE DID IN ACI WAS CHONDROCYTES
SUSPENSION BUT HELD IN PLACE BY
PERIOUTSIDE YUM SO THERE WAS NO
-- DEVELOPED FOR CHONDRAL
LESIONS ALONE NOT'S CENTRAL
CHONDRAL NECESSARILY, THEY ARE
SUSPENDED WITH THAT. OF COURSE
THE NEXT GENERATION WHICH
ASSISTED IN THE CONCEPT OF
TISSUE ENGINEER CARTILAGE MATRIX
ASSISTED ACI WHERE WE GROW THE
CELLS ON A SCAFFOLD, COLLAGEN
SCAFFOLD FOR LOCALIZATION WITHIN
A DEFECT. NEXT GENERATION OF
THAT IS SOMETHING DEVELOPED BY
NOVACART 3-D, IT IS THE SAME
CONCEPT OF ACI BUT THEY ARE
ALLOWED TO BE EXPANDED MINIMALLY
AND THEY USE A DIFFERENT
MATERIAL BIPHASIC COLLAGEN
SCAFFOLD, I WILL SHOW YOU IN A
MINUTE BUT CURRENTLY U.S.DA FDA
TRIALS RIGHT NOW U U.S. PHASE 3
AND THE PRODUCT IS REGULATED AS
A BIOLOGIC DEVICE IN COMBINATION
PRODUCT TAKE SMALL BIOPSY OF
CARTILAGE, EXPAND AND PUT ON A
SCAFFOLD AND IN A CONTROLLED BUY
REACTOR SITUATION WHERE YOU GET
REALLY GOOD REGENERATION OR NOT
REGENERATION BUT EXPRESSION OF
THE CHON CRYOGENIC PHENOTYPE.
YOU CAN SEE HERE THIS IS THE
MEME PAIN USED BY THEM, IT IS IN
THE -- MEMBRANE, IT IS A
BIPHASIC SCAFFOLD THAT HAS A LOT
OF PROPERTIES DIFFERENT FROM ALL
THE OTHER AVAILABLE SCAFFOLDS
WITH REGARDS TO -- WITH REGARDS
TO COLLAGEN. YOU CAN SEE ALSO
THAT THEY GET GOOD INFILTRATION
OF THE CHONDROCYTES INTO THE
SCAFFOLD. THE WAY THAT THE
SCAFFOLD IS -- AS THEY PURPORTED
TO BE THAT HAS BETTER PHENOTYPIC
EXPRESSION MORE AGGREGATE
SYNTHESIS THAN MONOLAYER CULTURE
AND COMPARED TO SOME OF THEIR
COMPETITORS. THIS IS A -- FROM
THEIR PRODUCT YOU CAN SEE THEY
HAVE VERY GOOD TYPE 2 STAINING,
THEY HAVE GOOD STABBING WITH
DMMD, CLINICAL EVIDENCE ON
ARTHROSCOPY AND BIOPSY SHOWS
DECENT CARTILAGE REPAIR
CARTILAGE WITH EXPRESSION OF
TYPE 2 COLLAGEN, AND AGRICAN AND
NICE RESURFACING. SO T A THE END
OF THE DAY THEY PROVIDE CLINICAL
EVIDENCE FOR IMPROVED PAIN AND
FUNCTION AND BOTH RETROSPECTIVE
STUDY THEY DID AS WELL AS
PROSPECTIVE STUDY THIS IS TWO
YEARS FLOW UP. ONE THING DR.
GUILAK WILL TALK MORE IN DETAIL
BUT AS I MENTION THESE WERE
FOCAL DEFECTS, AS DR. ROBEY
MENTIONED BEFORE THE BREAK,
FOCAL DEFECTS ARE DIFFERENT
ANIMAL OR PATIENT RATHER THAN OA
SO DR. GUILAK DEVELOPED A
CONCEPT FOR USING BASICALLY
USING A WOVEN SCAFFOLD MATERIAL,
RESORBABLE ALSO TO SEED CELLS,
BE ABLE TO RESURFACE ENTIRE
DEFECTS ENOUGHS JOE ARTHRITIC
PATIENTS. HE WILL TALK NEXT
LEVEL HE HAS ALREADY DONE FOR --
WITH THAT CONCEPT. THE NEXT
GENERATION -- NEXT THING ON THE
HORIZON IS BIOPRINTING. HERE IS
WORK WE DID WITH ETH AND ZURECK
USING A CARTILAGE ECM ADDED TO
THE BIOLINK. WITH THAT YOU CAN
DO SOMETHING WE HAVEN'T DONE
BEFORE TO ACHIEVE ZONAL
REORGANIZATION THAT HAS BEEN A
REAL CHALLENGE FOR RESEARCHERS
IN THIS AREA, HOW TO RECONSTRUCT
SUPERFICIAL MIDDLE AND DEEP
ZONES OF CARTILAGE
RECAPITULATING THAT CAGE, THAT
IS SOMETHING WE NEED TO DO. AS I
MENTIONED TISSUE ENGINEERED
CARTILAGE NEEDS TO INTEGRATE
WITH SURROUNDING CARTILAGE AS
WELL AS SUBCHONDRAL BONE,
MECHANIC A.M. PROPERTIES MATCH
OF THE ADJACENT TISSUE.
ENGINEERING CARTILAGE COPES WITH
INFLAMMATORY MEDIATOR, THAT
WOULD BE ELEGANTLY PRESENTED BY
DR. GUILAK. THE IDEA
RECAPITULATING THE ZONAL
ARCHITECTURE OF CARTILAGE IS
IMPORTANT. NOW I WILL MOVE TO
MATRIX BASED APPROACHES TO
CARTILAGE REPAIR, ONE THAT IS
VERY NEAR AND DEAR IS AUTOLOGOUS
MATRIX INDUCED CHONDROGENESIS.
WE USE THE MICROFRACTURE
TECHNIQUE TO PLACE A COLLAGEN
SCAFFOLD IN THE MATRIX, IN THE
DEFECT. RECENT SYSTEMATIC REVIEW
LOOKED AT AUTOLOGOUS AMIC VERSUS
MATRIX ASSISTED ACI. THEY FOUND
AMIC PERFORMED BETTER FOR THE
CHONDRAL DEFECTS AT 40 MONTHS.
THE RATE OF COMPLICATIONS WAS
LOWER IN THE AMIC GROUP AND
TEGNER AND VAST SCORES EQUIVOCAL
BUT LYSOME AND IDKE CELLS
EXCEEDED THE ACID IN FAVOR OF
AMIC. THAT IS SOMETHING TO KEEP
IN MIND WHEN WE TALK ABOUT COST
BENEFIT RATIO IS FOR SYSTEM OF
THESE PRODUCTS AND APPROACHES.
I DID A EDITORIAL FOR NATURE
REVIEWS, ON NEWER CONCEPT WHICH
I THINK HAS A LOT OF PROMISE BUT
NOT WIDELY DEVELOPED AND THAT IS
THE CONCEPT OF USING SCAFFOLDS
WITH LOADED WITH MOLECULES THAT
WOULD BE ALLOW FOR MIGRATION OR
ZONAL MIGRATION INTO SCAFFOLD BY
HOMING. YOU CAN SEE USING THE
BODY'S OWN ABILITY TO HEAL IN
THAT CONTEXT. BST CARGEL IS A
CHITOSAN PRODUCT SIMILAR ARCMIC
AND ADJUNCT TO MICROFRACTURE AND
USE BLOOD OR PRP TO COAGULATE OR
POLYMER RISE THE MATERIALS IN
VIVO. FILL AS WELL AS CALL OF
REPAIR, USING T 2 MAPPING MRI.
BETTER SCORES, MUCH BETTER FILL
OVERALL. BIOCART LAG IS ANOTHER
ADJUNCT MATERIAL FOR
MICROFRACTURE. IT IS ALLOGRAPH,
DEHYDRATED, MIX WITH PRP. THE
IDEA IS THAT IT IMPROVES REPIR
OF TISSUE. YOU HAVE BETTER
COLLAGEN TYPE 2 FORMATION IN A
TREATED GROUP. BASICALLY THE
OPTIONS FOR CARTILAGE HAVE
REPAIRED, THAT REMAIN THE SAME
FOR THE LAST 20 YEARS, ALLOGRAPH
TRANSPLANTATION. ACI WHICH IS
MACI, PAL LOW GRAPH,
PARTICULATED OR MINCED AUTO
GRAPH. INDICATED FOR FOCAL
DEFECT BUT OFF LABEL EXPANDED TO
INCLUDE EARLY OA. MICROFRACTURE
YIELDS WANING CLINICAL EFFECT
DUE TO PRODUCTION OF
FIBROCARTILAGE. WHILE OTHER
YIELD OSTEO CHONDRAL ALLOGRAPH
YIELD HIGH LINK CARTILAGE,
OTHERS ARE WHAT WE CALL HYALIN
LIKE AND NOT THE PARTICULAR ARC
CONNECT CHURL CARTILAGE. WE ALSO
HAVE TO THINK ABOUT CONUNDRUM,
CELLS ARE EXPENSIVE SO IF YOU
HAVE TO DO MACI OR OTHER, THESE
ARE QUITE EXPENSIVE FOR THE
PATIENT, THESE -- EVEN IF YOU
USE ALLOGRAPH THEY ARE 15 TO
16,000, EXPENSIVE PROPOSITION.
THIS MATERIAL FROM ARAGONITE.
WE HAVE A LONG HISTORY USING
CORALS AS A SCAFFOLD FOR BONE
REPAIR BUT NOT CARTILAGE. SEES
THIS CONCEPT AS INFLUENCE SIDE
OF THE POORS INFLUENCE MSC
DIFFERENTIATION. THEY FOUND THAT
THIS CONCEPT TO GET GOOD BONE
HEALING LETS CREATE A BIPHASIC
IMPLANT BY CREATING FOR'STY AT
THE CHONDRAL PHASE, LEADING TO
REGENERATION OF HIGHER END
CARTILAGE, SO THEY CAME UP WITH
THIS WAY TO DRILL HOLES OF A
SPECIFIC PROPRIETARY DIAMETER
THAT ALLOWS FOR CELLS TO COME UP
INTO IN A MODEL OF OSTEO
CHONDRAL DEFECT CELLS COMING UP
FROM THE MARROW TO BECOME
CONTRACYTES OR DIFFERENTIATE --
CHONDROCYTES. SO WORK DONE BY
SUSAN SKY IN VITRO MODEL TO GET
MECHANISM OF ACTION, DONUT
SHAPED HUMAN CART LAG FROM A
PATIENT -- FROM CADAVER PUT THE
IMPLANT IN YOU CAN SEE OVER TIME
NICE CARTILAGE FLOW ENHANCED
THROUGH DRILL HOLES. YOU CAN SEE
CHONDROCYTES MIGRATE ACROSS THE
TYPE OF THE SCAFFOLD AS WELL AS
FROM UNDERNEATH. THIS IS SHOWING
STUDIES LIKE TRACING THE CELLS.
SO THEY HAVE A MECHANISM OF
ACTION FOR THAT MATERIAL FOR
THAT. EVENTUALLY THEY MOVE TO A
GOAT MODEL, THERE ARE NICE
COLLAGEN TYPE 2 AND NICE AGRICAN
FORMATION IN DEFECTS MICROCT
SHOWING VERY NICE REPAIR OF THE
SUBCHONDRAL BONE. FIRST IN MAN
WAS DONE IN EASTERN EUROPE, THEY
RECEIVED THE 2016 CE MARK AND
MOVED TO NUMBER OF THINGS. ONCE
THE FOCAL DEFECT IN PATIENTS ARE
DOING WELL THEY ADDED PATIENTS
WITH KL 2 AND 3 DEGENRE ACTIVE
JOINT DISEASE TO THE MIX. THIS
IS SHOWING MMRIs, GOOD REPAIR,
NICE BIOPSY, NICE COLLAGEN TYPE
2 STAINING AS WELL AS
(INAUDIBLE) STAINENING THOSE
PATIENTS. THE CLINICAL
EXPERIENCE SO FAR WITH COHORT OF
126 MAS126 PATIENTS RESULTED INE
BREAK DOWN OF THE PATIENTS BUT
THE BOTTOM LINE IS WITH MRI
RESULTS YOU HAVE A GOOD FILL
OVER TWO YEARS, THE PRIMARY END
POINTS FOR THE SCORES ALSO VERY
GOOD. THESE ARE PATIENTS WITH
MILD TO MODERATE OA. THIS IS THE
FIRST DEVICE MATRIX BASED DEVICE
NOW APPROVED IN THE U.S.
RECENTLY, APPROVED FOR OA AS
WELL AS CARTILAGE REPAIR. WHAT I
WOULD LIKE TO SAY IN SUMMARY, I
THINK WE NEED TO LOOK AT
CARTILAGE REPAIR AND OA IN
GENERAL AS WE NEED TO LOOK AT IT
AS AN INTEGRATED APPROACH TO HOW
WE LOOK AT IT, PUTTING IMPLANT
IN WITHOUT LOOKING AT SAY MMP
INHIBITOR OR SOME OTHER MOLECULE
OR IS WRONG WE NEED TO LOOK AT
THE ENTIRE PICTURE HAVE
INTEGRATED APPROACH TO CARTILAGE
REPAIR. WITH THAT, THANK YOU. I
APPRECIATE BEING HERE TODAY.
>>NICE OVERVIEW, IMPLANT BRINGS
UP THE IMPORTANCE OF PAYING
ATTENTION TO SUBCHONDRAL BONE AS
WELL, ONE CONCERN OF COROLLARY
MATERIALS IS SLOW RESORPTION IN
REMODELING, LOOK AT THEIR DATA,
BETTER THAN TRADITIONAL CORAL
STAY AROUND FOREVER AND IS A
MISMATCH IN YOUR MATERIAL
PROPERTIES OF THESE MATERIALS
SUBCHONDRAL BONE SO THAT IS ONE
CONCERN, JUST A COMMENT COMES UP
WITH ANY BIPHASIC MATERIALS. THE
SECOND IS, THIS ISSUE OF
CARTILAGE REPAIR, OSTEOARTHRITIS
THAT SLIDE SHOWED A MOMENT AGO
THE COMPANY CAME TO TALK TO US
ABOUT IMPLANT, FOUR IMPLANTS,
MOST OF US AS CLINICIANS, THAT'S
CALLED OSTEOARTHRITIS. NOT GOING
TO DO FOUR IMPLANTS. CURIOUS HOW
FIELD IS EVOLVING LOVE TO FOLLOW
PATIENTS BECAUSE THAT GETS TO
THE ISSUE OF PATIENT SEPARATE
IMPLANT -- DEFECTS YOU ARE
TREATING, THERE ARE CHANGES IN
BONE GEOMETRY, REALLY FAVORABLE
TO HEALING REMODELING, I DON'T
KNOW. THOSE ARE -- COME UP
VERSUS USING THESE THINGS FOR
MORE TYPICAL SINGLE FOCAL
CHONDRAL DEFECT.
>>THANK YOU, DAN, I WANT TO
FOLLOW-UP ON THAT, THE
RADIOGRAPHIC CRITERIA, I BELIEVE
YOU SAID WAS KL 2 TO 3.
>>YES.
>>THERE WERE ABOUT HUNDRED PLUS
PATIENTS TREATED.
>>124.
>>CAN YOU GO MORE IN DETAIL ON
THE OUTCOMES OF THAT ARM OF THE
STUDY? THOSE ARE ARTHRITIC
KNEES. RAID YES GRAPHIC GENE.
>>ACTUALLY KEN MY COLLEAGUE DID
THAT STUDY. ON BEING
NON-CLINICIAN. I DON'T HAVE
UNFORTUNATELY MORE DATA ON THAT.
I'M SORRY. DEMONSTRATE GOOD
OUTCOMES CLINICAL PROMs AS DAN
SHOWED THEM. WE HAVE THE SAME
TREATING MULTIPLE DEFECTS MANY
THE KNEE, WE TRULY REGENERATE
CARTILAGE AND THAT HARSH
ENVIRONMENT, MOB WE WOULD LIKE
TO, I DON'T KNOW THE ANSWER.
>>I AGREE WITH YOU, IT IS A
FIRST STEP IN THAT DIRECTION.
CERTAINLY THE FACT THAT THEY
HAVE GOTTEN APPROVAL FOR OA IS
THEY CONVINCE THE FDA. DR.
LATTERMANN HAS A QUESTION.
>>I CAN ANSWER THAT, I WAS
INVOLVED IN THIS STUDY. AND I
HAD ONE PATIENT I PLANTED FIVE
OF THESE. WHO RELIABLY FAILED.
ONCE YOU START PUTTING MORE THAN
TWO IN, TWO OF THESE IMPLANTS
IN, FAILURE RATE IS HIGH. UP TO
TWO IMPLANTS EVEN IN KO 3
CLASSIFIED X-RAYS, THEY DID VERY
WELL. THIS IS ONE OF THOSE
SUBGROUPS LOOKS LIKE KL 3 AND WE
KNOW HOW DIFFICULT THAT IS TO
DIFFERENTIATE, SAY A TWO OR
SOMETIMES A 1. CLINICALLY THEY
ACTUALLY NOT THAT HARD TO ARREST
IS THAT. THAT IS A CONSIDERATION
TO YES EARLY OA. IT WORKS IN
THOSE PATIENTS, ESTABLISHED OA
STILL GOING TO BE A CHALLENGE.
ITCH ANOTHER COMMENT, THAT IS
FOR YEARS WE HAVE HAD DIFFERENT
TECHNIQUES AND TECHNOLOGIES THAT
ARE SUCCESSFUL IN TREATING
CARTILAGE DEFECTS. WE HAVE A
FEW THE ACI FOR OVER 20 YEARS WE
HAVE OSTEO CHONDRAL LOW GRAPH,
WE CAN TREAT CARTILAGE DEFECTS
WHAT WE CAN'T TREAT IS
PROGRESSION OF DISEASE. THAT IS
WHAT WE NEED TO FIGURE OUT AND I
THINK THAT'S WHAT WE NEED TO --
WHAT WE NEED TO FOCUS ON. WE ARE
TALKING ABOUT EARLY
OSTEOARTHRITIS BECAUSE CARTILAGE
IS A CASUALTY. WE HAVE
EXPERIENCE ALL TIME AND SURGEONS
ON THE CALL KNOW THAT, IT IS
EXTRAORDINARILY DIFFICULT TO
PATIENT EVEN IF YOU GO WITH
ULTRA SCOPE WHO IS AT THAT
JUNCTION BETWEEN 1 TO 2 CHONDRAL
CHANGES, WHERE YOU SAY IT IS NOT
BAD ENOUGH TO DO -- AND THERE'S
ONE FOCAL LESION. IF YOU TREAT
THE FOCAL LESION YOU GO BACK
ISN'T TWO YEARS LATER AND THAT
FOCAL LESION LOOKS BEAUTIFUL AND
THE REST OF THE JOINT IS BROKEN
DOWN. THAT'S THE TYPE OF PATIENT
WE NEED TO IDENTIFY. AND TREAT
DIFFERENTLY. THAT'S THE PATIENT
THAT IS ON THE PAST
OSTEOARTHRITIS AND THAT IS
BASICALLY WHAT WE NEED TO STUDY
>>THAT BRINGS UP THE QUESTION
OF HOW DO WE STAGE THOSE
PATIENTS AND WHAT MARKERS CAN BE
USED BECAUSE WE DON'T HAVE GOOD
MARKERS FOR EARLY OA YET. DO WE
>>THE BIG SEARCH, YOU CAN -- IT
IS NOT GOING TO BE -- I THINK IT
NEEDS TO BE A COMBINATION OF
IMAGING AND MOLECULAR MARKERS
AND POSSIBLY SYSTEMIC MARKERS WE
ALL HAVE PATIENTS THAT JUST GO
ALONG GO ALONG AND ONE DAY IT IS
LIKE SOMETHING SWITCHED. AND HOW
YOU CAN NO LONGER MANAGE THEIR
DISEASE OR THEY GO INTO PHASE OF
RAPID PROGRESSION. THOSE ARE
SWITCHES. THIS IS ONE OF THE
RESEARCH NEEDS, WHAT ARE THE HOW
DO WE SUBTYPE OA DO A BETTER JOB
STRUCTURALLY THAN LAWRENCE WHICH
WAS DEVELOPED IN THE 50s,
1950s. AND YOU HAVE PATIENTS
THAT HAVE OSTEO DIET BUS STILL
HAVE A JOINT SPACE AND OTHER
WHOSE HAVE NO OSTEOCYTES BUT
THEY HAVE CHONDRAL FLATTENING.
SO THE GRADING NEEDS TO BE
BETTER STRUCTURALLY AND ALSO
INCLUDE MECHANICAL AND
BIOLOGICAL AND MOLECULAR
PROFILING IN TO THE ALGORITHM.
>>WHAT WE CALL OSTEOARTHRITIS
IS 25 DIFFERENT CONDITIONS.
>>MAYBE MORE THAN THAT. AT
LEAST WE CAN SUB CATEGORIZE
BETTER THAN WE DO NOW.
>>THE PRACTICAL ANSWER
SEPTEMBER OF 2022 IS IMAGING.
MR. QUANTITATIVE MR. WE LIKE
THESE SERUM BIOMARKERS OR URINE
BIOMARKERS OR SYNOVIAL FLUID
BIOMARKERS. WE ARE NOT THERE BUT
WE USE IMAGING NOT PERFECT AND
HETEROGENEITY. AS WE
CHARACTERIZE THE PHENOTYPE LEADS
TO POTENTIAL PRECISION MEDICINE
APPROACH. ONE SIZE DOES NOT FIT
ALL. PATIENT NEEDS -- THIS NEEDS
PRP, THIS ONE NEEDS TO BE SMALL
MOLECULE, THIS PATIENT WILL DO
(INAUDIBLE) IF YOU DO NOTHING.
>>THOSE PATIENTS EXIST. TREAT
THE PATIENT NOT THE MRI.
>>SHOULD WE -- ANY OTHER
QUESTIONS, SHOULD WE MOVE ON?
>>I HAVE A QUESTION.
>>LARISS LARISSA. SHE HAS HER
>>KNEW FOR THE NICE OVERVIEW OF
THE CHONDROCYTE IMPLANTATION
PRODUCTS. I WILL TAKE MY
REGULATORY HAT OFF AND PUT MY
SCIENTIFIC ON SO I HAVE A
QUESTION FOR YOU ABOUT YOUR
THOUGHTS ON WORKING WITH SOME OF
THESE PRODUCTS, HOW CAN WE
POSSIBILITY ACHIEVE MORE
FORMATION VERSUS CARTILAGE, NO
MATTER HOW WELL THEY PERFORM
SOMETIMES NOT WELL, IN VIVO
EVENTUALLY WAS YEARS, THE
FIBROCARTILAGE FORMATION WITH
THESE PRODUCTS SO ANY THOUGHTS
ON THIS?
>>I THINK ACTUALLY DANIEL SARIS
WAS INVOLVED WITH THIS. THERE
WAS A EFFORT BY A COMPANY THAT
IS NO LONGER DOING TIGENICS
WHICH LOOKED AT HOW THE
PERFORMANCE OF THE CHONDROCYTE
WAS BEFORE IMPLANTATION. SO IN
OTHER WORDS WE KNOW THAT WE
EXPAND CHONDROCYTES FOR PERIOD
OF TIME IN CULTURE, THEY
DIFFERENTIATE. SO WHEN WE PUT
THEM BACK IN, EARLY ACI WITH THE
ADDITION OF THE HYPERPLASIA OF
THE PERIOUTSIDE YUM, HOW THE
CHONDROCYTES BEHIND IN THOSE
PRODUCTS IS IMPORTANT AND WAYS
TO ENSURE ADEQUATE MATURATION.
THE NOVA CARD HAS MADE THAT A
BETTER APPROACH TO THAT IN THE
SENSE THEY HAVE A MORE ROBUST
CARTILAGE FORMATION BECAUSE AS I
MENTION YOU HAVE GOOD CARTILAGE
IT WILL RESIST FIBROUS. BUT
FIBROUS INVASION. BUT THE REAL
PROBLEM I THINK IS THE SITE OF
ARCHITECTURE OF CARTILA CARTILAE
HAVE THAT UNIQUE ENGINEER -- IF
YOU WANT TO CALL IT DIVINE
ENGINEERING BUT THE ARCADE IT IS
WAY THE COLLAGEN FIBERS ARE
ORIENTED, HAS NOT BEEN
REPRODUCED BY ANYONE. WE MIGHT
AS WELL PUT IN A PLUG OF EAR
CARTILAGE OR RIB CARTILAGE
BECAUSE IT IS JUST -- IT HAS NO
STRUCTURAL INTEGRITY AS FAR AS
I'M CONCERNED, AS FAR AS THE
ORGANIZATION OF THE
CYTOARCHITECTURAL LEVEL. THAT IS
A KEY CHALLENGE FOR US. THAT
WOULD BE SOME OF MY COMMENTS ON
THAT.
>>THANK YOU, THE REAL ISSUE IS
DURABILITY OF THE EFFECT. TWO OR
THREE YEARS DOWN THE ROAD WE SEE
DATA, OTHER SURGERIES NEEDED OR
OTHER THINGS HAPPENING. SO
REALLY TRYING TO DO UP FRONT A
PRODUCT BETTER WITH EVENTUAL
HYALIN CARTILAGE FORMATION WOULD
BE A GOAL HERE.
>>WE CAN MOVE ON
>>PLEASURE TO ENTER DEUCE MY
FRIEND AND COLLEAGUE DANIEL
SARIS, PAST PRESIDENT OF THE
ICRS, CURRENTLY ON THE
ORTHOPEEDIC STAFF MAYOR CLINIC
ROCHESTER WHERE HE FIRST
PROGENITOR, PROFESSOR
REGENERATIVE MEDICINE AT MAYO
CLINIC. HE TRAINED AT AMSTERDAM,
COMPLETED Ph.D. IN THE
NETHERLANDS, BIOLOGICAL JOINT
RECONSTRUCTION AND HE'S
DEPARTMENT OF ORTHOPEDICS FOR 17
YEARS, PART OF THE FOUNDING
MEMBER AND ORGANIZER FOR
REGENERATIVE MEDICINES IN
UTRECHT. HE ESTABLISHES JOINT
PRESERVATION APPROACHES IN
EUROPE AND THE USA AND TALK
ABOUT THE ROLE OF EXOSOMES AND
EXTRA CELLULAR VESICALES.
>>THANK YOU VERY MUCH, SCOTT
FOR ORGANIZATION OF PUTTING THIS
TOGETHER. PROVIDING ME WITH
CHALLENGE OF READING UP DOING
SOME THINKING ON WHAT I FEEL
ABOUT THIS. WHAT THE SCIENCE
SAYS AND WHAT I FEEL COMFORTABLE
SHARING. THAT WAS AN INTERESTING
ONE. SO I WAS ASKED TO ADDRESS
THE ROLE IF ANY FOR USING EXTRA
CELLULAR VESICLES OR EXOSOMES
FOR TREATMENT OF OSTEOARTHRITIS.
FAIR TO SAY THERE IS A ROLE,
THERE ARE CONSIDERABLE
CHALLENGES AND I WOULD LOVE
DISCUSS WITH GROUP REALITIES
WHERE WE ARE NOW AND WHERE WE
ARE GOING TO BE. I KNOW TOLD US
PREPARATION WHICH IS METICULOUS
DON'T SAY THE SOLUTION IS MORE
MONEY AND I WILL STICK TO THAT.
NOT GOING TO SAY WE NEED MORE
MONEY. WE NEED MORE
UNDERSTANDING FIRST. BUT I DO --
I KNOW I'M PREACHING TO THE
CHOIR, I FEEL THAT WE AS WE DO
SO IN OUR SCIENCE AND GRANTS AND
PRESENTATIONS NEED TO BE WARE OF
THE FACT FOR THE UNITED STATES
NUMBERS ARE DAUNTING BECAUSE
NUMBER OF PEOPLE WITH
SYMPTOMATIC OA IS 11, 12% AT THE
MOMENT, EXPECTED TO DOUBLING IN
15 YEARS WHICH HAS ECONOMICAL
BURDEN. WE DID SOME MODELING FOR
ASIA, INCLUDING INDIA AND CHINA.
IF YOU LOOK AT THE VOLUME OF
PEOPLING THE EFFECTED BY THIS,
IT IS CONSIDERABLE. WITH
CONSIDERABLE ECONOMIC DRIVE TO
DO SO SO DON'T DISREGARD THE
FACT IT IS SEVERE DISEASE, WHO
CONSIDERED IT SEVERE DISEASE, UP
THERE WITH CANCER, PSYCHIATRIC
CHALLENGES AND CARDIOVASCULAR
AND WE SHOULD ZOOM IN FOR NEEDS
WE HAVE AS A FIELD. THAT IS ALL
I NEED TO SAY ABOUT THAT PAR PA.
MONEY FOR US TO FIND NOT THROUGH
THIS PROGRAM AND NOT TODAY. IF
YOU LOOK AT THE LITERATURE ABOUT
EXTRA CELLULAR VESICALS WE DID
THIS WEEK, I NEED TO THANK MY
FRIEND AND COLLEAGUE FOR HIS
WORK PREPARING THIS. IT IS CLEAR
IT IS RAPIDLY DEVELOPING YOUNG
FIELD WITH INCREASING NUMBER OF
PUBLICATIONS ON EXOSOMES AND
EXTRA CELLULAR VESICALES BUT
ALSO STILL VERY EARLY DAYS. IF
YOU COMPARE THIS TO ANY TOPICS
DISCUSSED TODAY, THERE'S WAY
LESS PUBLICATIONS. YOU CAN SEE
THERE SEEMS TO BE A SHIFT OF
PUBLICATIONS ON MSCs. TO MAYBE
NOW SHIFT ON PEOPLE SAYING YOUR
LAB AND YOU DO WORK ON MSC, OUR
MOVE TO FOCUS ON EXOSOMES
BECAUSE MAYBE MORE COMPLEX TO
USE CELLS AND MAYBE USE OFF THE
SHELF TECHNOLOGY WHERE WE USE
EXOSOMES AS END PRODUCT OF MSC
OR END PRODUCT OF SOME OF THESE
CELLULAR COMMUNICATION METHODS
TO INFLUENCE OSTEOARTHRITIS OR
INFLUENCE OTHER DISEASES. THIS
SLIDE SHOWS THE RAPID INCREASE
IN THE FIELD BUT ALSO STILL
LIMITED KNOW HOW. WHICH IS
INTERESTING BECAUSE THE FIRST
DESCRIPTIONS OF WHAT I THINK WAS
MEANT TO BE THE DESCRIPTION OF
EXOSOMES WAS PLATELET DUST, THAT
IS WHAT IT SAYS IN THE PAPER
THAN 1960s. AND WE ARE TRYING
TO DEFINE THIS IS SIMILAR TO
DISCUSSION THAT DR. RODEO AND WE
ALL HAD EARLIER ON IN OUR
UNDERSTANDING OF MSC. WE ARE
STILL TRYING TO DEFINE WHAT
EXOSOMES AND WHICH DIFFERENT
EXOSOMES ARE THERE. THEY PLAY A
ROLE IN INTRACELLULAR
COMMUNICATION. THEY THEREFORE
PLAY ROLE IN CELLULAR RESPONSE,
TISSUE RESPONSE TO TRAUMA,
DISEASE, MALIGNANCY AND ALSO
RESTORE HOMEOSTASIS.
INTERESTINGLY ENOUGH ONGOING
EVIDENCE THAT NOT ONLY DO
EXOSOMES PLAY ROLE IN CELL
TISSUE OR TISSUE CELL
COMMUNICATION, THEY CHANGE WHAT
IS IN THE EXOSOME OR WHAT THE
EXOSOME DOES WITHIN THE TISSUE
LISTENING TO THE ENVIRONMENT
WHICH THEY ARE BEING SECRETED.
THIS MEANS IT IS A SMART
FEEDBACK SYSTEM, WHICH FOR ME IS
SUPER INTERESTING BUT IT CREATES
A FUNDAMENTAL CHALLENGE IN THE
CONCEPT OF USING THEM OFF THE
SHELF INSTEAD OF MSCs OR OTHER
CELL SOURCES. MORE DYNAMIC THAN
THEY ARE CURRENTLY BEING THOUGHT
OF THAN THE WAY I UNDERSTAND THE
SCIENCE BEING DISCUSSED. I STILL
THINK THE FIELD IS YOUNG, EARLY
DAYS, THERE ARE COUPLE OF EXPERT
CENTERS HERE IN THE UNITED
STATES, WHERE I THINK WE ARE
STILL TRYING TO FIGURE OUT WHAT
IS EXOSOME AND WHAT ARE OTHER
CELL SECRETORY MECHANISMS
AVAILABLE THAT ARE SIMILAR AND
HOW DO THEY KNIFER FROM EACH
OTHER. AT THE MOMENT WE ARE
STILL IN A PHASE SEPARATION OR
COLLECTION OF EXOSOMES AND
FUNCTIONAL DESCRIPTION IS BEING
DONE BY THINGS WE CAN SEE AND
MEASURE IN ELECTRON MICROSCOPY,
SIZE DETERMINATION, EARLY
STUDIES THAT FOCUS ON EXOSOME
FUNCTION. IT IS ONE OF THE
CHALLENGES IN THE THERAPEUTIC
APPLICATION OF EXOSOMES, TRYING
TO FIGURE HOW TO GET IT FROM THE
FLUID OR TISSUE THEY ARE
FUNCTIONING IN. THE WAY I READ
LITERATURE, THERE ARE FOUR WAYS
AT THE MOMENT SIMPLE RELIABLE IS
ULTRA CENTRIFICATION, HAS
ADVANTAGES BUT DOWN SIDES AS
WELL BECAUSE ON INDIVIDUAL
PATIENT TO PATIENT BASIS IT WILL
BE DIFFICULT TO MAKE THIS
APPLICABLE. AS YOU TRY TO DO FOR
LARGER VOLUMES AND COHORT THERE
WILL BE LIMITATIONS ON
FLEXIBILITY AND EFFECTIVENESS OF
CHOICE. THERE ARE MORE SPECIFIC
METHODS SUCH AS SIZE TECHNIQUES
WITH ULTRA FILTRATION AND
CHROMATOGRAPHY AND PRETTY
DIFFICULT HOW TO UP SCALE THOSE.
MAYBE EXOSOME PRECIPITATION
FILTERING IN RUDIMENTARY WAY UP
SCALE, BUT ONCE WE START
UNDERSTANDING SPECIFIC EXOSOME
FUNCTIONS THEREFORE LIKELY THAT
IMMUNE AFFINITY CAPTURE BASED
TECHNIQUES WOULD BE LIKELY TO
ADDRESS CERTAIN EXOSOMES TO BE
EXTRACTED AS MAYBE TRYING
SECRETE FROM MSC CONTROLLED
ENVIRONMENT OR EVEN SYNOVIAL
FLUID CONTROLLED ENVIRONMENT
THAT PREDICTABLY CREATE EXOSOME
POPULATION YOU WANT TO FIND MANY
A MORE INDUSTRIAL ENVIRONMENT.
SEEMS TO BE FAR AHEAD OF THE
FIELD BUT LEARNED IF YOU DON'T
KNOW HOW TO UPSCALE AND MAKE
APPLICABLE YOU HAVE TO WONDER
WHAT THE FUNDAMENTAL RESEARCH
NEEDS TO BE STEER US TOWARDS,
THIS IS STILL VERY MUCH WHERE
THE EXOSOME FIELD IS AT. SO
WHAT IS THERE AND HOW IS THIS
GOING TO BE APPLICABLE TO OA
TREATMENT, WAS THE QUESTION WE
TRIED TO READ MORE. IT IS CLEAR
AS I REFERRED TO BEFORE, MS A
FIELD UNDERSTANDING THE ROLE OF
MSCs IN IMMUNE MODULATORY BUT
ALSO IN SECESSION OF BIOACTIVE
FACTORS, THAT IS VERY MUCH
FOCUSED ON THE ROLES OF EXOSOMES
AS INTRACELLULAR MECHANISM. IT
IS CLEAR AS WE HEARD TODAY AND
HAVE SEEN BEFORE, THERE IS AN
EFFECT OF MSCs ON OSTEO
ARTHRITIC JOINTS ON
DEGENERATION, SYNOVIAL PROCESS,
WE ARE STILL IN THE PROCESS OF
GAINING BETTER UNDERSTANDING OF
THAT. BUT IT IS CLEAR EXOSOMES
PLAY A ROLE IN THAT. THEREFORE
WE SEE THESE JUNE YUP SLOPE IN
PUBLICATION ON EXOSOMES SINCE WE
NOW MORE ACCEPT AND UNDERSTAND
THAT THE PARACRINE FUNCTION OF
MSC MIGHT BE MORE IMPORTANT THAN
TISSUE DIFFERENTIATION AND
REGENERATION FROM MSC PER SE.
THEREFORE MAKES SENSE THAT YES
THERE IS A HYPOTHESIS THAT'S
STRONG ENOUGH INITIAL IN VITRO
EVIDENCE THAT EXOSOMES DO PLAY A
ROLE IN THE POSSIBILITIES AND IN
THE PORTFOLIO OF MAYBE DOING
SOMETHING IN EARLY PHASE
INTERVENTION OF THIS CASCADE OF
THINGS THAT EVENTUALLY IT WAS
OSTEOARTHRITIS. THERE ARE FEW
REVIEW PAPERS THAT STEER US
TOWARDS BETTER UNDERSTANDING.
THERE ARE SOME PAPERS THAT SHOW
MECHANISMS OF ACTION AND MOST OF
THEM ARE ARE NOW MSC DERIVED
EXOSOMES AND HOW DO THEY PROTECT
CARTILAGE OR HOW DO THEY PROTECT
BONE FEE FORMATION OR MODULATE
SYNOVIAL INFLAMMATORY PROCESSES
THEY ARE SUFFICIENT EVIDENCEED
FROM EXOSOME BASE RESEARCH
MAINLY FROM MSC DERIVED EXOSOME
DERIVED MSC THAT THERE IS A
CHONDRAL PROTECTIVE EFFECT THERE
IS CHONDRAL SUPPORTIVE EFFECT
THROUGH BOTH CHONDROCYTE
APOPTOSIS AND MACROPHAGE
ACTIVATION. WHICH IS THE
DISCUSSION DR. LATTERMANN AND
ROBEY HAD BEFORE. THE PAPERS IN
MY UNDERSTANDING, SAY THAT THERE
IS STILL A GREAT HETEROGENEITY,
NOT ONLY IN THE CELL LINES
LOOKED AT TO STUDY EXOSOMES BUT
ALSO IN THE PREPARATION OF THE
SECRETOMES AND PANEL MODELS IN
VITRO MODELS, AND UNDERSTANDING
HOW TO USE SECRETOMES OF
RESOLUTION OF INFLAMMATION AND
CARTILAGE REGENERATION, WE TOOK
A LITTLE BIT OF PEAK IN ROLE OF
EXOSOMES IN OTHER FIELDSES I GET
THE SENSE ONCOLOGY FIELD IS
FURTHER AHEAD IN UNDERSTANDING
AND APPLICATION IN SOME OF THE
MALIGNANCIES. CARDIOVASCULAR
FIELD? SIMILAR PHASE AS WE ARE
IN NOW. WHEN WE DID SEARCH FOR
CLINICAL TRIALS THERE ARE MORE
THAN 30 REGISTERED CLINICAL
TRIALS ON CLINI CLINICALTRIALS.V
THAT CIRCLE EXOSOME APPLICATION
BUT TWO-THIRDS ARE DIAGNOSTIC
PURPOSE, THERAPEUTIC PURPOSES
AND ALL BY FIVE OR SIX IN THE
ONCOLOGY FIELD. NONE AS FAR AS I
WAS ABLE TO FIND IN OUR SEARCH
TWO WEEKS AGO ARE IN THE
OSTEOARTHRITIS OR REGENERATION
CARTILAGE FIELD. I FEEL THE
BASIC SCIENCE SHOWS IN WHATEVER
ANIMAL MODEL YOU CHOOSE, THERE
IS SUFFICIENT EVIDENCE MSC BASED
EXOSOMES PLAY A ROLE IN SOME WAY
SHAPE OR FORM INFLUENCING
BENEFICIALLY ROLE OF CARTILAGE
REPAIR AND OUTCOME OF CARTILAGE
REPAIR THERE, IS A SOLID REASON
TO STUDY THIS. SO THEREFORE THE
CHARGE FOR TODAY'S EXPLORATION
WAS USEFUL. THERE ALSO SEEMED
SUFFICIENT EVIDENCE THAT
SYMPTOMATIC RELIEF FROM
OSTEOARTHRITIS COMPLAINTS
MEASURED BUT SYNOVIAL FLUID OR
THICKENING OR CHANGES CAN BE
MODIFIED BY THE APPLICATION OF
EXOSOMES, WE ARE THINKING DOSING
AND CLIMBING, THINKING
INTERACTIONS WITH THE GOAL
THERAPEUTIC TISSUES SO THAT
NEEDS TO BE SOLVED. THERE ARE
MORE CHALLENGES AT THE MOMENT
THAN REAL SOLUTIONS AND TO ME
THERE IS NOT A CLEAR PATH
FORWARD YET. IT IS DIFFICULT TO
UNDERSTAND HOW WE HARVEST THEM,
DIFFICULT HOW TO DELIVER THEM.
THERE ARE SOME BUY LOGICAL
CHALLENGES IN THE -- BIOLOGICAL
CHALLENGES IN THE INTERARTICULAR
ENVIRONMENT WHICH IS SIMPLER TO
SOLVE IF WE GO FOR ORGAN
SOLUTIONS OR INTRAVASCULAR
SOLUTIONS. IT IS DIFFICULT TO
UNDERSTAND WHAT WOULD BE THE
IDEAL SOURCE FOR MSC TO ISOLATE
EXOSOME FROM AND IF YOU WANT TO
UPSCALE, HOW TO COLLECT EXOSOMES
IN AN EFFICIENT MANNER FROM MSC
POPULATION. WOULD BE A
DIFFERENT CHALLENGE. BUT I DON'T
THINK WE NEED TO ADDRESS THAT
YET. WE ARE IN THE PHASE TO
LOOK AT MECHANISTIC EXPLORATION
AND UNDERSTANDING, THE ROOT OF
DELIVERY AND DOSAGE. FREQUENCY
PATIENT SELECTION COMES LAST.
BUT THERE CLEARLY IS A EXCITING
OPPORTUNITY TO USE EXOSOMES FOR
TREATMENT OF OSTEOARTHRITIS. I
WOULD SAY THAT BUNDLING OF
FORCES FOCUS RESEARCH PROJECTS
AND PROTOCOLS AND PROBABLY CON
SOURCE IS IMPORTANT AND MAYBE
THIS GROUP CAN PLAY A ROLE IN
SOME WAY SHAPE OR FORM. I THINK
WHAT IS IMPORTANT AND MENTIONED
BY DR. RODEO, STANDARDIZATION OF
PROTOCOLS AND DESCRIPTION OF
WHAT IS MY EXOSOME I'M WORKING
ON HOW DID I GET IT, HOW DO
OTHERS USE IT REPRODUCIBLY IN
THE SAME WAY. THOSE ARE NEEDED
BEFORE WE CAN START THINKING
ABOUT CLINICAL TRIALS IN
OSTEOARTHRITIS. I FEEL THE
LIBERTY OF SCIENTIFIC
EXPLORATION IS PROBABLY A LITTLE
BIT BIGGER IN ONCOLOGY FOR
OBVIOUS REASONS. I THINK THERE
IS EVEN A POSSIBILITY OF
ENGINEERING EXTRA CELLULAR
VESICALES AND EXOSOMES WHICH IS
MORE CONTROLLABLE. THAT IS NOT
REALISTIC FOR CELLS, MIGHT BE
POSSIBLE TO ENGINEER FULL
EXOSOME IN A WAY THERAPEUTIC
OPTION DIFFERENT THAN APPLYING
SMALL MOLECULES. THERE ARE
THOUGHTS USING MSC EXOSOMES FROM
YOUNGER DONORS TO BE STORED IN
THEIR LIFE LATER ON WHICH IS
SOMETIMES ALLEVIATE CHALLENGES
THAT WE KNOW. USED AS A VESICLE
FOR DRUG DELIVERY. THAT IS WHERE
WE STAND WITH OUR UNDERSTANDING
AND I FEEL CONFIDENT AND
CHALLENGED ENOUGH TO SAY THAT
PRE-CLINICAL EVIDENCE SUGGESTS
THAT MSC DERIVED EXOSOMES JOINT
HOMEOSTASIS AND MAY PREVENT
OSTEOARTHRITIS IN ANIMAL MODELS
THERE'S ANTI-INFLAMMATORY
EFFECTS IN PATIENT CARE THAT
SHOULD BE TRIED WHEN WE KNOW HOW
TO DO SO SAFELY. SIGNALING OF
EXOSOME CHANGES AS THEY ARE
ENVIRONMENTS THAT CHANGE. I
THINK AS I SAID BEFORE THAT IS A
FUNDAMENTAL CHANGE TO OFF THE
SHELF USE BECAUSE WE MAY NOT BE
SMART ENOUGH TO DESIGN THE
EXOSOME THAT NEEDS TO BE USED
FOR CHANGING ENVIRONMENT THAT
THE PATIENT PRESENTS US WITH. SO
I THINK THAT FOR NOW WE SHOULD
TRY TO FOCUS AND CONCENTRATE THE
RESEARCH AND CREATE ROBUST
FOUNDATION OF UNDERSTANDING
BEFORE WE END UP IN APPROACHES
WE HAVE SEEN WITH THE OTHER
TECHNOLOGIES. THAT IS ALL I HAVE
FOR YOU IN THIS BUT I THINK IT
IS EARLY BUT EXCITING FIELD.
THANK YOU VERY MUCH FOR THE
CHALLENGE.
>>THANK YOU, DANIEL. GREAT
SUMMARY, IT NEEDS TO FURTHER
WORK. LIKE EVERYTHING ELSE,
CHARACTERIZATION OF THESE
PREPARATIONS IS SO CRITICAL.
>>AGREE.
>>NICE TALK, DANIEL. DO YOU
HAVE SOME SUGGESTIONS FOR HOW TO
CHARACTERIZE EXOSOME?
>>NO, I DON'T. THAT IS NOT AN
EASY ANSWER, I FEEL PRETTY EARLY
ON, IT IS THE CONTENT OF THE
EXOSOME AND WHAT IS IN THERE.
THAT IS WHY WE NEED TO
UNDERSTAND SOME FACTORS IN THE
EXOSOME ARE PUT IN THE EXOSOME
AND SECRETED BY THAT CELL AND
ENVIRONMENT AT THAT TIME. THAT
MEANS WE NEED TO REVISIT THAT
PART OF OUR UNDERSTANDING OF
SOME OF THE MECHANISMS THAT WE
ARE LOOKING AT. I THINK JUST
LOOKING AT SURFACE MARKERS OF
THE EXOSOME WILL BE ENOUGH
BECAUSE IT IS ABOUT THE CONTENT
MORE. WE ARE TOO EARLY A PHASE,
MAYBE MY UNDERSTANDING IS TOO
LIMITED TO BE ABLE TO SAY WHAT
THE ROLE OF THAT EXOSOME IS
GOING TO BE IN THE BIOLOGICAL
SYSTEM, IT'S SECRETED IN. WE
NEED TO WORK ON THAT BEFORE WE
CHARACTERIZE THEM WELL ENOUGH.
HAPPY TO ENTERTAIN INPUT FROM
OTHER EXPERTS ON THE PANEL
TODAY. I DO THINK THAT ONE WAY
OF IMPROVING OUR UNDERSTANDING
OF FUNCTION IS WE CAN USE
CONTROL ENVIRONMENT SUCH AS
VARIATION OF SYNOVIAL FLUID,
VARIATIONS OF MSC POPULATIONS,
STUDYING THEIR EXOSOME RESPONSE
FROM DEFINABLE CHALLENGES AND
THERE IS EXCITING WORK DONE IN
VANDERBILT AND OTHERS, ALSO IN
ASIA, THE PROGRESSION IS
QUICKLY, IT IS STILL TOO EARLY
TO SAY WE NEED TO DO THIS AND
THIS AND THIS PANEL. SO THE
PAPER ON EXOSOMES IS STILL
PENDING.
>>IF WE ACCEPT IT EXSOMES
REPRESENT THE CELL CARGO
SIGNALING MOLECULE FROM CELLS WE
GET TO A POINT ONE DAY USING
EXTRA CELLULAR VESICALES AND NO
CELLS ANY MORE.
>>I THINK THE ANSWER COULD BE
YES. NOT CERTAIN YET. THAT IS A
FAVORITE QUOTE. CELLS ARE
SMARTER THAN SURGEONS AND THAT
IS WHY I THINK CELL LISTENS TO
ITS ENVIRONMENT, IT DOES WHAT
THE ENVIRONMENT SEEMS TO NEED
AND SECRETE WHAT IS THE
ENVIRONMENT NEEDS. I ALSO THINK
THE MOMENT CELLS ARE SMARTER
THAN SCIENTISTS, YES, IT IS
POSSIBLE SCOTT AND I THINK WE
SHOULD BE TRYING TO GO THAT
DIRECTION. IT WOULD BE THAT YOU
HAVE AN AS PARTICIPANT OF
SYNOVIAL FLUID FROM THE PATIENT
JOINT. YOU CHALLENGE THE MSC
POPULATION WITH SYNOVIAL AS
PARTICIPANT AND WE CAPTURE THE
EXOSOMES THAT SECRETES AND APPLY
THOSE TO PATIENTS KNEE OR OTHER
JOINTS. MIGHT BE SOMETHING MORE
CREATIVE.
>>I THINK WE STILL NEED TO KNOW
WHAT IS IN THE EXOSOMES AND HOW
THAT MIGHT CHANGE WITH THE
PATIENT OR THE CELL PRODUCING
IT. MUCH LIKE UPS OR FEDEX TRUCK
DRIVING DOWN THE ROAD AND WE
HAVE PACKAGES IN THEM, MAYBE
ONLY ONE OR TWO DESIGNATED FOR
YOU OR THAT YOU WANT TO HAVE
OPEN.
>>MOST -- NEIGHBOR AT THE
CORNER HAD NINE BOXES EVERY DAY
>>THANK YOU. LOOKING AND IF
THERE IS NO FURTHER QUESTIONS WE
CAN MOVE TO DR. GUILAK'S TALK.
FARSHID IS WELL KNOWN, THE
PROFESSOR OF ORTHOPEDIC SURGERY
WASU AND DIRECTOR OF RESEARCH
FOR THE ST. LOUIS SHRINERS
HOSPITAL. HE HAS WON THREE KAPPA
DELTA AWARDS AND RECENTLY
ELECTED TO THE NATIONAL ACADEMY
OF ENGINEERING. HIS
CONTRIBUTIONS TO MECHANOBIOLOGY
AND MECHANIC KNOW MEDICINE,
LOOKING FORWARD TO YOUR
DISCUSSION ON GENE EDITING FOR
ARTHRITIS.
>>THANK YOU DR. CHU AND
ORGANIZERS FOR THIS FANTASTIC
SYMPOSIUM SO FAR. THERE'S BEEN A
NUMBER OF CELL BASED THERAPIES
FOR VARIOUS FORMS OF ARTHRITIS,
MOSTLY IN TRY THOUGHT TREAT
FOLKAL DEFECT, LESS SO
RHEUMATOID ARTHRITIS, AS WE HEAR
TODAY VARIOUS APPROACHES FOR
OSTEOARTHRITIS. IN PARTICULAR,
THESE FORMS OF ARTHRITIS ARE
VERY IMPORTANT TARGET BECAUSE
HOW DEBILITATING THEY ARE, THIS
PATIENT ON THE RIGHT WAS GOT A
HIP REPLACEMENTED AGE 18 AND
SECOND HIP ON THE BOTTOM AGE 22,
HE NEEDS A JOINT REPLACEMENT SO
ANYTHING WE CAN DO TO TRY TOLL
PRESERVE JOINTS LIKE THIS, IN
THE KNEE OR THE HIP OR OTHER
JOINTS BECAUSE OF THE DISABILITY
CAUSED COULD BE VERY IMPORTANT.
WE HEARD STEM CELL THERAPIES AND
DR. RODEO GAVE A BACKGROUND. I
PUT FORTH THAT ALL STEM CELL
THERAPIES ARE NEITHER STEM CELLS
NOR THERAPIES. Z WHAT IS OFFERED
ARE CELLS EVEN IF THEY ARE
CELLS, JUST A MIX OF DIFFERENT
TYPES OF NON-STEM CELLS,
NON-THERAPEUTIC CELLS
>>BEING ADVERTISED AS YOU SEE
SPECIALIZED CELLS THAT KNOW WHAT
YOU NEED, WHERE YOU NEED IT,
AUTOMATICALLY GO WILL, BECOME
IT, THEY SOLVE EVERYTHING AND
TURNED OUT UNTRUTHFUL, THESE
CELLS DON'T HOME TO SITE OF
INJURY, THEY DON'T DO EXACTLY
WHAT THEY NEED TO DO. AND THEY
ARE GOING -- THERE HAVE BEEN A
NUMBER OF REPORTS OF OFF TARGET
EFFECTS OF CELL INJECTION SO
THEY ARE NOT HARMLESS, THEY CAN
HAVE CASES OF OVERGROWTH AND
HYPERPLASIA HIGH PER TROPHY
OSSIFICATION IS COMMON IN
CARTILAGE REPAIR AND MEDICAL
TOURISM LIKE A MUCOUS PRODUCING
NOSE LIKE ORGAN OR TUMOR
FORMATION AND VERY BAD CASE OF
COMPLETE VISION LOSS IN PATIENTS
FEW YEARS AG AGO. ONE BIGGEST IE
WE HAVE IN OUR FIELD IS THERE
ARE VERY FEW PROSPECTIVE
RANDOMIZE TRIALS PERFORMED AND
THIS WAS ALLUDED EARLIER, MANY
STUDIES DON'T HAVE CONTROL
GROUPS. WE SAW FROM SOME DATA
PRESENTED, SOME ARE DOSE
RESPONSES WITHOUT A PLACEBO
GROUP. UNFORTUNATE LITTLENESSES
HALF STEM CELL CLINICAL TRIALS
ARE EVER PUBLISHED. STEM CELLS
REGARDED INFLAMMATORY RESPONSE
COMMON TO ARTHRITIS INCLUDING
OSTEOARTHRITISST OSTEOARTHRITIS,
RHEUMATOID ARTHRITIS DRIVEN BY
KEY CYTOKINES COMMON INTERLEUKIN
1, TNF ALPHA, INTERLEUKIN 6 AND
MAYBE 17 IN CERTAIN CASES. WE
MAY HEAR MORE ABOUT DRUG
DELIVERY BUT THE PROBLEM IS
CLEARANCE AND DELIVERY TO JOINT
AND CARTILAGE IF THAT'S THE
TARGET. WE HAVE MANY TARGET IN
OA BUT ONE THAT'S ATTEMPTED IS
INHIBITOR OF INTERLEUKIN 1
ANAKINRA OR AND IT HAS A SHORT
HALF LIFE OF TWO HOURS IN THE
JOINT AND THERE'S BEEN SOME
EVIDENCE TO SAY HELPFUL IN RA,
EVEN EARLY PTOA FOLLOWING ACL
ENTRY BUT LONG TERM STUDIES
DIDN'T SHOW SUCCESS. INCREDIBLE
STUDY RECENTLY WITH THE
(INAUDIBLE) TRIAL, IL 1 BETA
ANTIBODY, 10,000 PATIENTS
STUDIED WITH THROMBOSIS. POST
HOC THEYNALSIS, THERE WAS A
SIGNIFICANT REDUCTION OF 40% HAD
RATIO OF .58 FOR JOINT
REPLACEMENT. SUGGESTING THAT IF
POTENTIALLY DELIVERED PROPERLY,
COMPOUND SUCH AS INHIBITOR OF
INTERLEUKIN 1 COULD BE TREATMENT
FOR OSTEOARTHRITIS. THIS WAS NOT
THE MAIN GOAL STUDY SO MORE WORK
NEEDED TO DETERMINE THIS BUT
THIS IS ONE LARGE EFFECT SIZE
EVER SEEN IN OSTEOARTHRITIS
RELATED STUDY. WHY CAN'T MSC BE
ABLE TO DO THIS? MAJOR
ADVANTAGES IN BONE MARROW OR
ADIPOSE READILY ACCESSIBLE
MULTI-POTENT CAPABILITY BUT VERY
POOR HOMING RETENTION IF
INJECTED, LIMITED UNCONTROL
THERAPEUTIC RESPONSES WHICH ARE
QUITE WEAK FROM
ANTI-INFLAMMATORY STANDPOINT.
DIFFERENTIATE WITHOUT DIRECT
QUEUES OR CONTEXT OR MATRICES,
ONE ISSUE IS VARIABILITY, THERE
IS SOME DISCUSSION FROM DR.
ROBEY IN THE CHAT SINGLE CELL
ANALYSIS. BUNCH OF SINGLE CELL
ANALYSIS ON BONE MARROW MSC
ADIPOSE DEFINED BY VARIOUS
ISOLATION PROCEDURES. NOT ONE
CELL TYPE THERE, MIX OF 2 TO 7,
SOMETIMES TEN CELL POPULATIONS
IN THIS PLOT SINGLE CELL
ANALYSIS. PURPORTEDLY LESS THAN
ONE IN TEN THOUSAND ARE STEM
CELLS WE CALL MSCs. THE OTHER
TOPIC WAS THAT OF INFLAMMATION
AND RESOLVING INFLAMMATION. WE
NEED INFLAMMATION FOR WOUND
REPAIR AND TISSUE REPAIR BUT WE
NEED TO FORM INFLAMMATION THAT
RESOLVES SO INITIAL ONSET OF
INFLAMMATION AND RESPONSE TO
WOUND, RESOLUTION PHASE AND POST
RESOLUTION PHASE WHERE ADAPTIVE
IMMUNE CELLS CAN CLEAN THINGS
UP. THE PROBLEM IS NOT RESOLVING
INFLAMMATION, BUT CHRONIC
INFLAMMATION. THIS IS PRESENT
IN MANY FORMS OF ARTHRITIS OR
INJURY. OBESITY AS RISK FACTOR
FOR ARTHRITIS, WHERE LEVELS OF
CYTOKINES ARE CONTINUOUSLY HIGH.
NOT ONLY HIGH BUT IN FLAIRS
THESE CAN BE DIE YOUR HONORRAL
OR CIRCADIAN ON DAILY BASIS OR
ENVIRONMENTALLY TRIGGERED AND
DRUG THERAPIES CURRENTLY FOR
RHEUMATOID ARTHRITIS ARE HIGH
LEVEL PROTEIN THERAPIES.
SUPPRESS THE IMMUNE RESPONSE AND
NUMBER OF SIDE EFFECT INCREASE
INFECTION RISK. WE WILL HEAR
PROTEIN DELIVERY WORKING WELL IN
CERTAIN CASES MASSIVE RESEARCH
BUT WHERE IT FAILS ARE THINGS
LIKE I DESCRIBED, HIGH LEVELS
ANTI-CYTOKINE BIOLOGIC DRUGS
THAT RESPOND TO STIMULUS LIKE
ENVIRONMENTAL TRIGGER OR
CIRCADIAN TRIGGER HAVE RAPID
RESPONSE TIMES OF MINUTES TO
HOURS AND BE THERE AND BE
DELIVERED FOR MONTHS OR YEARS.
ONE REASON EXOSOMES ARE NOT LONG
TERM DELIVERY INSTEAD OF CELLS
IS CELLS CAN DELIVER
CONTINUOUSLY DRUGS FOR LONG TIME
EXOSOMES AS WE SAW POTENTIAL
STRENGTH DELIVERED REPEATEDLY
AND OVER AND OVER. WE THINK
ABOUT THIS, OUR GOAL WAS TO
DEVELOP TECHNIQUES TO CREATE
SMARTER CELLS THAN WE JUST HEARD
ABOUT. TO USE SYNTHETIC BIOLOGY
TO CREATE CELLS THAT CAN
SELF-REGULATE PROVIDE
APPROPRIATE DRUGS APPROPRIATE
TIMES IN RESPONSE TO STIMULI.
THINK ABOUT DRUG DELIVERY AND
PROTEIN, IT IS HAVING A LEAKY
BUCKET OF DRUGS, PATIENT SIDE
THE BODY, THE DRUG LEAKS OUT AND
WHEN FINISHED REPLACE THE BUCK
OR REFILL WHICH MANY CASES WILL
WORK. IF YES USE GENE THERAPY
APPROACHES, WITH CONSTITUTIVE
PROMOTER WE HAVE LARGE AMOUNTS
OF DRUG GUSHING OUT. IN CERTAIN
CASES SUCH AS HEMOPHILIA, THIS
MAYBE A GOOD APPROACH. GENE
THERAPIES WITH INDUCIBLE
PROMOTERS LIKE HAVING A FAUCET
YOU CAN TURN ON AND OFF, BUT
NEED TO KNOW WHEN TO TURN ON AND
OFF TO FIGHT INFLAMMATION. A
CELL HAS A SENSOR, DELIVER DRUGS
WHEN IT SENSES ANY OTHER
TRIGGTRIGGER. WE THOUGHT WE CANE
A CELL LOOK AT RECEPTORS,
INTERNAL GENE CIRCUITS AND
APPROPRIATE OUTPUT PATHWAYS
WHETHER CYTOKINE INHIBITORS PAIN
TARGETS OR ANABOLIC FACTORS, AND
REPROGRAM USING CRISPER CAS 9
ENGINEERING IN IPSCs IN OUR
CASE. DEVELOP CELLS WITH
INFLAMMATORY RESPONSE, WE CAN
COME IN TO LEAK IT ON GENETIC
BASIS IN ITS PLACE PUT FEEDBACK
LOOP TO CREATE BIOLOGIC DRUGS.
IT IS REPROGRAMMABLE CELL LIKE
iPHONE YOU PUT THESE LITTLE
APPS INTO THE iPHONE AND APPS
ARE DESIGNED TO DELIVER WHAT WE
NEED DELIVERED. FIRST WORK DONE
BY GRADUATE STUDENT JONATHAN ON
FACULTY AT VANDERBILT, HE
DEVELOPED IL 1 AND TNF RESPONSE
SYNTHETIC CIRCUITS. ACTED BY
CYTOKINES HE THEN LOOKED AT
EFFECTOR GENES AND IN THIS CASE
FOUND CCL 2 WAS ONE OF THE BEST
MARKERS OF TNF OR IL 1 ACTIVITY
OUTSIDE THE CELL. FROM THAT HE
WAS ABLE TO BUILD SYNTHETIC GENE
CIRCUIT WITH TNF RECEPTOR OR IL
1 AS TARGET. WHEN IT WAS
ACTIVATED AND CRL 2 WAS
ACTIVATED, ALSO TOOK ONE ALLELE
AND CREATED THE INHIBITOR DRUG
FOR TNF OR IL 1 AS THE OUTPUT.
INSERT TNF -- WHEN THE CELLS SEE
TNF INSTEAD OF TWO COPIES OF CCL
2, IT MAKE IT IS INHIBITOR WHICH
GOES BACK AND BLOCKS TNF
ACTIVITY. WHEN WE DO THIS
EVERYTHING WORKED IN H VITRO AND
MORE RECENTLY TESTED THIS IN A
MODEL OF RHEUMATOID ARTHRITIS,
MOLECULES SUCH AS IL 1 TNF ARE
IMPORTANTOR IMPORTANT PLAYERS.
TO KEEP CELLS IN PLACE THEY WERE
ENGINEERED TO A SMALL DISC OF
CARTILAGE WHERE THEY SAT
SUBCUTANEOUSLY SINCE THE
ENVIRONMENT FOR INFLAMMATION AND
DELIVERED DRUGS SYSTEMICALLY
THEY SHOWED NICELY HAVING DRUG
DELIVERY IN THIS ON DEMAND
SYSTEM, COULD ALLEVIATE PAIN
SENSITIVITY, RED IS TREATED
GROUP, INCREASED OR DECREASE
PAIN THRESHOLD IN THE CONTROL
AND CONTROL TREATED GROUPS
SIGNIFICANTLY INCREASED. ON AN
ON DEMAND BASIS. WE SAW COMPLETE
-- NEVER ACCOMPLISHED BY DRUG
THERAPIES IN RHEUMATOID
ARTHRITIS. WE USE IT AS A MODEL
BECAUSE WE KNOW THE INFLAMMATORY
TARGETS SO WELL STILL NEED TO
IDENTIFY IN OSTEOARTHRITIS. WE
HAVE NOW SEVERAL OTHER
APPROACHES USING, iPHONE
PROGRAM APPS INTO IT, WE HAVE
APPS BUILT TO FIND OURSELVES OR
FIND MY iPHONE BY USING
LUCIFERASE OR GFP, WE CAN TAG
SIGNAL TO ANTI-CYTOKINE THERAPY
AND GET SIGNAL INTENSITY. WE CAN
TURN ON AND OFF SYSTEM
EXOGENOUSLY, USING THINGS LIKE
TEAT OFF OR ON SYSTEM SO IF YOU
TEMPORARILY WANT TO SHUT OFF THE
GENE CIRCUIT WE CAN DO IT WITH
TETRA CYCLINE RESPONSIVE
ELEMENT. THESE ARE IPSCs TRUE
STEM CELLS WITH PLURIPOTENT
CAPABILITY SO WE CAN BUILD U
SELF-DESTRUCT SIGNALS IF THEY
ESCAPE FROM THE CONSTRUCT AND
NEED TO BE ELIMINATED. MOST
RECENTLY WE HAVE BEEN TRYING TO
DEVELOP SYSTEMS THAN CAN
DISTINGUISH DIFFERENT CYTOKINES
AND RESPONSES BECAUSE AS WE
HEARD EARLIER THERE, IS NO ONE
ANTI-CYTOKINE THERAPY THAT IS
GOING TO TREAT ALL THE DISEASE
OR ALL OA, WE CAN IDENTIFY
FINGERPRINTS USING MICRORNA
SIGNATURES ACTIVATED BY PRESENCE
OF DIFFERENT CYTOKINES AND WE
CAN BUILD GENE CIRCUITS BASED ON
THESE. IN THE LAST FEW MINIS
WILL TELL YOU ABOUT TWO OTHER
CIRCUITS WE BUILD THAT HAVE BEEN
FUN. ONE IS A FORCE RESPONSIVE
TOUCH SENSOR DELIVERING DRUGS IN
RESPONSE TO MECHANICAL LOADING.
ARE MECHANICALLY SENSITIVE. BONE
GROWS WHEN YOU LOAD IT, MUSCLE
GROW, CARTILAGE DOES THE SAME
THING, IT HAS MECHANIC KNOW
SENSITIVITY, YOU CAN SEE A PIECE
BEING SUPPRESSED CAUSING CALCIUM
SIGNAL. WE TRACK DOWN SENSORS ON
THE CELLS THAT ARE RESPONSIBLE
FOR MECHANIC KNOW TRANSDUCTION
AND ISOLATED TO THE FAMILY,
PARTICULARLY TRIP V 4 AS PRIMARY
MECHANIC KNOW SENSORS AND
CARTILAGE. WITH THAT KNOWLEDGE
WE THEN WENT AND BUILT SYNTHETIC
GENE CIRCUITS MECHANIC KNOW
GENETICS H. WE BUILT GENE
CIRCUITS WHERE MECHANICAL
LOADING VIA TRIP V 4, TO DO THAT
WE ISOLATED SIGNALING CHANNELS
LOOK AT THE MECHANIC KNOW
TRANSDUCTION PATHWAYS
DOWNSTREAM, USE BIOINFORMATICS
AND CHAIRMAN SEQ TO FIND NODE
AND HUB GENES THAT ACTIVATE
RESPONSE AND BUILD GENE CIRCUITS
USING CRISPER OR LENTIVIRAL
APPROACHES TO TAG DRUG ON TO THE
MECHANICCAL LOADING PATHWAY. SO
GENE ARRAY DATA SHOWING ACT
VISION OF ION CHANNEL BY
CHEMICAL OR MECHANICAL MEANS,
YOU CAN SEE THAT THE RESPONSE IS
QUALITATIVELY AND QUANTITATIVELY
SIMILAR FROM CHIPOTLE CHIP SEQ,Y
POST DOC BOB MIMS AND A STUDENT
BUILD MECHANIC KNOW SENSITIVE
MOTIFS, WHERE THEN MECHANICAL
LOADING ACTIVATE PRODUCTION OF
OUR DRUG, FAVORITE DRUG IN THIS
CASE IL 1 RA SO EASY TO MEASURE
AND DOESN'T DO ANYTHING UNLESS
IS, UL 1. ONCE WE TRANSDUCE INTO
EXPLANTS AND CHONDROCYTES AND
INTO ENGINEER CONSTRUCTS, WE CAN
SHOW DIFFERENT TIME AND DOSE
DEPENDENT RESPONSES, THIS IS
LUCIFERASE ACTIVITY, SHOWING THE
RESPONSE TO ACTIVATING ION
CHANNEL WHETHER NF KAPPA B
RESPONSIVE CIRCUIT OR PT GS 2
RESPONSIVE CIRCUIT IN TERMS OF
MAGNITUDE AND DURATION. WE
BUILT CIRCUITS WITH PREDEFINED
RESPONSES OR DRUG DELIVERY,
DURATIONS AND RECOVERY TIMES.
WE ALSO SHOWED WHEN YOU
MECHANICALLY LOAD THEM YOU CAN
GET PRODUCTION OF IL 1 RA IN
RESPONSE TO LOADING WHICH THE
CELLS DON'T NORMALLY MAKE.
FINALLY, THE MOST RECENT
APPROACH IS TO CREATE A CLOCK,
GENE CIRCUIT BASICALLY ONE BASED
ON THE CIRCADIAN CLOCK OF THE
CELL, SO THAT WE CAN DO DIE YOUR
HONORRAL DRUG DELIVERY. THIS IS
IMPORTANT BECAUSE AS I SHOWED
YOU, FLAVORS FLARES CAN BE DIE R
HONORRAL AND RECENT AREAS OF --
DIURNAL, MATCHING DRUG DELIVERY
TO TIME OF DAY, BECAUSE
INFLAMMATION GOES UP AND DOWN
AND FOR EXAMPLE IN RHEUMATOID
ARTHRITIS PEAK AROUND 3 IN THE
MORNING RARELY WHEN DRUGS ARE
GIVEN SO WE LOOK AT THE CORE
CLOCK GENES IN CHONDROCYTES AND
THEY HAVE STABLE -- THIS IS A
MOUSE IN PA DARK INCUBATOR THAT
PSYCHS A WEEK AFTER TAKEN OUT.
YOU CAN SEE IT FLASHING AND
USING THIS CONCEPT OF
CHRONOTHERAPY WE CAN EXCITE GENE
CIRCUITS THAT DELIVER DRUGS AT
SPECIFIC TIME OF DAY ON THE
CONTINUING BASIS FOR ARTHRITIS
TARGETING EARLY MORNING. WE
CREATED CLOCK GENE CIRCUITS BY
HR 2 AND OTHER CLOCK COMPONENTS
DRIVING OUR DRUG, IN FACT
ENGINEERED TO CARTILAGE Z THESE
CELLS OSCILLATE ON A 23, 24 HOUR
BASIS AND SHOWED CIRCADIAN GENE
EXPRESSION OF OUR DRUG AND
CIRCADIAN PROTEIN PRODUCTION OF
DRUG DELIVERY. ONCE IMPLANTED IN
MICE THEY SYNCHRONIZE WITH THE
MOUSE AND DELIVER FIVE TIMES
MORE DRUG DURING THE NIGHT CYCLE
THAN THE DAY CYCLE. ONE MORE
EXAMPLE, CONCLUDE THERE AND SAY
THAT WE CAN TAKE STEM CELLS AND
MAKE THEM EVEN SENATOR AND
BETTER BY EDITING THEIR GENOME
THEIR EPIGENOME, CREATE
ARTIFICIAL GENE CIRCUITS WITH
CONTROLLED OUTPUTS, REPACKAGE AS
GENE THERAPY, CELL THERAPY,
IMPLANT THERAPIES OR HOPEFULLY
EVENTUALLY ENTIRE JOINT
RESURFACING THERAPIES FOR
VARIOUS FORMS OFFER ARTHRITIS.
I'LL CONCLUDE THERE, THANKS TO
COLLABORATORS AN LAB WHO DID
THIS WORK AND NIH AS WELL AS
SHRINERS AND ARTHRITIS
FOUNDATION. FROM THE
>>THANK YOU. THANK YOU FOR THAT
TOUR INTO THE FUTURE AND SO MANY
EXCITING CONCEPTS YOU PUT INTO
RESEARCH AND BROUGHT TO NICE
STUDIES. I WANTED TO ASK ABOUT
THE IMPLANT, WHERE YOU HAVE
ENGINEERED CELLS WITHIN
CARTILAGE CONSTRUCT. SO WHEN
PEOPLE INJECT THAT AND OTHER
THINGS INTO THE BODY IT'S
RESORBED. CAN YOU COMMENT HOW
LONG THIS IMPLANT LASTS AND HOW
LONG THE CELLS SURVIVAL WITHIN
THE CARTILAGE MATRIX?
>>GREAT QUESTION, THE REASON WE
USE THAT AS IMPLANT, IT IS
AVASCULAR AND IT SHIELDS THE
CELLS, THEY ARE ENCASED SO THEY
CAN'T CRAWL AWAY. CARTILAGE
IMPLANTED SUBCUTANEOUSLY LIKE
THIS OR IN A JOINT, LASTS MONTHS
OR YEARS. KELSEY COLLINS IN OUR
GROUP TESTED THIS OUT FOR SIX
MONTHS SO FAR, WE HAVE SOME THAT
ARE I THINK STILL GOING. BUT AT
LEAST SIX MONTHS THOSE ARE JUST
SITTING THERE AND THEY DON'T GET
ENCAPSULATED BECAUSE CARTILAGE
IS NON-STICK AND CELLS DON'T
ATTACH TO IT AND CAUSE ANY
PROBLEMS. SO FOR OUR PURPOSES
AT LEAST SIX MONTHS IF NOT
LONGER.
>>FANTASTIC. LOOKING FOR
QUESTIONS I WILL ASK ANOTHER
ONE. I THINK WHAT YOU ARE
SHOWING IS VERY EXCITING. HOW
WOULD YOU ENVISION TRANSLATING
SOME OF THIS IN TO CLINICAL
PRACTICE?
>>THAT IS ALSO A --
>>CLINICAL RESEARCH FIRST.
>>WE WON'T SKIP THAT STEP. THAT
IS ONE OF OUR BIGGEST CHALLENGES
IS SCALE UP AND DOSING BECAUSE
WE NEED TO KNOW EXACTLY HOW MANY
CELLS WE NEED. THERE ARE ALL
DIFFERENT WAYS TO CONTROL THE
OUTPUT BESIDES CELLS NUMBER SO
WE DON'T WANT TO HAVE IMPLANTS
HUGE BUT THERE IS GOOD EVIDENCE
FOR HAVING LONG TERM BIOMATERIAL
IMPLANTS IN THE BODY. SOMETHING
LIKE NOR PLANT IMPLANT
SUBCUTANEAIOUSLY DELIVERS, BIRTH
CONTROL HORMONES OVER PERIOD OF
COUPLE OF YEARS WE FOLLOWED THAT
NOW DEVELOPED FLEXIBLE HYDRO GEL
RODS THAT CAN BE INJECTED
WITHOUT SURGERY SUBCUTANEOUSLY
AS A TRANSLATIONAL APPROACH. FOR
A CELL POPULATION, WE ARE
THINKING WE ARE GOING TO HAVE A
REPROGRAMMED ALLOGENEIC MASTER
CELL WE ARE GOING TO USE BECAUSE
IT WOULD BE WAY TOO EXPENSIVE TO
TRY TO DO THESE EDITS AND
TESTING ON PERSONALIZED IPSCs
TO CREATE IPSC TO REPROGRAM IT,
TEST IT, QUALITY CONTROL,
TALKING MILLIONS OF DOLLARS PER
IMPLANT VERSUS BANK OF SHELF
IMPLANTS. SO A WE HAVE TO SCALE
UP TO MID SIZE ANIMALS AND MAKES
SURE IT WORKS AND THEN HOPEFULLY
OVER THE NEXT DECADE TO CLINICAL
STUDIES.
>>SCOTT HAS HIS HAND UP SO WE
WILL GO TO SCOTT AND THEN A FEW
OTHERS.
>>FARSHID BRINGS UP AN
IMPORTANT POINT, AFFECT
MECHANICAL LOAD ON CELLS. ALL
THE TUCK ABOUT BIOLOGY AND THIS
MACROPHAGE AND THAT AND THIS
CYTOKINE BUT THE WHOLE OTHER
PART OF THE EQUATION, THIS IS
NOT LIVER OR PANCREAS. SO THANKS
FOR JUST POINTING OUT THAT
CRITICAL IMPORTANT, ALL STUDIES
IN BIOLOGY OF CELLS.
>>NOT JUST AS A LOAD BEARING
TISSUE, IT HAS TO WITHSTAND TEN
TIMES YOUR BODY WEIGHT BUT ALSO
CAN WE USE AS A SIGNAL TO DRIVE
WHATEVER OUTPUT WE WANT. FOR
EXAMPLE WE BUILT GENE CIRCUITS
THAT DELIVER APT PAIN COMPOUNDS
IN RESPONSE TO LOADING AND DO IT
DIFFERENT MAGNITUDES OF LOADING
ACTIVATION OF CERTAIN ION
CHANNEL VERSUS HIGHER THRESHOLD
ION CHANNEL. WE CAN TUNE ION
CHANNELS DOWN BY MUTATING THEM
AND CHANGING ON OFF DYNAMICS. SO
THERE IS A LOT OF FLEXIBILITY
BUT BECAUSE THERE IS FLEXIBILITY
A LOT OF QUESTIONS TO BE
ANSWERED. AMBIKA.
>>HI, FARSHID, THANK YOU FOR
GREAT TALK, EXCITING WORK.
GENETIC REPROGRAMMING YOU DO IN
THESE CELLS, DO YOU KNOW TIMED
RESPONSE IS THIS A APLASTIC
EFFECT? HOW LONG DOES THE
RESPONSE STAY? AS WE DELIVER
THESE REPROGRAM CELLS, WHAT
HAPPENS TO SURROUNDING CELLS, DO
YOU EXPECT THEM TO CHANGE IN
ANYWAY?
>>GREAT QUESTION, REPROGRAMMING
IS DONE BY CRISPER EDITING IN
IPSCs, WE IDENTIFY SINGLE CELL
WITH EDITS DONE PROPERLY WITHOUT
OFF TARGET EFFECTS. WHICH WE CAN
SEQUENCE AND THEN CLONE THAT ONE
SINGLE CELL. SO A RELATIVELY NOT
COMPLETELY BUT RELATIVELY
UNIFORM POPULATION. BECAUSE EVEN
CLONED CELLS COME FROM SINGLE
CELL ANALYSIS ARE NOT UNIFORM.
SO THAT IS THE CELL, THE EDITS
CANNOT TRANSFER TO ANY NEARBY
CELLS BUT WHAT WE FOUND IN
CO-CULTURE, THESE CELLS WILL
PROTECT OTHER CELLS AROUND THEM
FROM THE CYTOKINE EFFECT. I
DIDN'T SHOW IN VITRO DATA
BECAUSE IT WAS PUBLISHED A FEW
YEARS AGO BUT A SMALL NUMBER OF
EDITED CELLS PROTECT LARGE
NUMBER OF NATIVE CELLS.
>>WHAT IS THE LIFETIME OF THESE
EDITED CELLS?
>>AS I MENTIONED TO DR. CHU WE
HAD THEM SIX MONTHS SO FAR, THAT
IS LONGEST AND WE ARE -- THEY
ARE ACTIVATABLE AT SIX MONTHS IN
THE BODY SUB Q. IF WE INJECT AND
DON'T FORM IMPLANT THEY HAVE A
LIFE OF TWO DAYS. THEN THEY ARE
CLEARED AND GONE. WE MANAGE TO
DIFFERENTIATE SOMETHING TO
MACROPHAGES THAT WILL STICK
AROUND FOR A FEW WEEKS BUT THAT
IS WHAT THE CELL INJECTION,
WHEREAS THE IMPLANT IS MONTHS OR
LONGER.
>>THANK YOU.
>>GEORGE MUSCHLER.
>>I HAVE BEEN FASCINATED BY
YOUR WORK FOR A LONG TIME, AND
CHALLENGE NOT ONLY OF HAVING A
VERY SPECIFIC DRUG BUT ALSO
TIMING AND DURABILITY DELIVERY.
MY QUESTION, THERE'S TWO
QUESTIONS, YOUR STRATEGY TAKING
IPS CELLS AND USING THAT AS YOUR
PLATFORM ON WHICH TO BUILD
STABLE CELL THERAPY, THAT GIVES
YOU THE OPPORTUNITY TO ROUND OUT
A LOT OF VARIABILITY TAKEN FROM
EITHER AUTOLOGOUS CELLS OR
DIFFERENT BATCHES OF MSCs FROM
THE SAME INDIVIDUAL. TWO
QUESTIONS THERE TECHNICALLY DO
YOU EXPECT TO NEED TO TAKE I P,S
CELLS THROUGH AN MSC TYPE
PHENOTYPE ON WAY TO BECOMING
THERAPY? OR DO YOU CARE? WHETHER
THEY GO THROUGH PARTICULAR MSC
PHENOTYPE. RELATED TO THAT WHERE
WOULD YOU LIKE TO DELIVER THESE
CELLS, CAN YOU FEEL NEED TO MAKE
CARTILAGE CELLS THAT DELIVER
DRUGS OR BE HAPPY WITH A CELL
THAT REMAINS DURABLY RESISTANT
AND SYNOVIAL?
>>WE DO GO THROUGH, I DON'T
CALL IT MSC STATE BUT WE GO
THROUGH A STEP WISE
DIFFERENTIATION PROTOCOL THAT
ONE OF MY POST DOCS DEVELOPED
WHICH BASICALLY RECREATES THE
STEPS DURING EMBRYO GENESIS OF
CARTILAGE. SO 12 DAY CULTURE WE
HAVE TO CHANGE MASSIVE NUMBERS
OF GROWTH FACTORS DURING THOSE
12 DAYS. THEY ARE IN THAT
CHONDROGENNIC PHASE AND FORM
CARTILAGE. WE WANT CARTILAGE SO
WE DON'T NECESSARY -- THE MOUSE
CELLS EASIER, THEY GO THROUGH
EARLY MICROMASS PHASE WITH AND
AFTER THAT MESENCHYMAL AND
TURNED TO CARTILAGE. WE WANT
THEM TO FORM STABLE CARTILAGE.
AID NEEDS TO BE FUNCTIONAL
CARTILAGE, IF SUB Q IT NEEDS TO
ENCAPSULATE CELLS, TO PROTECT,
SURVIVE IN AVASCULAR ENVIRONMENT
AND PREVENT INVASION WHICH MOST
CARTILAGE TENDS TO DO THAT.
THESE ARE IPSCs SO WE CAN
DIFFERENTIATE TO NEURONS, INTO
FIBROBLASTIC TYPE CELLS, INTO
MUSCLE CELLS, IF THAT WERE
POTENTIAL AND WE HAVE DONE THIS
WITH SOME ANTI-FIBROTIC CELLS WE
DEVELOPED WITH IN COLLABORATION
WITH JOHNNY HUARD,
DIFFERENTIATED INTO MUSCLE AND
IMPLANTED IN MUSCLE TO PREVENT
MUSCLE FIBROSIS IN RESPONSE TO
TGF BETA. SO STEM PART GIVES YOU
FLEXIBILITY IN HOW YOU
DIFFERENTIATE IT BUT HOW WE GET
THERE FOR THIS WE CARE LESS,
MORE THE END PRODUCT THAT
MATTERS.
>>THANK YOU. HAND OFF TO SCOTT
RODEO YOU ARE ON MUTE.
>>SORRY; I WAS THINKING -- DR.
BARRY IS MANY THE TRANSLATIONAL
MEDICINE INSTITUTE AT COLORADO
STATE UNIVERSITY. ALSO PROFESSOR
CELLULAR THERAPY AFFILIATED WITH
REGENERATIVE MEDICINE AT THE
NATIONAL UNIVERSITY OF IRELAND,
DR. BARRY IS A MAJOR CONTRIBUTOR
TO THE FIELD OF TISSUE
ENGINEERING AND REGENERATIVE
MEDICINE. HIS WORK CONTRIBUTED
TO OUR CURRENT UNDERSTANDING OF
THE PHENOTYPIC ATTRIBUTES OF
MESENCHYMAL STROMAL CELLS,
IMPORTANTLY COMMITTED TO
DEVELOPMENT OF METHODS FOR
AUTOMATED SCALABLE CELL
EXPANSION FOR GMP APPLICATION
AND THAT WORK COORDINATED
CLINICAL TRIALS TO TEST EFFICACY
OF STROMAL CELL DELIVERY AND
REGENERATIVE ARTHRITIS AND
RECIPIENT OF THE MARSHALL AWARD
FOR EXCELLENCE FROM THE ORS.
ALSO ELECTED MEMBER OF THE ROYAL
IRISH ACADEMY LAST YEAR SO
WELCOME, WE WILL HEAR TALK ON
MSC THERAPY FOR OSTEOARTHRITIS.
>>THANK YOU VERY MUCH, DR.
RODEO FOR THAT NICE
INTRODUCTION. I HAVE TO SAY THIS
ENTIRE DISCUSSION HAS BEEN
FASCINATING AND INFORMATIVE.
VERY PRIVILEGED TO CONTRIBUTE.
THE REQUEST WAS TO TALK ABOUT
LIMITATIONS AND CHALLENGES IN
CLINICAL USE OF BIOLOGICS BUT
GOING TO FOCUS ON -- MY
DISCUSSION ON MSC BECAUSE THIS
IS TOPIC THAT I KNOW MOST ABOUT
WAITING FOR SLIDES TO ADVANCE.
MOVE TO NEXT SLIDE PLEASE
BECAUSE THESE ARE CONFLICTS TO
MENTION AT THE BEGINNING OF THE
TALK, NEXT SLIDE PLEASE. I WANT
TO TALK ABOUT FOR FOUR TOPICS.
ONE WHERE WE ARE IN TERMS OF
CLINICAL ASSESSMENT OF MSC
THERAPY FOR TREATMENT OF
OSTEOARTHRITIS, WHAT HAS AND
NEEDS TO BE DONE. SECONDLY
TECHNICAL STRATEGIES
PARTICULARLY AROUND PRODUCTION
OF THE CELL PRODUCT PROBLEMS WE
ARE AWARE OF THERE. THIRDLY,
WHAT WE UNDERSTAND ABOUT
MECHANISM OF ACTION OF CELLS TO
DELIVER TO THE JOINT AND FINALLY
SOME IDEA WAY FORWARD, WHAT WE
NEED TO DO IN TERMS OF ADVANCING
THE FIELD FORWARD. SO FIRST A
QUICK SUMMARY OF WHAT WE HAVE
BEEN DOING IN TERMS OF CLINICAL
ASSESSMENT OF UTILITY OF MSC
TREATMENT IN OSTEOARTHRITIS. SO
THE CONTROL IS NOT WORKING FOR
ME, SO I WILL ASK YOU PLEASE TO
KEEP ADVANCING. THIS IS THE
CLINICAL PATHWAY, CLINICAL
TRIALS PATHWAY THAT WE NEED TO
FOLLOW WHEN WE ARE LOOKING AT
EXPANDED MSC TREATMENT FOR ANY
CONDITION, THE STANDARD PHASED
CLINICAL TRIAL PICTURE WHERE WE
GO THROUGH PHASE 1 TO PHASE 4
POST MARKETING ASSESSMENTS AND
SUBSEQUENT PHASE WE TREAT BIGGER
NUMBERS OF PATIENTS SO PHASE 2
STUDY THINKING ABOUT 100 TO 500
PATIENTS IN PHASE 3 STUDY
THINKING A LARGER NUMBER THAN
THAT IN ORDER TO BUILD BODY OF
EVIDENCE TO BE RELIABLE AND
CONVINCING. THIS IS AN
INTERESTING PAPER PUBLISHED JUST
RECENTLY I BY (INAUDIBLE) WHICH
IS ANALYSIS OF THE STATUS OF
CLINICAL TRIALS, UTILIZING
CULTURE EXPANDED MSC FOR WHOLE
VARIETY OF DIFFERENT INDICATIONS
LOOKS OVER MULTIPLE YEAR PERIOD
YOU CAN SEE HERE THE PHASE 1
STUDIES IN BLUE, PHASE 2 ORANGE
FADES 3 IN GRAY. WHAT IS
STRIKING ABOUT THIS PICTURE IS
THE LACK OF PROGRESSION TO PHASE
3 STUDY SO THERE'S MULTIPLE
PHASE 1 TRIAL IN FACT HUNDREDS
OF THEM, PHASE 2 TRIALS BUT
LIMITED PROGRESSION BEYOND PHASE
2 TO PHASE 3. TRUE FOR EVERY
TARGET INDICATION. SO RESULTS OF
EARLY TRIALS ARE NOT GOOD ENOUGH
OR DESIGN GOOD ENOUGH BECAUSE
THE PROGRESSION TOPAZ 3 IS
LIMITED. SO THERE IS A PIPELINE
BUT THAT PRION IS NOT
PROGRESSING. I HAD A QUICK LOOK
AT THE CURRENT CLINICAL TRIAL
REGISTRY IN THE CONTEXT OF MSC
TRIALS FOR OSTEOARTHRITIS. ABOUT
120 OR SO TRIALS LISTED LOOKING
AT MSC TREATMENT FOR OA. ABOUT
50 ARE PHASE 1, 60 PHASE 2 AND
HANDFUL ARE PHASE 3. LOOK AT
PHASE 3 TRIAL ON THE REGISTRY,
SIX OF THOSE ARE REPORTED BEING
COMPLETED THE REST RECRUITING OR
AMONG STATUS OR NOT STARTTH
STARTED. ONE IS NOT RELEVANT TO
MSC, BIGGEST IS THE MILE STUDY,
WHICH IS COMPLETE BUT RESULTS
NOT POSTED AS I UNDERSTAND IT.
THE OTHER PHASE 3 STUDY LISTED
ARE RATHER SMALL AND IT IS HARD
TO UNDERSTAND IF THEY REALLY ARE
JUSTIFIABLY REFERRED TO AS PHASE
3 TRIALS WHEN THEY REPRESENT THE
BODY OF EVIDENCE WE NEED TO HAVE
TO ANSWER THE QUESTION
CONVINCINGLY WHETHER THIS
TREATMENT WORKS OR NOT. SO WE
HAVE BEEN DOING CLINICAL STUDIES
IN EUROPE VERY QUICKLY SUMMARIZE
WHERE WE ARE WITH THIS. WE
CARRIED OUT PHASE 1 STUDY WHICH
COMPLETED HOE WHICH WAS
COMPLETED IN 2015 OR 16. LOOKING
AT AUTOLOGOUS EXPANDED ADIPOSE
DERIVED CELLS FOR TREATMENT OF
MODERATE TO SEVERE
OSTEOARTHRITIS OF THE KNEE. SO
VERY SIMPLE PROTOCOL, PATIENTS
INFER STRONG VASCULAR FRACTION
IS REPAIRED, CELLS ISOLATED
EXPANDED FROM SPF AND AT THE END
OF PASSAGE 2 CELLS ARE DELIVERED
BACK TO THE KNEE JOINT OF THE
PATIENT, IN THIS PHASE 1 STUDY
WE TREATED 18 PATIENTS AND THREE
COHORT, LOW MEDIUM AND HIGH DOSE
AND THEN IN THE NEXT SLIDE,
INCLUSION EXCLUSION CRITERIA ARE
SUMMARIZED HERE OBVIOUSLY A VERY
COMPREHENSIVE LIST OF INCLUSION
AN EXCLUSION CRITERIA, I'M
SUMMARIZING THE CRITICAL POINTS,
THOSE PATIENTS HAD SYMPTOMATIC
PRIMARY OSTEOARTHRITIS OF THE
KNEE, AT LEAST KL 2 OR 3, 50 TO
# 0 YEARS OLD, WITHOUT ANY
SECONDARY OSTEOARTHRITIS OR
EVIDENCE OF OA OR OTHER
CONDITIONS. NEXT SLIDE. THE
STUDY WAS SIX PATIENTS PER GROUP
NOT STATISTICAL SIGNIFICANCE.
THE OTHER SYMPTOM MODIFYING ONLY
THERE WAS NO ATTEMPT MADE TO
LOOK FOR DISEASE MODIFIED
OUTCOME. BASED ON SMALL STUDY
THERE WAS INTERESTING
OBSERVATION, SIGNIFICANT
REDUCTION IN PAIN SCORES IN ALL
THE PATIENTS WITHIN 24 HOURS OF
RECEIVING THE TREATMENT. THE
NEXT SLIDE A SIGNIFICANT
INTRODUCTION IN THE WOMAK SCORE
IN THE PATIENT THAT RECEIVED THE
SUB TREATMENT. THE OTHER
INTEREST OBSERVATION THERE WAS
IMPROVEMENT IN SYMPTOMS BUT
MOSTLY THE LOWEST CELL DOSE
WHICH GAVE RISE RISE TO BEST
RESPONSE IN THESE PATIENTS. SO
BASED ON THESE OBSERVATIONS AND
THE STUDY WAS ENTIRELY SAFE WITH
NO ADVERSE EVENTS REPORTED, WE
WENT TO PHASE 2B STUDY. THIS IS
DESIGNED AS MULTI-CENTER PLACEBO
CONTROLLED FULLY RANDOMIZED
CLINICAL TRIAL TO ASSESS
AUTOLOGOUS EXPANDED ARC
TREATMENT IN MICE MODERATE TO
SEVERE OSTEOARTHRITIS AND THIS
STUDY HAS JUST COMPLETED, IT WAS
SEVERELY IMPACTED BY COVID AND
WAS BADLY DELAYED AS A RESULT OF
COVID SO WE DIDN'T REACH THE END
POINT OF 153 PATIENTS THAT WE
INTENDED TO. NONETHELESS STUDY
IS FINISHED AND THE PRIMARY
CLINICAL OUTCOME WILL BE
AVAILABLE IN A MONTH'S TIME. THE
DESIGN OF THE STUDY IS HOPEFULLY
SUFFICIENT TO UNDERSTAND WHETHER
THERE IS A STRUCTURE OR DISEASE
MODIFYING AFFECT ASSOCIATED WITH
THE TREATMENT OPPOSED TO MERELY
SYMPTOM MODIFYING EFFECT. SO ALL
TOGETHER PATIENTS COME FOR NINE
VISITS, THE FIRST TWO ARE FOR
SCREENING AND ENROLLMENT. AND
FOR COLLECTION OF THE ADIPOSE
TISSUE. THIRD IS FOR TREATMENT
WITH CELLS AND THEN ALL
SUBSEQUENT VISITS UP TO 24
MONTHS ARE FOR RADIOLOGY,
CLINICAL ASSESSMENT RADIOLOGY
AND MRI. HOPEFULLY WHEN THESE
DATA ARE COMPLETED WE WILL HAVE
A GOOD IDEA WHETHER THERE IS A
TISSUE RESPONSE OR REGENERATIVE
RESPONSE ASSOCIATED WITH CELL
TREATMENT. AND IF THE RESULTS OF
THIS, SIGNAL WE SEE MONTHS'S
TIME WHEN WE -- WHEN SIX MONTH
TIME POINT POST TREATMENT IS
REACHED THEN WE WILL START
PLANNING FOR A PHASE 3 LARGE
STUDY. WE ALSO SWITCH FROM
AUTOLOGOUS TO ALLOGENEIC
TREATMENT BECAUSE THE LO LISTICS
AND PRACTICALITY OF DOING
AUTOLOGOUS EXPANDED CELL THERAPY
IN LARGE GROUP IS TOO DIFFICULT.
THE IDEA WILL BE IF THINGS LOOK
GOOD TO MOVE TO PHASE 3
ALLOGENEIC STUDY WITH SOME
IMPROVEMENT AND MANUFACTURING
PROTOCOL BASED ON LESSONS
LEARNED FROM THE -- WHAT WE HAVE
DONE PREVIOUSLY. THE TECHNICAL
STRATEGY RELATING TO HOW DO YOU
PRODUCE THE CELLS IN THE HIGHLY
CONSISTENT REPRODUCIBLE AND HIGH
QUALITY FASHION TO USE IN STUDY
LIKE THIS AND ULTIMATELY TO USE
IN THE WIDE IRPATIENT
POPULATION. SOMETHING WE HAVE
GIVEN GREAT DEAL OF THOUGHT TO
AND TO NEXT SLIDE PLEASE THIS
SHOW IT IS MANUFACTURING
PROTOCOL WE HAVE USED IN
PRACTICALLY EVERY GROUP THAT
PREPARES MSC FOR ANY PURPOSE USE
PROTOCOL BASICALLY. FROM THE
TISSUE, WE EXTRACT THE CELLS AND
EXPAND THE CELLS OVER SEVERAL
PASSAGES USING A MULTI-STEP
PROTOCOL SUCH AS WHAT YOU SEE
HERE, WE UTILIZE DIFFERENT
QUALITY CONTROL TESTS TO ASSURE
-- ASSESS THE QUALITY OF THE
CELLS AND MAKE SURE THAT THEY
ARE FREE OF ANY MICROBIAL
CONTAMINATION, SO ON. AT THE END
OF THE CELL EXPANSION PROTOCOL
WE USE THE ISCT STANDARD TESTING
METHODS TO -- BEFORE CELLS ARE
RELEASED. NEXT SLIDE PLEASE.
THIS IS WHERE THINGS START TO
GET COMPLICATED AND WHAT WE ARE
TREADING ON THIN ICE BECAUSE
MENTIONED BY DR. ROBEY AND ONE
OF THE QUESTIONS SHE ADDRESSED
EARLIER THERE ARE DIFFERENT
DIFFERENCES PHENOTYPIC
DIFFERENCES DEPENDING WHERE THE
CELLS ARE ISOLATED FROM, DR.
GUILAK MENTIONED MSC PRESENCE
ARE A COMPLEX MIXTURE OF CELLS
TYPES. IT IS BORRIS THAN THAT.
BEKNOW NUMBER ONE, THE CULTURE
EXPANDED MSC HAS LITTLE
RELATIONSHIP TO IN VIVO CELL
PHENOTYPE. NUMBER TWO, A MIX IN
HETEROGENOUS POPULATION OF
CELLS, THE HETEROGENEITY AND
BIOLOGICAL PHENOTYPE IS REALLY
DEPENDENT ON THE CULTURE --
PHENOTYPE IS DEPENDENT ON THE
CULTURE CONDITIONS, WHEN YOU
VARY THE CULTURE CONDITIONS YOU
VARY THE PHENOTYPE. I'M SHOWING
TYPICAL PROCESS VARIABLES THAT
PEOPLE USE ISOLATING EXPANDING
MSCs FROM DIFFERENT TISSUES,
USING DIFFERENT MEDIA,
COMPOSITIONS, WHERE CELLS
DELIVERED TO THE RECIPIENT USING
DIFFERENT DELIVERY VEHICLE, ALL
THESE CONDITIONS HAVE POTENTIAL
TO IMPACT BIOLOGICAL PHENOTYPE
OF CELL AND INDEED THERAPEUTIC
ACTIVITY OF THE CELL. NEXT SLIDE
PLEASE. THIS IS A SIMPLE
EXPERIMENT WHICH ILLUSTRATES THE
POUND I'M MAKING WELL MSC FROM
FRESH DONOR CELLS HEALTHY DONOR
AND EXPAND UNDER DISTINCT MEDIA
CONDITIONS SO SERUM FREE,
DIFFERENT CONFIGURATIONS,
DIFFERENT COMPOSITIONS OF
FEASIBLE EVENTS, THEY
PROLIFERATE WELL UNDER
CONDITIONS BUT LOOK AT SURFACE
PHENOTYPE OF THE CELLS EXPANDED
FROM THE SAME DONOR, DIFFERENT
MEDIA YOU CAN SEE BASED ON THIS
HEAT MAP SURFACE PHENOTYPE
DIFFERS DRAMATICALLY WHEN THE
GROWTH CONDITIONS ARE VARIED. Z
DIFFERENTIATION PROPENSITY OF
THE CELLS FROM SAME DONOR VARIES
WIDELY DEPENDING ON HOW THE
CELLS EXPAND AND I DON'T HAVE
THE DATA TO SHOW BUT WE KNOW THE
IMMUNOMODULATORY TIFTED OF THE
CELLS IS DIFFERENT UNDER
CONDITIONS THEY ARE EXPANDED. WE
ARE TALKING A PROCESS THAT IS
VARIABLE AND GIVES RISE TO CELLS
WITH VARIABLE PHENOTYPE, WHEN WE
COMPARE DIFFERENT STUDIES, THAT
BECOMES DIFFERENT BECAUSE WE ARE
NOT ASSURED OF THE CONSISTENCY
Z, AN STANDARDIZATION OF CELL
PRODUCT. THIS IS SOMETHING WE
NEED TO ADDRESS AND IT HASN'T
BEEN PROPERLY ADDRESSED TO THIS
DATE. NEXT SLIDE PLEASE. THIS
SHOWS, THIS IS REALLY IMPORTANT
PIECE OF INFORMATION DESPITE PIE
LOGICAL VARIABILITY WE SEE IN
THE CELL EVEN FROM THE SAME
DONOR WHEN UNDER DIFFERENT
CONDITIONS WHEN WE USE THE ISCT
STANDARD MARKERS NONE OF THESE
-- THIS BIOLOGICAL VARIABILITY
IS EVIDENT BECAUSE YOU SEE CD
73, CD 19 EQUALLY HIGHLY EXPRESS
IN CELLS DESPITE BIOLOGICAL
DIFFERENCES THAT WE SEE NEGATIVE
MARKERS ALL EQUALLY NEGATIVE
DESPITE, SO THESE MARKERS DON'T
FULFILL THE PURPOSE,
DOING/HIDING MULTITUDE OF SINS,
WE NEED TO CHANGE THIS. SO WE
HAVE TAKEN A STRONG ENGINEERING
APPROACH TO TRY TO STANDARDIZE
MANUFACTURING PROTOCOLS FOR MSC
DEVELOPING A FULLY ROBOTIC FULL
HI CLOSED AUTOMATED
MANUFACTURING SYSTEM WHERE NO
HUMAN HANDS ARE INVOLVED AND
ENTIRE PROCESS FROM HARVEST TO
TISSUE TO DONOR TO FILLING VILE
OF CELLS BEFORE DELIVERY TO
PATIENT IS CARRIED BY ROBOTIC
ARMS, THE MONITORING OF THE
STATUS OF THE CELLS IS DONE
REMOTELY. USING SENSORS. THIS IS
AN EXAMPLE, I THINK OF WHERE WE
NEED TO GO IN TERMS OF
STANDARDIZATION OF THE MSC
PRODUCTION METHODOLOGY. NEXT
SLIDE PLEASE. SO EVERYTHING
DEPENDS ON ROBOTIC ARMS.
EVERYTHING DONE IN FULLY
STANDARDIZED WAY SO THERE IS NO
VARIATION IN THE PROCESS. FROM
BATCH TO BATCH. MOVE ON FROM
THIS. WE HAVE ALSO DEVELOPED
WITH ENGINEERING PARTNER A BONE
MARROW AUTOMATED BONE MARROW
HARVESTING DEVICE WHICH
SUCCESSFULLY CARRIES OUT THE
BONE MARROW BIOPSY INTO A FULLY
CLOSED VESSEL AND CLOSED VESSEL
ENTERS THE AUTOMATED PLATFORM
WITHOUT EXPOSURE TO THE
ENVIRONMENT THE SPIRE PROCESS
FROM THE DONOR RIGHT THROUGH TO
THE PATIENT FULLY CLOSED
AUTOMATED WITH NO OPERATOR
INVOLVED. THIS IS AN EXAMPLE
WHERE WE NEED TO GO IN TERMS OF
STANDARDIZING MANUFACTURING
PROTOCOLS. WE NEED TO
STANDARDIZE CONDITIONS AS WELL
IN TERMS OF MEDIA AND IDEAL LIE
USING DEFINED XENOFREE MEDIA
RATHER THAN MEDIA CONTAINING
BIOLOGICAL SUPPLEMENTS. IN
TERMS OF MECHANISM OF ACTION, I
RUN THROUGH THIS QUICKLY BECAUSE
IN THE INTEREST OF TIME, WE HAVE
TAKEN TWO APPROACHES. TO TRY TO
UNDERSTAND MECHANISM OF ACTION.
THESE ARE BOTH BASED ON THE
PREMISE THAT WHAT IS REALLY
IMPORTANT IS PHENOTYPE OF THE
CELL ONCE EXPOSED TO THE DISEASE
ENVIRONMENT. LOOKING AT THE
PHENOTYPE OF CELL IN PLASTIC
DISH ISN'T GOING TO TELL US HOW
THE CELL RESPONDS. ONCE
TRANSPLANTED TO THE IN VIVO
ENVIRONMENT, WE NEED TO
UNDERSTAND THE RESPONSE OF
SURGERY IN VIVO ENVIRONMENT. WE
CAN DO THAT TWO WAYS BY TRYING
TO REPLICATE IN VIVO ENVIRONMENT
IN VITRO EXPERIMENTS SO CALLED
LICENSING AND THAT IS WHAT I
WILL TALK ABOUT HERE IN THE NEXT
SLIDE. WE CAN DEVELOP CONDITIONS
WHERE WE TRY TO REPLICATE IN
VIVO ENVIRONMENT USING
INFLAMMATORY SITE CYTOKINES IL 1
BETA, HYPOXIA, THEN LOOK AT THE
RESPONSE OF THE CELLS TO THIS
TIME OF CONDITIONING THAT THIS
IS POTENTIAL TO PREDICT HOW
CELLS RESPOND AND DELIVERED TO
THE ENVIRONMENT WITH OA JOINTS.
WE HAVE DONE THIS WITH BOP
MARROW DERIVED CELLS TAKEN FROM
THE SAME DONOR TO TRY TO
UNDERSTAND IN A WELL DESIGNED
EXPERIMENT, THE VARIABLE
RESPONSE OF CELLS FROM DIFFERENT
SOURCES. WITHOUT GOING THROUGH
THE DATA IN TOO MUCH DETAIL,
TAKE HOME MESSAGE IS THERE IS A
CHANGE IN PHENOTYPE OF CELLS
WHEN EXPOSED TO THESE
INFLAMMATORY CYTOKINES, IN
GENERAL TERMS ADIPOSE DERIVED
CELLS PRODUCE MORE
ANTI-INFLAMMATORY CYTOKINES,
THAN BONE MARROW CELLS SO THINK
THERAPEUTIC EWE UNTIL I HAVE
THESE CELLS BASED ON THESE
EXPERIMENTS THE RUG ROLLS
SUGGEST ADIPOSE DERIVED CELLS
ARE MORE USEFUL THAN BONE MARROW
DERIVED ESPECIALLY IN CONTEXT OF
ANTI-INFLAMMATORY CYTOKINES
ANGIOGENIC FACTORS AND ALSO
NEUROTROPIC FACTORS. IF I CAN
MOVE TO THE NEXT SLIDE. THIS
SHOWS RELEASE INFLAMMATORY
MOLECULE BUSINESS THE CELLS AN
EXPOSED TO THESE LICENSING
CONDITIONS YOU CAN SEE THE
ADIPOSE DERIVED CELLS
QUANTITATIVELY HAD PA HIGHER
RESPONSE. MOVING ON THE SAME IS
CASE WITH CHEMOKINE RELEASE AND
NEXT SLIDE, ALSO WITH PRO
ANGIOGENIC FACTORS. THE NEXT
SLIDE. THE SECOND EXPERIMENTAL
STRATEGY IN TERMS OF
UNDERSTANDING MECHANISM OF
ACTION IS THROUGH THE FOLLOWING.
SO WE DELIVER CELLS TO OA JOINT
TYPICALLY A MOUSE MODEL
OSTEOARTHRITIS FLUORESCENTLY
LABELED THEN SUBSEQUENT TIME
POINTS WE RETRIEVE CELLS FROM
THE JOINT TO UNDERSTAND HAPPEN
TYPE OF CELLS ARE MODULATED
DURING TIME OF RESIDING WITH OA
JOINTS SO TRANSPLANTED STUDIES
ARE USEFUL AND WE LEARNED ABOUT
THE BEHAVIOR OF THE CELLS SO WE
HAVE DONE THIS IN A NUMBER OF
DIFFERENT EXPERIMENTAL
STRATEGIES, WE ARE JUST PUTTING
THE RESULTS TOGETHER NOW. AND
SUBMITTING THE WORK. BUT WHAT WE
FOUND IS THERE IS A SIGNIFICANT
DIFFERENCE IN GENE EXPRESSION
PROFILES BETWEEN CELLS THAT ARE
RETRIEVED FROM THE CELLS
DELIVERED. NEXT SLIDE PLEASE. SO
WE WERE ABLE TO EXTRACT CELLS
PURIFY THEM FROM THE OA JOINTS
BACK INTO CULTURE UNDERSTAND
ABOUT THEIR CHRONOGENICITY AND
PHENOTYPE AND LOOK AT PROFILES
IN THE RETRIEVED CELLS VERSUS
CONTROL CELLS. WE CAN LOOK AT
THE GENE PATHWAYS THAT ARE
ACTIVATED BY CELLS DURING TIME
RESIDE WITHIN OA JOINT AND THIS
IS A SNAP SHOT WE SEE
SIGNIFICANT CHANGES IN
BIOLOGICAL PROFILE OR PHENOTYPE
OF THE CELLS, THAT WE RETRIEVE
FROM THE JOINTS, SEEMS THOSE
CELLS WHICH PERSIST WE CAN
RETRIEVE FROM THE OA JOINT HAVE
MUCH MORE PROGENITOR PHENOTYPE
THAN STARTING POPULATION AS IF
THE EXPOSURE TO OA ENVIRONMENT
SELECTS FOR THIS PHENOTYPE SO
THAT IS REFLECTED IN THE GENE
PATHWAY THAT WE ARE SEEING HERE
LOOKING AT EXTRA CELLULAR MATRIX
ORGANIZATION, POST TRANSLATION
HAL MODIFICATION AND SO ON. SO
THESE ARE INTERESTING, THEY ARE
NOT DONE YET BUT THEY WILL HELP
US TO SHED LIGHT ON THE
MECHANISM OF ACTION. SO ON THE
BASIS OF WHAT I TALKED ABOUT
CLINICAL TRIALS MANUFACTURING
TECHNOLOGY AND MECHANISM OF
ACTION HAVE COME UP WITH
RECOMMENDATIONS WHICH REPRESENT
-- (OVERLAPPING SPEAKERS) SHARE
THEM. IN THE FIRST INSTANCE
FOCUS ON STANDARD MANUFACTURING
AND THERE'S BEEN NO ATTEMPT AT
ALL TO STANDARDIZE MANUFACTURING
OF CELLS WE DO NEED TO DEVELOP
-- (OVERLAPPING SPEAKERS)
>>THAT IS ONE THING --
>>SOMEBODY'S VOICE IS COMING
THROUGH HERE. BUT I'M ALMOST
DONE. CONSISTENT MANUFACTURING
MODELS WITH DEFINED MEDIA ARE
CRITICAL THINGS TO PAY
ATTENTIATTENTION. THESE SAME STS
FORWARD PRETTY EVERY DAY
QUESTIONS, BUT THEY HAVE NOT
BEEN PROPERLY ADDRESSED. WE
NEED AN INTERNATIONAL STANDARD
TO DEFINE MSC FOR THERAPEUTIC
USE THOUGH ATTEMPTS MADE IN THE
PAST TO ACHIEVE IT, IT'S NOTE
BEEN SUCCESSFUL SO IT MIGHT BE
POSSIBLE FOR THE ORGANIZATIONS
LISTED HERE FDA TO SOMEHOW GET
TOGETHER TO DRIVE QUESTION
FORWARD, IT IS YOU ARE GENERALLY
NEEDED BECAUSE WE ARE NOT ABLE
TO INTERPRET THE CLINICAL TRIAL
DATA PROPERLY UNTIL WE HAVE
CONFIDENCE IN THE CONSISTENCY OF
MANUFACTURING OF CELL. WE NEED
TO ESTABLISH NEW SET OF CRITICAL
QUALITY ATTRIBUTES FOR RELEASE,
BIOLOGICALLY MEANINGFUL AND DO
TELL SOMETHING REALISTIC ABOUT
THE CELL SO KNEW DISEASE
SPECIFIC POTENCY TESTS ARE CLEAR
PREDICTIVE VALUE WE DON'T HAVE
CURRENTLY. MY OPINION WE NEED TO
RESCIND ISCT RECOMMENDATIONS
BECAUSE THEY ARE NOT INFORMATIVE
BUT ALSO HIDING PROBLEMS. THIRD
QUARTER THEN THINK ABOUT
PRODUCING LARGE SCALE ALLOGENEIC
USE IT IS POSSIBLE TO THINK
ABOUT ELABORATE BIOLOGICAL SO
YOU CAN AFFORD TO INVEST LARGE
ARRAY OF TESTS TO GET MAXIMUM
AMOUNT OF BIOLOGICAL
INFORMATION. GENOMIC SEQUENCING
SINGLE CELL SEQUENCING MENTIONED
ALREADY, IMMUNE ET CETERA. WE
CAN AFFORD TO DO THESE TESTS,
THIS IS WHAT WE NEED IN TERMS OF
PROPER CRITERIA. IN TERMS OF
MECHANISM OF ACTION WE NEED MORE
INSIGHT INTO WHAT THE CELLS ARE
ACTUALLY DOING WHEN DELIVERD TO
THE HOST AND WE NEED TO BE
CAREFUL TO DISTINGUISH BETWEEN
LOCAL DELIVERY AND SYSTEMIC
DELIVERY BECAUSE LOCAL DELIVERY
AND -- GIVES RISE TO DIFFERENT
SET OF RESPONSES COMPARED TO
SYSTEMIC DELIVERY. SO LET ME
FINISH THERE. THANK YOU ALL VERY
MUCH FOR YOUR ATTENTION.
>>BEAUTIFUL TALK RIGHT BACK TO
CONNIE CHU'S TALK AT THE
BEGINNING THE TREMENDOUS
HETEROGENEITY ALL THESE
FORMULATIONS MAKES IT SO
CHALLENGING TO STUDY THEM AND
THE NEED TO CHARACTERIZE
IDENTIFY SENTINEL MARKERS OF
POTENCY PURE REACTIVITY. YOU
MAKE IMPORTANT POINT ABOUT
ALLOGENEIC PREPARATIONS ALLOW US
TO DO THAT, NOT PRACTICAL TO DON
AUTOLOGOUS TISSUE. HOW MANY DAYS
IS CULTURE EXPANSION YOU USE?
>>FOR AUTOLOGOUS STUDY 14 DAYS
FROM HARVESTING THE MATERIAL TO
DELIVERING THE CELL BACK TO THE
PATIENT. IT WAS A MAXIMUM OF 14
DAYS.
>>PAM HAS HER HAND UP.
>>THANK YOU, COMPREHENSIVE
OVERVIEW OF THE CHALLENGES. ONE
QUESTION IN TERMS OF EXPERIMENTS
WITH LICENSING CELLS, VERSUS
THOSE YOU RETRIEVE FROM IN VIVO
EXPERIENCE, HAVE YOU HAD
COMPARISON BETWEEN THE TWO IN
TERMS OF GENE EXPRESSION
ANALYSIS WHAT IS UP AND DOWN IN
THOSE TWO DIFFERENT TYPES OF
POPULATIONS?
>>BROADLY SPEAKING THERE IS TWO
SETS OF GENES UPREGULATED IN
BOTH SETS OF EXPERIMENTS. GENES
CALLING FOR ANTI-INFLAMMATORY
PROTEINS AND GENES CALLING FOR
SECRETED PROTEINS ARE DOMINANTLY
UPREGULATED SO PARACRINE
RESPONSE OF THE CELLS IS HIGHLY
MODULATED BY BOTH IN VITRO
LICENSING ENVIRONMENT AND IN
VIVO OA ENVIRONMENT. I WOULD SAY
WE ARE NOT DONE WITH THIS
ANALYSIS YET. SO WE DON'T HAVE
THE FINAL STORY YET.
>>SECOND QUESTION ABOUT TWO
PREVIOUS TRIALS, THERE'S
RESPONDER PATIENT AND
NON-RESPONDER PATIENTS, COULD BE
BECAUSE OF THE PATIENT CONDITION
BUT IT ALSO COULD BE BECAUSE OF
THE CELL PRODUCT. ARE YOU ABLE
TO LOOK AT PRODUCT GIVEN TO
RESPONDERS TO SEE IF THERE WAS A
PATTERN IN THAT, THAT WAS LIKE A
COMMON THEME?
>>THAT IS PART OF THE STUDY,
TRYING TO COMPARE THE SUB
PREPARATION CLINICAL OUTCOME,
BECAUSE THE STUDY IS BLINDED WE
DON'T KNOW WHERE IT WILL GO BUT
IT IS DONE FOR SURE.
>>FOR THE FIRST TRIAL, IS THAT
AVAILABLE?
>>AVAILABLE IN LIMITED WAY FOR
THE FIRST TRIAL BUT I THINK
THERE WASN'T ENOUGH PATIENTS TO
BE CONCLUSIVE ABOUT THAT. IN
FACT, IN THE GROUP I HAD 506 WAS
POSITIVE AND ONE WAS NEGATIVE SO
SNEAD MORE PATIENT DATA TO DO
THAT PROPERLY. FORGIVE ME IF I
MISINTERPRETED THE DRUG
DEVELOPMENT PATHWAYS THAT YOU
ARE PURSUING. I KNOW THE TRIALS
ARE NOT BEING PERFORMED IN THE
STATES BUT YOU MENTIONED GOING
FROM AUTOLOGOUS CELLS PHASE 2 TO
POSSIBLY SWITCHING OVER TO ALLO
IN PHASE 3, WHAT IS THE
REGULATORY PLAN FOR THAT
APPROACH GIVEN IT WILL LIKELY BE
CLASSIFIED A DIFFERENT BIOLOGICS
ONCE YOU KNOW FROM ALLO SORRY
FROM AUTO TO ALLO?
>>I HAVE TO BE HONEST, WE DON'T
YET KNOW WHAT THE REGULATORY
RESPONSE TO THIS REQUEST IS
GOING TO BE. IT IS BASED ON THE
FACT WE KNOW LARGE SCALE USE OF
AUTOLOGOUS EXPANDED CELLS IS
IMPRACTICAL AND NEXT TO
IMPOSSIBLE TO ACHIEVE. IT IS TOO
COSTLY AND LOGISTICS ARE TOO
COMPLICATED SO IF WE PROCEED
WITH THIS, WE HAVE TO MAKE THAT
SWITCH FROM AUTOLOGOUS TO
ALLOGENEIC. ARE NOT ALLOWED TO
SAY WHAT THE REGULATOR WOULD
REQUIRE EXCEPT WIDE USE OF AL
ALLOGENEIC CELL THERAPY APPROVED
IN EUROPE AND AT LEAST ONE OTHER
INDICATION SO WE MAY HOPEFULLY
RELY ON THAT EXPERIENCE. WE MAY
HAVE TO GO BACK AND DO
COMPARISON STUDIES BUT WE ARE
NOT CERTAIN YET ABOUT HOW IT
WILL GO.
>>MARVELOUS TALK, LOVE THE TALK
MORE ABOUT AUTOMATION. MY
QUESTION I WILL ASK HERE IS ONE,
YOU MENTIONED THAT GENERAL
DISFASHION WITH THE ISCT
GUIDELINES WHICH ARE WELL
INTENTIONED BUT PRIMARILY
FOCUSED ON TECHNOLOGY AT THE
TIME, FLOW CYTOMETRY. WE NOW AS
YOU POINT OUT HAVE NOT
INEXPENSIVE BUT SINGLE CELL RNA
SEQ AND SINGLE CELL ANALYSIS ARE
DONE LARGER SCALE. ARE YOU READY
TO GIVE UP ON FLOW CYTOMETRY OR
-- AND JUST FOCUS ON THE OTHER
TWO OMIC STRATEGIE STRATEGIES? E
QUESTION. SECOND, THIS VARIATION
YOU HAVE DEMONSTRATED, BETWEEN
MSC BATCHES AND CULTURE
CONDITIONS, HOW MUCH OF THAT IS
CLONAL SELECTION AMONG
POLYCLONAL MSC POPULATION AND
HAVE YOU BEEN ABLE TO LOOK AT
THAT?
>>IN RELATION TO THE FIRST
POINT I AGREE THE ISCT STANDARDS
WHEN PUBLISHED THE INTENTION WAS
VERY CLEAR. I THINK THE ISCT HAS
MADE SOME NEW RECOMMENDATIONS IN
RELATION TO THIS BUT THE FIRST
SET OF MARKERS STILL STICK AND
EVERY SINGLE PIECE OF
INFORMATION YOU SEE ABOUT MSC
INVOLVE IT IS SAME MARKERS,
BECAUSE THEY ARE EASY TO DO,
ALWAYS POSITIVE SO THEY GIVE
THIS SENSE OF SORT OF SENSE OF
CONFIDENCE WHICH IS NOT
MISPLACED. I THINK WE CAN'T
AFFORD TO GIVE UP FLOW
CYTOMETRY, IF IT IS LARGE SCALE
ALLOGENEIC, WE CAN AFFORD TO
INVEST HEAVILY IN ELABORATE
MATRIX OF TESTS. JUST NEED TO
EXPAND CHARACTERIZATION OF
SURFACE PHENOTYPE MORE THAN
MARKERS WE ARE TALKING ABOUT.
PROBABLY SINGLE CELL SEQUENCING
OF THE PREPARATIONS TO SOMEHOW
DEVELOP STANDARD AROUND THAT.
BENEED TO DO THE BIOLOGICAL
ASSAYS THAT RELATED TO POTENCY,
WHICH WE HAVEN'T BEEN DOING
BECAUSE THERE ARE POTENT AND SUB
POTENT BATCHES, RIGHT NOW WE ARE
NOT ABLE TO TELL WHICH IS WHICH.
SO WE DON'T KNOW ENOUGH ABOUT
THE CELLS, WE ARE DELIVERING TO
THE PATIENTS IN THESE STUDIES.
THAT IS LARGE EXTENT OF VARIABLE
OUTCOMES BECAUSE THE PRODUCT IS
VARIABLE. LARISSA.
>>THANK YOU. SO I NOT GOING TO
COMMENT ON REGULATORY PATHWAY
BECAUSE I HAVE AN ENTIRE
PRESENTATION TO TALK ABOUT IT
BUT I WOULD LIKE TO ASK A
QUESTION, DR. BARRY. I DO NOT
WANT TO PUT YOU ON THE SPOT OR
ANYTHING BUT JUST TO INVITE YOU
TO DISCUSS THIS WITH ME. SO YOU
HAVE SHOWN ONE OF YOUR SLIDES
THAT PATIENTS WHO RESPOND SHOW
IMPROVEMENTS WITHIN THE FIRST 24
HOURS. THEN YOU TALK ABOUT
REGENERATIVE EFFECTS AND
REPAIRTIVE EFFECTS. SO TELL ME
ABOUT THE MECHANISTIC
POSSIBILITY OF A CELL THAT GETS
INTO INTERARTICULAR JOINT TO
DIFFERENTIATE OR BECOME A CELL
LOOKS LIKE CELLS IN THAT
INTERARTERIAL SPACE CONSIDERING
FOR EXAMPLE A LIFETIME OF
CHONDROCYTE OR SYNOVIALCYTE
INJECTING THE CELLS INTO THE
JOINT, HOW DO YOU EXPLAIN THE
PEOPLE IMPROVE WITHIN 24 HOURS?
I WILL GIVE YOU CONTEXT. YOU ARE
NOT PROBABLY THE FIRST TALKING
ABOUT IMPROVEMENTS AND I HAVE
SEEN DIFFERENT OPINIONS ONE
POSSIBILITY IS THESE CELLS ARE
JUST GOLD, THEY DO MAGIC THERE.
SOME ARE SAYING YOU HAVE AN
OSTEO ARTHRITIC JOINT. WHATEVER
YOU INJECT THERE, THE JOINT IS
THE SIZE OF THE DEGENERATIVE
ALSO MAL ALIGNED SOD YOU GET
VOLUME, YOU CHANGE THE THE MAL
ALIGNMENT A LITTLE BIT, YOU
REBALANCE IT SO PEOPLE MAY FEEL
BETTER. THEN THERE IS ALWAYS
PLACEBO EFFECT IN
OSTEOARTHRITIS. WHEN TALKING
ABOUT UNCONTROLLED SITUATIONS.
SO MAYBE JUST DISCUSS THIS IF
YOU COULD THE OBSERVATION OF THE
EARLY RAPID RESPONSE
>>I THINK IT IS VERY IMPORTANT
TO CULTURE WHEN WE REPORT
RESULTS VARIOUS STAGES OF TRIAL,
THEY MEAN A LOT. RAPID RESPONSE
OR IMPROVED RESPONSE IN PATIENTS
MAYBE A PLACEBO EFFECT BECAUSE
THESE ARE OPEN LABEL STUD STUDYU
CAN KNOW WHAT IT IS LIKE IF
PATIENT RECEIVES A STEM CELL
TREATMENT AND KNOW THEY HAVE
RECEIVED A TREATMENT, THERE IS A
REASONABLE PROBABILITY THERE IS
A STRONG PLACEBO AFFECT. IF
THERE IS A PAIN RESPONSE,
FUNCTIONAL RESPONSE EARLY AND
BIOLOGICAL RATIONALE IT IS TO DO
PROBABLY WITH THE UPREGULATION
OF ANTI-INFLAMMATORY CYTOKINES
BY THE CELLS ONCE DELIVERED TO
THE JOINT, WE HAVE SEEN THAT IN
THE DIFFERENT STUDIES WE HAVE
DONE. SO COULD BE CELLS ARE
HAVING SHORT TERM
ANTI-INFLAMMATORY EFFECT ON OA
ENVIRONMENT THAT MAY LEADS TO
POSITIVE PAIN RESPONSE. IN TERMS
OF LONGER TERM OUTCOME,
CONNECTIVE TISSUE PHENOTYPE OR
CARTILAGE CONTRACYTE. IT IS MORE
-- CHONDROCYTE, THIS IS
INFLAMMATORY OR IMMUNE MEDIATED
EFFECTS BY POLARIZING
MACROPHAGES TO ANTI-INFLAMMATORY
STATE OR BY REDUCING THE
ACTIVATION OF T-CELLS. IT IS
LIKELY INTERACTION BETWEEN
DELIVERED CELLS AND HOST IMMUNE
CELLS, THAN IT IS
DIFFERENTIATION OF CELLS TO MAKE
TISSUE, I DON'T ANY WE KNOW
ENOUGH TO BE CERTAIN BECAUSE
THESE ARE HARD ENOUGH TO DO THAT
IS WHAT I WOULD GUESS AGREE WITH
YOU, IT IS A CHALLENGE OF
DEVELOPMENT OF THESE TYPES OF
PRODUCTS THAT WE DON'T KNOW
ENOUGH ABOUT WHAT THEY ARE DOING
IN VIVO AND THERE ARE MANY
CHALLENGES AND DIFFICULTIES
STUDIES THESE. THAT IS ONE OF
THE GAPS IN T FELTED TO TRY TO
BETTER UNDERSTAND WHAT THEY DO.
REGENERATIVE ANTI-INFLAMMATORY
EFFECTS ARE GOING TO BE THERE.
>>THESE QUESTIONS ARE CRITICAL
TO ANSWER OTHERWISE WE WON'T
MAKE THE PROGRESS NEEDED. ALL
THE TECHNICAL WILL GISTICAL
BIOLOGICAL HURDLES THAT YET NEED
TO BE OVERCOME BEFORE WE CAN
MOVE FORWARD. WE HAVEN'T DONE A
GOOD JOB TO DATE. WE NEED TO
IMPROVE THIS IS ISSUES. --
THESE ISSUES.
>>THANK YOU SO MUCH. TED, WE
ARE KIND OF THROUGH THE BREAK
TIME, ALMOST ON TIME. SHALL WE
MOVE TO LARISSA'S TALK?
>>I VOTE TO DO SO.
>>DR. LARISSA LAPTEVA IS
ASSOCIATE DIRECTOR DIVISION OF
CLINICAL EVALUATION PHARMACOLOGY
AND TOXICOLOGY. FOR CBER. AS U
YOU HEARD HER LINE OF
QUESTIONING AND INTRODUCTION SHE
IS CLINICIAN SCIENTIST. SHE
CONTINUES TO PRACTICE
RHEUMATOLOGY AS AN ATTENDING
PHYSICIAN IN OUTPATIENT
RHEUMATOLOGY CLINIC NATIONAL
INSTITUTES OF HEALTH. SHE IS
CONTRIBUTING HER TIME AND
EXPERTISE TO TALK TO US AN
REGULATORY CONSIDERATIONS FOR
DEVELOPMENT OF BIOLOGICAL
PRODUCTS TO TREAT
OSTEOARTHRITIS.
>>THANK YOU FOR THE NICE
INTRODUCTION. GOOD AFTERNOON, A
PLEASURE TO BE PART OF THIS
ROUND TABLE DISCUSSION AND
PERSONALLY FOR ME IT IS NICE TO
COME BACK THE ALMA MATER AND SEE
FAMILIAR FACES AND ENGAGE IN
INTERESTING THOUGHT PROVOKING
CONVERSATIONS. SO I ASKED LAST
MONDAY TO GIVE ADDITIONAL TIME
BECAUSE I REALIZE THAT ONE OF
THE GAPS, THAT'S WHAT I THOUGHT
AFTER READING BACKGROUND
MATERIALS THAT MAYBE PRESENT IN
THE FIELD SCIENTIFIC AUDIENCE
AND INVESTIGATORS PARTICULARLY
IN MANY CLINICIANS I THOUGHT I
WOULD MAYBE EXPLAIN THIS A
LITTLE AND DO MULTI-TASKING, GET
THE PRESENTATION IN THE I WILL
HIGHLIGHT REGULATORY ASPECTS
PERTINENT TO DEVELOPMENT OF DRUG
AND BIOLOGICAL PRODUCTS FOR
OSTEOARTHRITIS AND FDA
PERSPECTIVE ON THIS TOPIC. AS
YOU CAN SEE FDA REVIEWING
REGULAR RATORY WORK ACCOMPLISHED
THROUGH FUNCTIONING OF DIFFERENT
CENTERS, I COME FROM CENTER FOR
BIOLOGIC AND OFFICE OF TISSUE
AND ADVANCE THERAPY MY
PRESENTATION WILL BE WILL BE
FOCUSING ON A NUMBER OF
BIOLOGICAL PRODUCTS THAT THE
OFFICE REGULATES WHICH YOU CAN
SEE HERE. XENOTRANSPLANTATION,
THERAPEUTIC VACCINES TISSUE
ENGINEER PRODUCTS, THE NUMBER OF
OTHERS. BECAUSE WE ARE TALKING
REGENERATIVE MEDICINE AND
THERAPIES, I WOULD LIKE TO
MENTION DEFINITION OF
REGENERATIVE MEDICINE THERAPIES
THE WAY IT WAS WRITTEN IN 21ST
SENTRY CURES ACT, THAT IS WHAT
FDA CONSIDERS REGENERATIVE
THERAPY. LIB FOR A MINUTE AS I
EXPLAIN. FDA IS A REGULATORY
AGENCY, EVERYBODY KNOWS, QUITE
WELL, AND REGULATION AND RULES
ARE EXTENSIONS OF LAWS. THE TWO
MAIN LAWS PUBLIC SERVICE ACT
BIOLOGICS DRUG DEVELOPMENT IS A
BUSINESS, IS HIGHLY DEPENDENT ON
INNOVATION AND IT HAS TO GO IN
PARALLEL WITH ADVANCEMENT IN
SCIENCE AND TECHNOLO TECHNOLOGYS
MEDICAL PRODUCT DEVELOPMENT
REFLECTIVE AND CONDUCIVE OF
THESE ADVANCEMENTS. SO TWO MAIN
ONES I NAMED GET UPDATED EVERY
FIVE YEARS THROUGH
RE-AUTHORIZATION OF THE LAW
CALLED PRESCRIPTION DRUG USER
FEE ACT TO REFLECT FIELD
ADVANCEMENTS AND MEET THE NEEDS
OF DAY AND SOMETIMES NEW LAWS
ARE WRITTEN AND PASSED
SEPARATELY AS WAS THE CASE WITH
21ST CENTURY CURES ACT, WHICH
WAS PASSED END OF 2017 AND STUM
LATE REGENERAL RATIVE THERAPIES.
THAT LAW DEFINED AS CELLULAR
THERAPIES, THERAPEUTIC TISSUE
ENGINEERING PRODUCTS HUMAN CELL
TISSUE PRODUCTS AND COMBINATION
OF THE ABOVE, IN P ESSENCE ALL
PRODUCTS THAT SUSTAIN EFFECT
HUMAN CELLS AND TISSUE. LAWS
ANDRAL RATIONS ARE BRING BY
LAWYERS AND POLICY MAKERS DRUG
DEVELOPMENT DONE BY SCIENTISTS
SO FDA FINDS ITSELF IN A
POSITION TO EXPLAIN TECHNICAL
EXPERTS HOW TO APPLY DIFFERENT
REGULATIONS. WE DO IT BY
PUBLISHING GUIDANCE, IT IS A
PUBLIC PROCESS. THAT IS HOW WE
INTERPRET WHICH PRODUCTSES TO
CALL AND WHICH NOT TO CALL.
REGENERATIVE MEDICINE. I WILL
SHOW YOU GUIDANCE ON LAST SLIDE
ALTHOUGH WE SEE DIFFERENT
PRODUCT PROGRAMS, THE LARGEST
BULK OFVATIONAL NEW DRUG
APPLICATIONS EACH IND
APPLICATION IS A SEPARATE
PRODUCT PROGRAM. SO THE LARGEST
WE SEE COMES FOR CELLULAR AN
GENE THERAPIES. WE USED TO SEE
MORE CELL THERAPIES COMPARED TO
GENE THERAPY BUT THE TRENDS
REVERSED IN 2016 ON THE SLIDE,
AND THE PEAK APPLICATION FOR
CELLULAR THERAPIES OBSERVED IN
YEAR 2020. WAS RELATED TO
COVID-19 PANDEMIC. HERE YOU SEE
IMPORTANT CONSIDERATIONS FOR
DEVELOPMENT OF CELLULAR
THERAPIES AND GENE THERAPIES
APPLY REGENERATIVE MEDICINES AND
THEY OBVIOUSLY APPLY TO PRODUCTS
DEVELOPED FOR OSTEOARTHRITIS.
ADVANCE THERAPY PRODUCTS ARE
EXPECTED TO HAVE PROLONGED
THERAPEUTIC EFFECTS WHICH FROM
PRODUCT DEVELOPMENT RESULTS IN
NEED FOR LONG TERM FOLLOW-UP FOR
BOTH EFFICACY AND SAFETY. AS
ALLUDED AND DISCUSSED MENTIONED
BY MANY PRESENTERS TODAY, THERE
ARE CHALLENGE WITH ASSESSING
PRECISE MECHANISM OF ACTION. FOR
THESE PRODUCTS. YOU SEE OUTGAS
THERAPIES. NOT ALLOGENEIC BUT
AUTOLOGOUS. EVALUATING BECAUSE
IT IS IMPORTANT TO SET UP
ESTABLISH APPROPRIATE DOSE OF
PRODUCT WHEN GIVEN TO PEOPLE SO
EVALUATING POTENCY IN THOSE
MAYBE DIFFICULT. WITH CELL
THERAPIES AS WELL AS GENE
THERAPIES, WITH CELL THERAPIES,
IT IS CHALLENGING TO PREDICT HOW
CELL POPULATION MAY HAVES IN
VIVO WHETHER -- BEHAVIOR IN VIVO
WHETHER IT EXPANDS CELLULAR
VIABILITY AND THAT BECOMES
IMPORTANT HERE. MANY CHALLENGES
AS WAS DISCUSSED BEFORE BUT THE
PRESENCE OF CHALLENGES DOES NOT
REALLY REASON -- IS NOT A REASON
NOT TO DO ADEQUATE INVESTIGATION
TO BETTER UNDERSTAND WHAT THE
PRODUCT DOES, WHERE IT GOES, HOW
GENE THERAPIES ARE DISTRIBUTED.
WE ASK WHEN PEOPLE COULD SHOW
DIFFERENT MECHANISMS OF ACTIONS
THAT HAVE BEEN SEEN IN SIMILAR
PRODUCTS IN BODY OF LITERATURE,
SOME REMOTELY, WE TRIED TO
EXPLAIN VERY IMPORTANT. TO IN
FACT DEMONSTRATE WHAT IS THE
PRODUCT DOES IN PATIENT
POPULATION, WHAT IS MECHANISM OF
ACTION AND IF THIS IS A PRODUCT
THAT CONTAINS CELLS THAT IS
THERE TO PROVIDE
ANTI-INFLAMMATORY RESPONSES FOR
CHONDROCYTES THAT MECHANISM OF
ACTION NEEDS TO BE DEMONSTRATED.
SO INVESTIGATORS NEED TO HAVE A
PLAN IN PLACE STARTING THOSE HOW
SPECIFIC PRODUCT ADMINISTRATION
MAYBE SUPPORTED BY A
PRE-CLINICAL PROGRAM. CELLULAR
-- BY DISTRIBUTION DEPEND ON
MANY FACTORS INCLUDING IN SITU
MICROENVIRONMENT AN DISEASE
STATE, COMMUNICATION AND NUMBER
OF OTHER FACTORS AND WE EXPECT
STUDIES TO BE DONE TO UNDERSTAND
WHERE THE PRODUCT GOES. I DID
PUT A LINK TO THE
RECOMMENDATIONS AND
BIODISTRIBUTION STUDIES HERE
FROM THE INTERNATIONAL
PHARMACEUTICAL REGULATORS
PROGRAM. YOU SEE AT THE BOTTOM
OF THE SLIDE. FOR PART OF THE
WORKING GROUP WRITING THIS PAPER
SO WE CONFORM TO THE
RECOMMENDATIONS PRESENTED THERE
IMMUNOGENICITY IS AN ISSUE WITH
BIOLOGICAL PRODUCT IN GENERAL
AND CELL AND GENE THERAPIES IN
PARTICULAR. TYPICALLY
IMMUNOGENICITY IS SOMETHING WE
ASK PRODUCT DEVELOPERS TO
ADDRESS. IN BASIC PROCEDURES FOR
PRODUCT DELIVERY IS ANOTHER
IMPORTANT ASPECT OF DEVELOPMENT,
BESIDES SAFE ADMINISTRATION OF
PRODUCT TO TENDED ANATOMICAL
SITE IT IS IMPORTANT TO ENSURE
THE PRODUCT IS IN FACT
COMPATIBLE WITH THE DEVICE USED
FOR ADMINISTRATION. WHATEVER
PRODUCT MATERIAL IS DELIVERED
WHEN IT FLOWS THROUGH THE DEVICE
SHOULD REMAIN VIABLE WHEN IT
GETS TO THE TARGET TISSUE. SO
FOR MANY DISEASE POPULATIONS IN
OSTEOARTHRITIS IS NO EXCEPTION,
WHEN A CELL OR GENE THERAPY
PRODUCT IS BEING DEVELOPED, DOSE
LIMITING TOXICITY ARE NOT
READILY OBSERVABLE EARLY IN
DEVELOPMENT SO THE DURATION OF
FOLLOW-UP FOR THE PRODUCTS THAT
WE ARE DEALING WITH MAY TAKE
LONGER COMPARED FOR EXAMPLE THAN
WITH DRUGS, MAY TAKE LONGER EVEN
INITIAL FIRST IN HUMAN STUDIES
BUT THIS SHOULD BE TAILORED TO
INDIVIDUAL PRODUCTS. WE REQUEST
CAREFUL PRODUCT ADMINISTRATION
AND INVESTIGATORS SHOULD
REMEMBER TO MONITOR WHAT
IMMEDIATE REACTIONS AND TO HAVE
STAGGERED ADMINISTRATION AND
STOPPING CRITERIA IN THE
PROTOCOL FOR BOTH INDIVIDUAL
SUBJECTS IN THE ENTIRE STUDY,
AND I KNOW NUMBER OF FOLKS FROM
THE EXTRAMURAL PROGRAM IS
PARTICIPATING IN THIS ROUND
TABLE, I KNOW YOU GUYS HELP
FACILITATE PROTOCOL DEVELOPMENT,
YOU SEE PROTOCOLS SO IF YOU SEE
PROTOCOL THAT LACKS STOPPING
CRITERIA FOR THE TOXICITY
PARTICULARLY WHEN IT IS FIRST IN
HUMAN STUDY, AND THE CRITERIA
SHOULD BE BOTH INDIVIDUAL
SUBJECTS AND THE ENTIRE STUDY,
IT MAY BE GOOD AND YOU PROBABLY
SERVE TO PATIENT SAFETY, GO BACK
TO THE INVESTIGATOR AND ASK THEM
TO REVISE PROTOCOL, IF YOU DON'T
DO THAT WE HAVE TO DO IT WHEN IT
COMES -- WHEN THE PROTOCOL COMES
TO US. WE HAVE SEEN NEW
OSTEOARTHRITIS PROGRAMS WITH
CELLULAR PRODUCTS PAIN AND
SWELLING AND REACTIVE SINUVITIS
WAS OBSERVED IN MAJORITY OF
PATIENTS WITH THE
INVESTIGATIONAL PRODUCT SO THESE
OCCURRENCES ARE NOT THEORETICAL,
WE HAVE SEEN BAD THINGS AND
THEREFORE IT IS IMPORTANT TO
PROCEED CAUTIOUSLY AND CAREFULLY
PARTICULARLY WHEN DEALING WITH
NOVEL PRODUCT. DURATION OF
MONITORING OFTEN DEPENDS ON
ANTICIPATED PRODUCT EFFECT AND
PRODUCTS WHERE REGENERATIVE
EFFECT OR IN VIVO CELLULAR
DIFFERENTIATION OR ENGRAFTMENT.
WE HAVE SEEN PRODUCTS WHERE
ENGRAFTMENT IS EXPECTED. WE SEE
MONITORING AND WE RECOMMEND
MONITOR FOR AT LEAST ONE YEAR OR
LONGER BECAUSE IF WE ARE TALKING
ABOUT REGENERATIVE THERAPY YOU
SEE DURABILITY OF THE EFFECT AND
CONSIDERATION SIS OF THE EFFECT
OVER TIME. IN TERMS OF SAFETY
LONG TERM WE WORRY ABOUT THINGS
LIKE ECTOPIC TISSUE FORMATION.
IF CELLULAR DIFFERENTIATION DOES
NOT GO IN THE INTENDED DIRECTION
AND FOLKS WHO WORK WITH CELL
CULTURE KNOW IF YOU INCREASE
NUMBER OF PASSAGES IN CULTURE
THAT INTRODUCES GENETIC
INSTABILITY SO PRODUCT
CHARACTERIZATION AGAIN WAS
DISCUSSED BEFORE TODAY. AND
DURING THE ROUND TABLE, PRODUCT
CHARACTERIZATION AND APPROPRIATE
PROTOCOL ARE EXTREMELY IMPORTANT
IN UNDERSTANDING WHAT THE
PRODUCT WILL EVENTUALLY DO IN --
WHEN INTRODUCED TO PATIENTS. A
POSSIBILITY OF ACCELERATION OF
CARTILAGE DEGRADATION. WHICH IS
AN EFFECT THAT IS COMPLETELY
OPPOSITE WHAT WE ARE TRYING TO
DO BUT THIS IS AGAIN NOT AN
UNHEARD OF SITUATION AND THIS
SOMETHING TO KEEP IN THE BACK OF
OUR MINDS. TUMORIGENITICITY IS
ALSO AN ISSUE WITH CELL PRODUCTS
INSERTIONAL MUTAGENESIS WOULD BE
SOMETHING THAT WE ARE LOOKING
NOT TO HAVE IN GENE THERAPY
PRODUCTS. SPECIFICALLY FOR GENE
THERAPIES FDA RECOMMENDATIONS
FOR LONG TERM FOLLOW-UP AFTER
TREATMENT WITH GENE THERAPIES
AND THE DURATION OF FOLLOW-UP
DEPENDS ON THE VIRAL VECTOR
CONSTRUCT IN ANY ANTICIPATED
POTENTIAL FOR INSERTIONAL
MUTAGENESIS. HERE ARE SOME
EXAMPLES OF PRODUCT PROGRAMS AND
TYPES OF PRODUCTS WE SEE FOR OA
DEVELOPMENT, BOTH CELLULAR AND
GENE THERAPIES FOR
OSTEOARTHRITIS AS WAS DISCUSSED
BEFORE, THEY ARE ALSO NUMBER OF
AUTOLOGOUS CARTILAGE
IMPLANTATION PRODUCTS THAT ARE
EITHER APPROVED BEING DEVELOPED
IN THE PIPELINE BUT THOSE ARE
DEVELOPED NOT NECESSARILY PER SE
DEVELOPED WITH DISTINCT
CARTILAGE DEFECT, OSTEOARTHRITIS
CAN BE PRESENT IN THE JOINT AS
CO-MORBIDITY SO TO SPEAK BUT
ESSENTIALLY THESE PRODUCTS ARE
STILL DEVELOPED FOR DISTINCT
CARTILAGE DETECTS. WE ALSO SEE A
NUMBER OF INVESTIGATIONAL DEVICE
APPLICATIONS. WITH PRODUCTS THAT
PRODUCE BIOLOGICAL OUTPUT
PURPORTED TO HAVE AFFECT IN
OSTEOARTHRITIS. I'M SURE YOU ARE
FAMILIAR WITH STANDARDS FOR
DEFINING EVIDENCE NEEDED FOR
PRODUCT APPROVAL FOR DRUGS AND
BIOLOGICS, APPROVAL USUALLY IS
BASED ON SUBSTANTIAL EVIDENCE OF
EFFECTIVENESS AND EVIDENCE OF
SAFETY. AND THAT EVIDENCE SHOULD
BE OBTAINED FROM ADEQUATE WELL
CONTROLLED STUDIES. AND FOR
DEVICES VALID SCIENTIFIC
EVIDENCE HAS TO BE THERE TO
DETERMINE WHETHER THERE IS A
REASONABLE ASSURANCE THE DEVICE
IS SAFE AND EFFECTIVE. THESE ARE
REGULATORY CONSIDERATIONS AND
LYNN GO SO TRANSLATING INTO
PLAIN LANGUAGE PREVALENT
CONDITIONS LIKE OSTEOARTHRITIS A
PRODUCT DEVELOPMENT PROGRAM
SHOULD CONSIST OF TWO ADEQUATE
WELL CONTROLLED STUDIES, SHOULD
BE RANDOMIZED BLINDED AND I HAVE
A CLINICAL CONTROL GROUP. FOR
THOSE WHO CONDUCTED TRIALS IN
OSTEOARTHRITIS POPULATIONS, OR
FOR FOLKS IN THE FIELD FOR A
WHILE DR. HOCHBERG AND OTHER
PARTICIPANTS HAVE DONE TRIALS IN
OSTEOARTHRITIS, NOT NECESSARILY
WITH BIOLOGICS BUT OTHER
COMPOUNDS, YOU PROBABLY KNOW
THAT ONE OF THE CHALLENGES THAT
PEOPLE OFTEN SITE SPECIFICALLY
WITH OA TRIALS IS THAT THERE IS
A HIGH PLACEBO RESPONSE BELIEVED
TO BE KNOWN WAXING AND WANING
SYMPTOMATOLOGY BECAUSE OF
DISEASE NATURAL HISTORY AND
PEOPLE HAVE OBSERVED EVEN IF YOU
ENROLL PATIENTS, WITH MODERATE
TO HIGH LEVEL OF PAIN, MOST
PEOPLE BY THE END OF THE STUDY,
THE PAIN WILL EVENTUALLY SUBSIDE
TO SOME MODEST DEGREES AND THAT
COULD HAPPEN REGARDLESS OF THE
INTERVENTION SO SPECIFICALLY FOR
OSTEOARTHRITIS TRIALS WE
RECOMMEND AGAINST HISTORICAL
CONTROLS, FOR NOVEL PRODUCTS
RELY ON EVIDENCE THAT COMES FROM
TRIALS WITH CURRENT CONTROL
GROUPS. ALONG THE SAME LINES, IN
ANY CLINICAL TRIAL WITH
OSTEOARTHRITIS POPULATION,
POPULATION OF THE DISEASE YOU
CHOOSE IT SHOULD BE SOME -- AT
LEAST TO THE DEGREE POSSIBLE
WELL MATCHED WILL ANTICIPATE
PRODUCT EFFECT AND THAT IS WHY
IT IS IMPORTANT TO UNDERSTAND
WHAT THE PRODUCT ACTUALLY DOES
BEFORE YOU ADMINISTER TO
PATIENTS. BEFORE THIS ROUND
TABLE TED TOLD ME THERE WAS SOME
INTEREST IN THE TOPIC WE CALL
TISSUE AND THE MEANING OF
MINIMAL MANIPULATION AND
AUTOLOGOUS USE BUTLY DO THAT
PART MAKING DINTS BETWEEN WHAT
WE CALL REGULATORY PATHWAYS 351
PATHWAY, AND 361 PATHWAY. NOW
REMEMBER I TOLD YOU EARLIER THAT
THE TWO LAWS WHICH GOVERN DRUG
BIOLOGICAL PRODUCT DEVELOPMENT
BY FOOD DRUG ACT AND PUBLIC
HEALTH SERVICE ACT. UNDER THE
FOOD DRUG AND (INAUDIBLE) ACT,
THE RESPECTIVE REGULATIONS
WHETHER OUTLINED HERE ON THE
SLIDE ANY USE IN THE UNITED
STATES OF THE DRUG NOT -- IT IS
MARKETING APPLICATION TO FDA
THERE IS A DEFINITION WHAT DRUG
MEANS FOR DRUG (INAUDIBLE) ACT
YOU CAN SEE HERE. NOTE THE
LITTLE FOOTNOTE ON THE SLIDE ALL
THIS IS APPLICABLE TO BIOLOGICAL
PRODUCTS TO WELL KNOWN TO ALL OF
US THERAPEUTIC BIOLOGICAL
PRODUCTS SUCH AS ANTIBODIES,
RECEPTOR FUSION PROTEIN,
ANTI-CYTOKINE TREATMENT MORE
NOVEL BY SPECIFIC ANTIBODIES. AS
WELL AS CELL AND GENE THERAPIES
AND TISSUE GENE PRODUCTS. IN
ESSENCE DRUGS REGULATED UNDER
FOOD DRUG AND BIOLOGICS
REGULATED UNDER SECTION 3651 OF
THE PUBLIC HEALTH SERVICE ACT.
REGULATED IN THE SAME WAY. SO
ALL THE CONCEPTS AND
CONSIDERATIONS THAT I HAVE SHOWN
YOU ON THE PREVIOUS SLIDE RELATE
TO THE REGULATION OF BIOLOGICS
UNDER THE 351 PATHWAY SHOWN HERE
IN RED ON THE SLIDE. SO LET'S
TALK ABOUT THE 361 PATHWAY WHICH
IS OUTLINED IN THE PUBLIC HEALTH
SERVICE ACT BUT BEFORE WE GO
INTO PATHWAY, LET'S FIRST LOOK
AT THE SUBSET OF BIOLOGICAL
PRODUCTS CALLED HUMAN CELLS
TISSUES AND TISSUE BASED
PRODUCTS ALSO KNOWN AS HCTPSS.
SURE YOU HAVE HEARD THIS TERM.
THE REASON THESE PRODUCTS WERE
DEFINED LIKE THIS AND WHY THE
TISSUE WAS EVEN CREATED WAS TO
PERMIT THE USE OF DONOR DERIVED
OR AUTOLOGOUS HUMAN TISSUES AND
CELLS PRIMARILY FOR CORRECTION
OF ANATOMICAL DEFECTS OR CELL
SUPPLEMENTATION IN LOWER RISK
SITUATIONS WHEN THERE IS A GOOD
ASSURANCE THERE WOULD BE NO
TRANSMISSION OF INFECTIOUS
DISEASE DO DONOR TO RECIPIENT.
THE DONOR COULD BE A LIVE DONOR
OR A -- A CLAYS IS EXAMPLE IS A
CORNEAL IMPLANT. JUST REPLACE
PROVIDED THE ADEQUATE QUALITY
AND PURITY, MANUFACTURER
RESPONSIBLE FOR MAKING THE
PRODUCT, THERE IS ABSENCE OF
TRANSMISSIBLE INFECTION WHICH
CAN BE ASSURED THROUGH
APPROPRIATE DONOR ELIGIBILITY
CRITERIA. YOU CAN DO THE
IMPLEMENTATION SURGICALLY. HCCP
REGULATION COLLECTIVELY KNOWN AS
TISSUE DEFINE TWO THINGS. THEY
DEFINE A NUMBER OF THINGS BUT
DEFINE TWO IMPORTANT THINGS,
IMPORTANT FOR OUR CONVERSATION
TODAY. HCTP PRODUCTS WHICH
TISSUE MAYBE APPLICABLE, A GROUP
OF PRODUCTS WHICH YOU SEE HERE
ON THE SLIDE, THEY ALSO DEFINE
CRITERIA WHEN HE IS PRODUCTS CAN
BE REGULATED UNDER TISSUE AND
NOT UNDER SECTION 351 OF PUBLIC
HEALTH SERVICE ACT. BY AND LARGE
MOST PRODUCTS WHEN THEY ARE
INTENDED FOR TREATMENT OF
DISEASES, THEY REGULATE UNDER
351 PATHWAY. LET'S TALK ABOUT
DEFINITION FIRST. HCTPs ARE
HUMAN CELLS AND TISSUE PRODUCTS
INTENDED FOR IMPLANTATION
TRANSPLANTATION AND FUSION OR
TRANSFER TO HUMAN RECIPIENTSS.
THEY COVER A RANGE OF PRODUCTS
YOU SEE HERE IN T SECOND BULLET.
PLEASE KNOW MOST PRODUCTS ARE
REGULATED AS DRUGS OR BIOLOGICAL
PRODUCTS PARTICULARLY WHEN THEY
ARE INTENDED TO TREAT MEDICAL
CONDITIONS. OSTEOARTHRITIS WAS
NO EXCEPTION HERE. SOME WOULD BE
REGULATED UNDER TISSUE IF THEY
MEET SPECIFIC CRITERIA, I WILL
SHOW YOU IN A MINUTE. THE HCTP
REGULATION DEFINE PRODUCTS NOT
HCTPs, THESE INCLUDE BLOOD
PRODUCTS PLATELET RICH PLASMA
AND SERUM. BECAUSE PRODUCTS ARE
NOT HCTPs, THEY ARE NOT
SUBJECTS TO THE FRAMEWORK OF THE
TISSUE OR THE 361 PATHWAYS. A
PATHWAY, THEY CANNOT BE MADE
AVAILABLE UNDER THIS FRAMEWORK.
THE REGS DR. CHU SHOWED US
BEGINNING 640 APPLY TO BLOOD
PRODUCTS INTENDED FOR
TRANSFUSION. NOTHING TO DO WITH
TREATING MEDICAL CONDITIONS.
THE REASON I ASK FOR A LITTLE
MORE TIME, I WANT TO MAYBE
DISPEL MYTHS OR EXPLAIN
MISCONCEPTIONS. THE FIRST
INCEPTION OBVIOUSLY YOU MIGHT
HEAR OPRP WOULD BE LEGALLY
MARKETED PRODUCT OR LEGALLY
MARKETED AS AN HCTP, HUMAN
TISSUE PRODUCT. THAT IS NOT
CORRECT. BECAUSE PRP IS NOT
HCTP, IT DOESN'T FALL UNDER
TISSUE. SO I WILL GIVE A LITTLE
HISTORY HERE. HCTP REGULATIONS
WERE ISSUED THROUGH NOTICE OF
COMMON RULE MAKING IN EARLY
2000s. ISSUED IN THREE PARTS
AND BECAME COLLECTIVELY KNOWN AS
THE TISSUE, THEY BECAME FULLY
EFFECTIVE IN MAY OF 2005. SO
HERE IS ANOTHER EXAMPLE OF THE
MISCONCEPTION WE OFTEN HEAR FDA
JUST STARTED REGULATING THIS
PRODUCT OR FDA DIDN'T REGULATE
THE PRODUCT BEFORE THEY
PUBLISHED THEIR DRAFT GUIDANCE
IN 2017. THESE STATEMENTS ARE
NOT ACCURATE. FDA HAS BEEN
REGULATING THESE PRODUCTS UNDER
THE SAME FRAMEWORK FOR MORE THAN
17 YEARS, THE GUIDANCE AND
MINIMAL MANIPULATION AND
HOMOLOGY GUS USE INCLUDE
MISDEMEANOR THE LIST OF READING
MATERIALS FOR THE ROUND TABLE,
AND OTHER RELATED GUIDANCE ABOUT
TISSUE WERE WRITTEN TO PROVIDE
CLARITY AROUND THE REGULATIONS
THEY DID NOT REALLY SERVE TO
BRING ANY PRODUCT UNDER THE FDA
AUTHORITY. HCTPs CAN BE
REGULATED AS I TOLD YOU AS DRUGS
OR BIOLOGICAL PRODUCTS. AND THAT
IS WHEN THEY ARE INTENDED FOR
MEDICAL TREATMENT OF DISEASE
CHRONIC MEDICAL CONDITIONS,
NEUROLOGICAL CONDITIONS
MUSCULOSKELETAL DISORDERS
INCLUDING OSTEOARTHRITIS. FDA
PRE-MARKET REVIEW APPROVAL WOULD
BE REQUIRED FOR THESE PRODUCTS
WHICH MEANS THEY CANNOT BE
MARKETED WITHOUT APPROVED
BIOLOGIC LICENSE APPLICATION AND
THEY CAN BE MADE AVAILABLE
ASVATIONAL PRODUCTS UNDER ACTIVE
IND OR IDE. THE SECOND SCENARIO
YOU SEE HERE ON THE SLIDE, WHEN
HCTP MEETS SPECIFIC CRITERIA
UNDER SECTION 361 PUBLIC HEALTH
SERVICE ACT IN THAT CASE HCTP
PRODUCT WOULDN'T REQUIRE FDA
PRE-MARKET REVIEW AND APPROVAL
AS EXPLAINED IN THE CASE OF
CORNEAL IMPLANT WHICH IS
PRODUCTS LIKE THIS CAN BE
MARKETED AND MADE AVAILABLE SO
LONG AS THEY MEET THE CRITERIA.
PLEASE NOTE HERE MANUFACTURERS
OF THESE PRODUCTS STILL HAVE TO
REGISTER WITH THE FDA AS
FACILITY THAT MAKES HCTPs AND
SUBJECT TO SAFETY REPORTING
MANUAL REPORTING WHICH MEANS IF
SOMETHING HAPPENS WITH HAIR
PRODUCT WHEN MARKETED AND IF
RELATED TO SAFETY THEY HAVE TO
REPORT THIS TO FDA AND WE WILL
LOOK AFTER SAFETY OF THESE
PRODUCTS TOO. HERE ARE THE FOUR
CRITERIA. DEFINED IN TISSUE.
PLEASE NOTE ALL OF THESE
CRITERIA MUST BE MET IN ORDER
FOR HCTP TO BE REGULATED SOLELY
UNDER SECTION 361. HERE THEY
ARE. THE PRODUCT HAS TO BE
MINIMALLY MANIPULATED, INTENDED
FOR HOMOLOGOUS USE, NOT COMBINED
ANOTHER ARTICLE OR SUBSTANCE AND
A PRODUCT HCTP REGULATED UNDER
361 CAN LOOK AT THE SYSTEMIC
EFFECT OR P DEPENDENT ON THE
METABOLIC ACTIVITY OF THE LIVING
CELLS FOR PRIMARY FUNCTION
AUTOLOGOUS PRODUCT INTENDED IN
THE USE OF FIRST OF SECOND
DEGREE RELATIVE OR FOR
REPRODUCTIVE USE. HERE IS
ANOTHER MISCONCEPTION WHICH I
NOT ONLY SAW IN THE RESPONSES TO
QUESTIONS, FOR THE ROUND TABLE
BUT ALSO HEARD DURING THE
DISCUSSION. WE HAVE HEAR FOLKS
SAY BECAUSE THIS PRODUCT IS AN
AUTOLOGOUS PRODUCT IT IS
AUTOMATICALLY HCTP AND
AUTOMATICALLY FDA. THIS IS NOT
TRUE BECAUSE WE HAVE MEN PLENTY
OF AUTOLOGOUS PRODUCTS REGULATED
UNDER 351. HCTP MUST IMMEDIATE
ALL FOUR CRITERIA TO BE
REGULATED SOLELY UNDER SECTION
361. SO THIS GUIDANCE SURE YOU
READ IT IF PREPARING FOR THE
ROUND TABLE, THIS GUIDANCE
DISCUSSES ROLE APPROACH TO
SELF-DETERMINATION OF WHAT
PRODUCT YOU ARE WORKING WITH AND
WHETHER THE PRODUCT WOULD FALL
UNDER THE TISSUE REGULATIONS, IT
PROVIDE AN ALGORITHM AND TALKS
ABOUT THE FIRST TWO CRITERIA
WHICH I WILL ALSO DISCUSS TODAY
NOT TOO EASY TO MOVE THE SLIDES,
NOT SURE WHY. SO THE FIRST
CRITERIA SAYS HCTP MUST BE
MINIMALLY MANIPULATED. THE
REGULATIONS LAY OUT TWO SEPARATE
DEFINITIONS OF MINIMAL
MANIPULATION. ONE IS STRUCTURAL
TISSUES AND THE OTHER IS
CELLULAR AND NON-STRUCTURAL
TISSUES. WHEN EVALUATING THE
MINIMUM NARRATION CRITERIA, IT
IS IMPORTANT TO REMEMBER THAT
THIS CRITERIA RELATES TO HOW THE
HCTP FUNCTION IN THE DONOR, IT
IS ESSENTIAL TO EVALUATE
PROCESSING STEPS AND BEGIN
ANALYSIS WITH THE HCTP AS
EXISTED IN THE DONOR. SO THIS
MEANS YOU LOOK AT THE PROCESSING
FROM START TO FINISH AND IN THE
PROCESSING ORDERS TISSUES
UTILITY IN THE DONOR, MEANING
THAT THE TISSUE LOST ABILITY TO
FUNCTION AS IT DID IN THE DONOR,
THEN WE WOULD CONSIDER THE
PROCESSING TO BE MORE THAN
MINIMAL MANIPULATION. GUIDANCE
INCLUDES A NUMBER OF EXAMPLES
BECAUSE YOU HAVE TO APPLY THESE
CRITERIA BASED ON NOT ONLY
PROCESS OF MANIPULATION BUT ALSO
APPLICATION TO DIFFERENT TISSUES
THAT MAY VARY, THE APPLICATION
MAY VARY FOR DIFFERENT TISSUES.
THE SECOND CRITERIA HERE IS THE
HOMOLOGOUS USE. HOMOLOGOUS USE
IS DEFINED IN THE REGS AS REPAIR
RECONSTRUCTION REPLACEMENT OR
SUPPLEMENTATION OF RECIPIENT
CELLS OR TISSUES WITH HCTP THAT
PERFORMS THE SAME FUNCTION OR
FUNCTIONS IN THE RECIPIENT AS IN
THE DONOR. KEY POINT HERE TO
KEEP IN MIND IS THIS CRITERION
RELATES TO THE INTENDED USE OF
THE HCTP IN THE RECIPIENT IF YOU
INTEND TO USE HCTP FOR THE
INTENDED FUNCTION IN RECIPIENT
IN ORDER TO MEET HOMOLOGOUS USE
CRITERION ACTION HCTP PERFORMED
THE SAME BASIC FUNCTION IN THE
DONOR. IT IS IMPORTANT TO
REMEMBER CLINICAL EFFECT OF
TISSUE THAT ARE NOT ALSO BASIC
FUNCTION OF THE TISSUE IN THE
DONOR, ARE NOT CONSIDERED BASIC
FUNCTIONS. THIS MEANS BECAUSE
SOMEONE DEMON INVESTIGATORY HUE
CAN PERFORM FUNCTION IN THE
RECIPIENT, THIS DOESN'T MEAN THE
FUNCTION IS NECESSARILY BASIC
FUNCTION. SO NEEDLESS TO SAY IF
YOU HAVE A PRODUCT THAT IS
INTENDED FOR TREATMENT OF
MEDICAL CONDITIONS LET ALONE A
MYRIAD OF DIFFERENT CONDITIONS,
THE SAME PRODUCT HCTP IS NOT
INTENDED FOR HOMOLOGOUS USE. I
PROMISED TO SHOW YOU GUIDANCE
AND I THINK THE FOUR GUIDANCES
THAT ARE HERE IN THE BULLETS ARE
MUST READ FOR FOLKS WHO ARE
DEVELOPING PRODUCTS, THE LINK ON
THE SLIDE WILL TAKE YOU TO OUR
WEBSITE WHERE YOU CAN FIND OTHER
GUIDANCE FOR DIFFERENT DISEASE
AND CONDITIONS AND OTHER
PRODUCTS THAT REGULATE NOT
NECESSARILY CELLULAR PRODUCTS
ALONE AS WELL AS ADDITIONAL
GUIDANCE ON THE TISSUE BECAUSE I
RECOGNIZE WE ARE TALKING ONLY
ABOUT ONE GUIDANCE TODAY. BY
POPULAR DEMAND. SO THIS LOOKS
LIKE MY LAST SLIDE. THANK YOU
FOR YOUR ATTENTION. HERE IS MY
EMAIL AND THE CONTACT
INFORMATION FOR THE OFFICE IF
YOU HAVE ANY QUESTIONS DO NOT
HESITATE TO SEND YOUR QUESTIONS
AND ASK THEM AND WE ARE
DEVELOPING MORE ONLINE RESOURCES
FOR STAKEHOLDERS PUBLISHED IN
THE UPCOMING YEAR. THANKS AND
GLAD TO JOIN DISCUSSION.
>>THANK YOU SO MUCH. PRETTY
CLEAR IN OUR DISCUSSION WE ARE
NEEDING BETTER CHARACTERIZATION,
WE ARE NEEDING TO KNOW BETTER
WHAT WE ARE GIVING PATIENTS SO
ALL THOSE AMOUNT TO DOING MORE
QUOTE UNQUOTE MANIPULATION AND
YOU GET ALL THE WAY UP TO WHAT
DR. GUILAK SHOWED WHERE IT IS A
VERY INTRICATE CELLULAR ENGIN
ENGINEERING SO I WOULD SAY IT IS
PROBABLY IMPORTANT FOR US TO AS
SCIENTISTS TO WALK AWAY FROM
THIS 361 AS A -- I THINK THAT
THAT HAS BEEN A I ALMOST WANT TO
SAY LOOP HOLE WHERE SO MANY
PRODUCTS SO TO SPEAK HAVE GONE
OUT TO THE COMMUNITY AND FOR US
TO START THINKING WE NEED TO GO
BACK TO BASICS AND SAY WHAT
PATHOLOGY AND PATHOGENETIC POINT
ARE WE TRYING TO CONVENE AT AND
HOW IS THIS A BIOLOGIC -- WE ARE
TALKING BIOLOGICS BUT WHERE IN
THAT PATHWAY IS THIS BIOLOGIC
INTENDED OR WE THINK IT ACTS
BASED ON RESEARCH WE HAVE DONE
IN PRE-CLINICAL MODELS IN VITRO
AND MOVE INTO CLINICAL
TRANSLATION. I DO WANT TO GET A
SPECIFIC CLARIFICATION REGARDING
PRP. WIDELY USED AND REALLY THE
PRP AS YOU MENTION, IS COVERED
UNDER BLOOD. THE WHOLE INTENTION
WAS FOR TRANSFUSION WITH PRP
BEING DISCUSSED BECAUSE IT IS AN
INTERMEDIATE STEP IN THE
CREATION OF FRESH FROZEN
PLATELETS. FFP AND PLATELET
CONCENTRATE. WHY DOES PRP
FOLLOW? BECAUSE USE IS OUT
THERE, GREATLY EXCEED ANYTHING
EVER IMAGINED FOR
TRANSPLANTATION -- BLOOD
TRANSFUSION.
>>WE DO HAVE BOTH ID
INVESTIGATIONAL DEVICE
APPLICATIONS ANDVATIONAL MU DRUG
APPROXIMATE -- INVESTIGATIONAL
DRUG APPLICATIONS PRP. WHEN IT
WAS INTENDED FOR TREATMENT FOR
DISEASE MEDICAL CONDITIONS WE
LOOK AT THOSE PROGRAMS.
OSTEOARTHRITIS IT IS ONE THING
USED FOR WOUND HEALING. SO WE
HAVE INVESTIGATIONAL DEVICE
EXEMPTION APPLICATIONS FOR POINT
OF CARE DEVICE PRP DEVICE COULD
BE PRODUCED IF IT HAS EFFECTS ON
WOUND HEALING FOR OTHER DISEASES
OR CONDITIONS WE SEE THOSE
DEVELOPMENT PATHWAYS AND
EVALUATIONS AND INVESTIGATION
DONE WITH PRP. CURRENTLY OUR
USE IN OSTEOARTHRITIS FALLS
UNDER A -- PHYSICIAN DISCRETION?
HOW WOULD YOU FROM FDA
STANDPOINT CHARACTERIZE THE
BASIS FOR USE IN OSTEOARTHRITIS
>>I DON'T USE IT IN
OSTEOARTHRITIS SO -- IT WOULD BE
INTERESTING TO UNDERSTAND WHAT
YOU ARE TELLING TO YOUR PATIENTS
WHEN YOU ARE OFFERING THEM THIS
TREATMENT WHETHER -- HOW DO YOU
EVEN SAY IT WOULD BE WORKING FOR
THEM AND I RECOGNIZE YOU
PROBABLY AS YOU EXPLAIN SEE THE
EFFECT WOULD BE VARIABLE IN THE
ABSENCE OF GOOD INVESTIGATION
ANY QUANTIFICATION POTENTIALLY
COULD BE AFFECT OF THIS
TREATMENT OF THE DISEASE YOU ARE
TREATING, IT IS HARD TO SAY, I
WOULD BE INTERESTED TO HEARD
WHAT YOU HAVE TO SAY BECAUSE YOU
ARE USING IT.
>>PRIMARILY IN CONTEXT OF MY
RESEARCH PROJECT. WE SAY TO
PATIENTS THAT WE DON'T KNOW WHAT
THE AFFECTS ARE. THOSE WHO I AM
TREATING SO PEOPLE WHO VOLUNTEER
BUT WE FIND THEY DON'T MEET
CRITERIA FOR THE STUDY IF THEY
DON'T HAVE MEDICAL
CONTRAINDICATIONS WE ARE GIVING
THEM INCORRECTION FOR JUST AS A
COURTESY. PRIMARILY MY INTEREST
IS IN OUTCOMES RESEARCH, IT IS
WIDELY USED, IT IS VERY, VERY
WIDELY USED. IT SOUNDS LIKE IT
IS BASICALLY WOULD YOU SAY OFF
LABEL? THERE IS NOT A LABEL
>>YEAH.
>>NO CHARACTERIZATION.
>>I WAS ALWAYS TOLD THE DEVICE
IS CLEARED DON'T GET IT BEYOND
THAT. IT MAKES IMPORTANT POINT
CHOCK RAN MADE ACCURATE POINT
PRP IS A LOT OF THAT DATA THAT
WORKS. AT THE SAME TIME THIS IS
USED, USED EVERYWHERE. NO DOUBT
TOO MUCH. PERHAPS OFTEN,
INDISCRIMINATELY, THE REALITY IT
IS USED. OKAY, THIS IS
ACCEPTABLE, THAT TRAIN LEFT THE
STATION. HOW TO WE STILL
CONTINUE TO STUDY PRP IN OUR
CLINICAL TRIALS. RECOGNIZE WE
USE AS CONNIE SAID VERY WIDELY.
TAKING CARE OF ATHLETES I SEE IT
ALL THE TIME. THE EXPECTATION,
SPEND MORE TIME TALKING TO
AGENTS PLAYERS AND MANAGERS OUT
OF IT OR WHY WE DON'T KNOW WHAT
IT DOES. THAT IS THE CLINICAL
SIDE OF THINGS, IF YOU WANT TO
UNDERSTAND.
>>I UNDERSTAND COMPLETELY. THAT
IS ANOTHER IN RESPONSE TO THE
QUESTIONS FOR THE ROUND TABLE.
IT IS A CERTAIN THINGS FOR USE
IN CLINICAL PRACTICE AND PEOPLE
HAVE NO IDEA WHAT THEY DO, WHAT
IS THE EFFICACY, I THINK WE OWE
THIS TO OUR PATIENTS, TO -- WHEN
WE GIVE THEM SOMETHING AS
TREATMENT WHEN WE PROMISE TO
TAKE CARE OF THEM AND HELP THEM
TO GIVE THEM PRODUCTS OR
TREATMENTS THAT ARE PROVEN
EFFECTIVE. WE ARE NOT HARMING
THEM.
>>AGREE. THERE ARE SOME HANDS
RAISED WE SHOULD GO THROUGH.
>>YES.
>>GEORGE.
>>FASCINATING DISCUSSION. I WAS
TRYING TO DECIDE WHETHER CONNIE
WAS GOING TO GO TO JAIL OR NOT.
SOMEWHERE THROUGH THIS PROCESS.
I'M WONDERING, I'M A CLINICIAN,
WE HAVE A PROGRAM JOINT
PRESERVATION CENTER WE DON'T
TALK ABOUT STEM CELLS, THAT PRP
PREPARATION IS APPROPRIATION OF
PATIENT OWN TISSUE. I DON'T
THINK PRP BEING IN A PRODUCT IS
THE DEVICE, IT IS THE PRODUCT
THEY OFFER, THE PROCESS TO
PREPARE THE PRP. AS AICALLY IN
ADDITION CLINICIANS CAN TAKE
SKIN FROM ONE PART OF THE
PATIENT BODY AND PUT IT IN
ANOTHER PART OF THE PATIENT BODY
AND TAKE FASCIA FROM ONE PART
AND USE IT FOR SOME OTHER
PURPOSE TO REPAIR ANOTHER TISSUE
AND ANOTHER PART OF THE PATIENT
BODY. LONG AS YOU ARE NOT NOT
MISROPINGSING WHAT YOU ARE DOING
AND WHY OR EXPERIMENTING WITH
THE INTENT GENERALIZABLE
INFORMATION, MY UNDERSTANDING AS
A CLINICIAN IS THIS IS PART OF
PRACTICE AND OUR OBLIGATION IS
TO BE STRAIGHT FORWARD AND
HONEST. IN OUR CASE WE HAVE A
REGISTRY, WE LOOK AT DATA, I
TELL PEOPLE THAT YOUR -- IF I
DID A KNEE REPLACEMENT WOULD BE
PROBABLY BETTER THAN PRP
INJECTION ON YOU BUT DATA
SUGGESTS SIX MONTHS AFTER PRP
INJECTION YOU ARE BETTER THAN
YOU ARE NOW WITH A HIGH
PROBABILITY, 80%. SO YOUR CHOICE
DELAYED SURGERY OR CONSIDER
USING THE PRP. THAT IS BASED ON
OUR OWN DATA. I WILL NARROW
THIS JUST TO A QUESTION. IT IS
-- IS THERE A FRAMEWORK WITH FDA
THAT SAYS THIS IS A PART OF
PHYSICIAN PATIENT RELATIONSHIP
AND PHYSICIAN DISCRETION AND THE
PRIMARY PLACE YOU REGULATE IS
HOW PEOPLE DESCRIBE AND MARKET
RATHER THAN THE ACTUAL DELIVERY
OF PRP BY A PHYSICIAN.
>>I THINK YOU ACTUALLY TOUCHED
UPON NUMBER OF TOPPINGS AND YOU
STARTED WITH SKIN TO SKIN OR
FASCIA FOR FASCIA. WHERE WILL IS
TRANSPORTATION OR RECONSTRUCTION
OF CLINICAL DEFECT. OR CORONARY
ARTERY BY SURGERY, TAKING
SOMEONE'S VEIN AND PUTTING IT
DIFFERENT PLACE TO HELP
CIRCULATION. THESE ARE THE TYPES
OF SITUATIONS WHERE OBVIOUSLY
THIS IS PART OF CLINICAL
PRACTICE AND THESE ARE TYPES OF
SITUATIONS WHERE THE TISSUE
WOULD APPLY. WHEN WE ARE TALKING
ABOUT GIVING SOME KIND OF
CELLULAR PREPARATION FOR THE
TREATMENT OF MEDICAL CONDITION,
IT IS AN ENTIRELY DIFFERENT
FRAMEWORFRAMEWORK COMPLETELY DIT
SITUATION FROM REGULATORY
PERSPECTIVE H. PRP PRODUCTS ARE
USED. AND THEY ARE USED IN
VARIOUS SETTINGS. NUMBER OF
DEVICES THAT HAVE BEEN SENT TO
US AS APPLICATIONS FOR USE OF
PRP IN DIFFERENT SETTING SETTIN.
COUNSEL ONCE WE SEE
INVESTIGATIONS AND THE DEVICE IS
IN CLEARANCE AND APPROPRIATE
QUALIQUALITY. AS AS LONG AS THE
INVESTIGATIONS ARE ALSO ETHICAL
AND CONDUCTED APPROPRIATELY IN
THE INTEREST OF PATIENTS THIS IS
ONE PATHWAY WHERE PRP COULD
POTENTIALLY FALL INTO -- THIS IS
SOMETHING WE DO. THAT WAS
ANSWERS THE QUESTION. IS PATIENT
DOCTOR RELATIONSHIPS FROM THE
NOTION OF WELL CAN WE STEM CELLS
IN THE BATHROOM SOMEWHERE AND
UNDER THE PATIENT RELATIONSHIP
OFFER IT BECAUSE WE BELIEVE WE
WOULD WORK PRP. BECAUSE THAT IS
PATIENT DOCTOR RELATIONSHIPS CAN
INCLUDE LOT OF THINGS. AGAIN WE
OWE THIS TO OUR PATIENTS TO GIVE
THEM PRODUCTS THAT ARE BEST
QUALITY WE KNOW.
>>ANALOGOUS, THE ANALOGOUS IS
ASPIRIN. ASPIRIN WE PRESCRIBE
ASPIRIN FOR LOTS OF THINGS AND
GRANTED THERE'S DATA BUT IF
ASPIRIN WAS ALREADY IN USE AND
ALREADY DOCUMENTED FOR LOTS OF
THINGS BUT FOR -- ANYWAY, THAT'S
A LITTLE STUFF. LET ME TURN
THINGS OVER TO SHANE.
>>SHANE, YES.
>>I WANTED TO GO BACK TO THAT
CONVERSATION THAT WE HAVE WITH
PATIENTS AND HOW IMPORTANT AND
VALUABLE AND HOW IN THAT
DISCUSSION AND SHARED DECISION
MAKING, WE COMMONLY DON'T
EXPLAIN MANY TREATMENTS, NO
PATIENT ASKS HOW TYLENOL WORKS
TO RELIEVE PAIN. THAT IS
SOMEWHAT WHAT GEORGE IS SAYING
WITH ASPIRIN. WE BELIEVE PRP HAS
A THERAPEUTICS AFFECT AND I ALSO
WANTED TO AT LEAST HIGH LIGHT
THERE MAYBE A LITTLE
DISAGREEMENT IN THE PANEL AND IN
TERMS OF STATE OF THE CURRENT
EVIDENCE BECAUSE THERE'S BEEN A
NUMBER OF WELL DESIGNED TRIALS
NOT ALL WHICH ARE POSITIVE
CERTAINLY SOME OF WHICH ARE
NEGATIVE BUT DO -- HAVE BEEN
ANALYZED SYSTEMATICALLY AND META
ANALYSES TO SEE THERE IS A
THERAPEUTIC EFFECT AND SYMPTOM
MODIFYING EFFECT FOR PRP. THAT
SAME EVIDENCE DOESN'T EXIST
NUMBER OF THE OTHER BIOLOGICS
DISCUSSED TODAY, THERE IS A
REASONABLE EVIDENCE BASED TO
HAVE THAT CONVERSATION WITH
PATIENTS SO THAT BRINGS BACK
AMYE TO THE CONVERSATION AND
PATIENT ADVOCACY COLLEAGUES
BECAUSE WHEN WE HAVE THESE
CONVERSATIONS WITH PATIENTS THIS
IS SOMETHING MY GROUP STUDY
EXTENSIVELY WITH MY BIOETHICAL
COMPLYINGS IN TERMS OF WHAT IS
THE PATIENT UNDERSTANDING OF HOW
BIOLOGIC THERAPIES WORK AND
PATIENTS THAT COMING IN M AS DR.
RODEO SAID, ATHLETES, LOOKING
FOR THESE TREATMENT, WHAT CAN
THEIR UNDERSTANDING AND CAN THEY
EVEN UNDERSTAND THE BIOLOGY WE
ARE ALL TALKING ABOUT HERE
ENOUGH TO GIVE INFORMED CONSENT
FOR TREATMENT OF THIS. THESE ARE
COMPLEX CONVERSATIONS THAT EVEN
IF WE DID KNOW EXACT MOLECULAR
MECHANISM OF HOW PRP RELIEVED
PAIN, IT IS UNLIKELY PATIENTS
WOULD BE ABLE TO UNDERSTAND IT
ENOUGH FROM INFORMED CONSENT
STANDPOINT. THAT IS THE JOB OF
THE CLINICIAN TO SYNTHESIZE IN
THE CLINICAL EVIDENCE AND THEN
BRING IT DOWN TO LEVEL OF
PATIENT UNDERSTANDING SO YOU CAN
HAVE APPROPRIATE INFORM CONSENT,
IT IS OUR JOB HERE IN THIS GROUP
AND PANEL AND SCIENTIFIC
COMMUNITY TO FIGURE HOW IT IS
THEY WORK. THAT IS DIFFERENT
THAN HOW WE TALK TO OUR
PATIENTS. THANK YOU. CRITICALLY
IMPORTANT ON WHICH PATIENT,
WHICH IS MOST LIKELY TO BENEFIT
BECAUSE WE ALL HAVE SEEN
PATIENTS WHO HAVE IMPROVED
FOLLOWING PRP TREATMENT BUT IT
ISN'T EVERYONE. GOING BACK TO --
SO NOBODY THINKS THAT'S AN --
BATS AN EYE ABOUT THE LONG
HISTORY OF CORTICOSTEROID
INJECTIONS. THAT IS ALMOST IN
PRIMARY CARE, THAT IS ALMOST THE
FIRST LINE INJECTION TREATMENT
BUT EVEN GOING BACK TO DR.
HINCH'S WORK, CLEARLY VERY
CLEARLY IN HIS ORIGINAL PAPER
FROM HIS NOBEL PRIZE HE SAYS IT
DOESN'T ALWAYS HELP IN
OSTEOARTHRITIS. THAT REFLECTS
THE DIVERSITY OF OA DISEASE
STATES WHICH WE HAVE TALKED
ABOUT VERY IMPORTANT, IT IS
SOMETHING I DO CLARIFY WITH MY
PATIENTS THAT I -- IT IS NOT THE
DATA SHOWS OVERALL SO I CAN
SPEAK ON MY OWN DATA HAS, I SHOW
MAIN BENEFIT. NOT EVERYBODY HAS
IMPROVED. THEY HEAR THAT. MOST
PEOPLE COMING IN, SCOTT
MENTIONED, THEY HAVE GOT ONE
THING ON THEIR MIND, I THINK
THAT THE PRP WILL BE BETTER THAN
THE OTHER INJECTIONS ALREADY. IF
A NUMBER OF THEM COME BACK VERY
HAPPY BUT IT IS NOT EVERYONE AND
IT IS OUR JOB TO FIGURE OUT TO
BETTER DEFINE DIFFERENT OA
DISEASE STATES AND WITH
THERAPYINGS MAY BE MORE
APPROPRIATE. FOR PEOPLE IN
DIFFERENT STATES OF DISEASE. --
THERAPIES.
>>I'M SORRY, GO AHEAD AMYE.
>>I WANT TO ADD TO THIS
CONVERSATION ABOUT STEM CELLS
AND PRP FROM THE PATIENT ANGLE.
HEARING TODAY, I THINK THE ONE
PIECE OF INFORMATION I BELIEVE
MARK INDICATED IS THAT DOD, THE
VA, ARTHRITIS FOUNDATION AND
AMERICAN COLLEGE OF RHEUMATOLOGY
EACH HAVE PUT OUT GUIDELINES
THAT SAY NOT RECOMMENDED. I
FOUND THAT SHOCKING IN THE SENSE
OF NUMBER ONE, CONSISTENCY AND
PROMPTED ME PROBABLY 25
QUESTIONS WHEN THE LAST TIME
THIS WAS DONE, THIS IS A
EMERGING FIELD, WHAT ARE
PATIENTS ASKING IN PARTICULAR.
IN MY EXPERIENCE IT COMES TO
TRUST BETWEEN CLINICIAN AND
PATIENT. A TYPICAL QUESTION I AM
ASKED AS IF I WERE THE HEALTH
CLINICIAN. IF I WERE YOUR
DAUGHTER WOULD YOU RECOMMEND
THIS TO YOUR DAUGHTER, WOULD YOU
RECOMMEND IT TO ME. DIDN'T COME
DOWN TO PROCESS, EQUIPMENT,
THERE WAS AN ASSUMPTION AND A
HUGE LEAP ABOUT WELL, IT IS MY
BLOOD. THEREFORE MUST BE OKAY.
SPIN OUT THE BAD STUFF AND KEEP
THE GOOD STUFF AND THAT WILL
HELP ME. WE DO THE COLLECTIVE WE
BECAUSE I DON'T AGREE WITH IT,
IT IS ALL GOING TO GO -- COME
FROM AND GO BACK TO THE
CLINICIAN. MAKING SURE A BODY
LIKE THIS AT NIAMS WORKING WITH
THE FDA HOW IS THE BEST WAY
COCHARACTERIZE THIS, TO LOOK AT
THE DIFFERENT IMPORTANT ASPECTS
OF THAT TO LOOK FOR CONSISTENCY
LONGEVITY, QUALITY, ALL THINGS
WE HAVE BEEN TALKING ABOUT TODAY
ARE INSTILLED INTO THIS ONE
PARTICULAR POTENTIAL, IT HAS A
LIFE OUTSIDE THE OFFICE KIND OF
SCENARIO. IS I DON'T WANT TO
SAY CONTAINED BUT MANAGED FROM
SYSTEMATIC PROCESS, DR. CHU,
CONNIE WAS TALKING ABOUT, TO BE
SYSTEMATIC. I THINK THAT IS THE
MOST IMPORTANT THING. WOULD I
GET IT? THE WAY I FEEL LIKE NOW,
NO.
>>ASK ME NEXT MONTH.
>>THANK YOU, THIS IS IMPORTANT
FOR ALL OF US TO HEAR. BECAUSE
IF WE WERE TO PROPOSE OR OFFER
TREATMENTS TO PATIENTS WE WANT
TO AT LEAST SEE GOOD CLINICAL
TRIALS DONE WITH THESE
TREATMENTS, DEMONSTRATING THAT
THE TREATMENTS ARE EFFECTIVE.
AND THEY'D ARE SAFE. ANECDOTAL
CASES OF EFFECTIVENESS EXIST
WITH EVERYTHING. INCLUDING
NORMAL SALINE BUT WHEN WE OFFER
AGAIN TREATMENTS PARTICULARLY
INJECTABLE TO PEOPLE WE NEED TO
MAKE SURE THEY ARE EFFECTIVE AND
WE CAN'T MAKE SURE THEY ARE
EFFECTIVE BASED ON THE EVIDENCE
THAT IS OUT THERE THAT'S
CONTROVERSIAL OPEN LABEL EARLY
STUDIES SMALL STUDIES. MANY CASE
SERIOUS, WE NEED GOOD TRIALS,
THAT IS ANOTHER I GUESS -- GAP
IN THE FIELD WHEN YOU PUT TRIALS
AND QUALITYVA QUALITY INVESTIGAO
SHOW WHATEVER PRODUCT WE BELIEVE
HAVE POTENTIAL, GREAT POTENTIAL
IN THEIR APPLICATION REALLY
UPHOLD TO THE LEVEL OF EVIDENCE
WE ARE WORKING FOR AND LEVEL OF
BENEFIT PATIENTS ARE WORKING FOR
IN THESE PRODUCTS.
A GOOD SEGUE TALKING ABOUT
THE DISCUSSION, THE FIRST
DISCUSSION QUESTION IS A HUGE
QUESTION WHAT EVIDENCE SUPPORTS
SAFETY AND EFFICACY OF THE
CLINICAL USE STATES OF THE ART
REGENERATIVE THERAPY FOR KNEE
OA. THIS PARTICULAR QUESTION IS
EXTREMELY LARGE BUT OUR
DISCUSSION UP TO THIS POINT ON
PLATELET RICH PLASMA IS COVERED
SOME OF THE ANGLES AND I AM
GOING TO PUT OUT THAT I WOULD
FAVOR MAYBE A LITTLE BIT
ADDITIONAL DISCUSSION ON THIS
BUT SPENDING MORE TIME ON WHAT
ARE THE EMERGING AND --
QUESTIONS 2 AND 3.
TALKING ABOUT EMERGING
APPROACHES IN AREAS OF RESEARCH
OFFERING NEW OPPORTUNITIES FOR
CARTILAGE PRESERVATION AND
RESTORATION IN KNEE OA. I WOULD
FAVOR SPENDING MORE TIME ON THAT
BECAUSE OVERALL SUMMATION OF
CLINICAL EVIDENCE FOR MOST
COMMON ORTHO BIOLOGICS AS WE
HAVE DISCUSSED WITH PRP VERY,
VERY IMPERFECT AND PRP TREATMENT
OF KNEE OA AS DR. SHAPIRO
MENTIONED HAS ARGUABLY THE
LARGEST BODY OF EVIDENCE. I
WILL THROW OUT MY OPINION HOW
MUCH TIME WE SHOULD SPEND ON
THIS AND WHETHER TO MOVE TO THE
NEXT QUESTION.
>>AGREE, CONNIE, WE SPENT A LOT
OF TIME ON QUESTION ONE, SAFETY
AND EFFICACY, I THINK WE CAN ONE
PART PUT IT TO BED. SAFETY,
MOST AUTOLOGOUS SEEM TO BE SAFE.
SO SECOND PART OF THE QUESTION
IS WHERE WE NEED DATA EVE DA
SCHISM WHAT SUPPORTS EFFICACY OF
AT LEAST OF THESE THERAPIES. WE
CAN DISCUSS THAT THE LAST FOUR
OR FIVE HOURS DATA IS THERE,
MIXED AT BEST. MODEST AT BEST.
QUESTIONS TWO AND THREE, IF
SOMEONE CAN PUT THEM IN THE
CHAT, THE MEAT OF THE
DISCUSSION. AS FAR AS PLANNING
MOVING FORWARD. EMERGING
APPROACHESES IN YARRS OF
RESEARCH OFFERING NEW
OPPORTUNITIES. WE DISCUSS,
EXOSOMES OR GENE THERAPY OR
APPROACHES WE HAVE HEARD NOVEL
APPROACHES, HAVE A DISCUSSION
HOW WE MOVE FORWARD TO FURTHER
EVALUATE THESE INNOVATIVE OR
EMERGING APPROACHES. WE PRPs
IN CELLS PRETTY GOOD NOT THAT
THERE AREN'T OUTSTANDING
QUESTIONS BUT WHAT IS NEXT ON
THE HORIZON?
>>YEAH. SHOULD WE TALK --
SHOULD WE FLIP THAT AND ACTUALLY
TALK ABOUT BECAUSE WE ARE
TALKING ABOUT CLINICAL
EVALUATION. SO OR WE CAN JUST GO
IN ORDER BUT REALLY THERE ARE
CHALLENGES AND GAPS, IN THE
CLINICAL EVALUATION OF CLINICAL
OUTCOMES THAT IS A MAJOR
IMPEDIMENT TO US HAVING THE
EVIDENCE WE NEED TO BASE OUR
TREATMENT DECISI DECISIONS BUT N
ORDER TO QUESTION TWO. DOES
JENNIFER, DID YOU HAVE SOMETHING
TO SAY?
>>I WANT TO BRING UP A POINT
THAT POTENTIALLY RELEVANT FOR
ALL THEM. T WE TALKED TODAY
ABOUT UNDERSTANDING THERAPEUTIC
MECHANISMS, BETTER CLINICAL
TRIALS BETTER THERAPIES. IT IS
STILL GENERAL THERAPIES THAT WE
THINK ABOUT, FIELDS SUCH AS
CANCER HAVE COMBINATION
THERAPIES THAT ARE REALLY MAKE A
HUGE DIFFERENCE, THINKING ABOUT
CELLS IN IMMUNE SYSTEM HANDLE
IMMUNE STROMAL COMMUNICATION
WHETHER IT BE STEM CELLS, OTHER
STROMAL PARTS THEN TALK IMMUNE
RESPONSE. WE HAVE SHOWN THIS
POSITIVE FEEDBACK LOOP YOU CAN
HIT ONE BUT THEN NOT -- THEY ARE
GOING TO FORM BECAUSE YOU ARE
NOT HITTING BOTH OF THE
PATHWAYS. I REELIZE THIS
INCREASES COMPLEXITY OF CLINICAL
TRIALS AND IF I BRING IT UP TO
PEOPLE THEY JUST SAY IT IS NOT
POSSIBLE TO DO THIS TYPE OF
TRIAL REGULATORY PATHWAYS TOO
DIFFICULT BUT I THINK IT IS
POTENTIALLY CRITICAL FOR THE
FIELD.
>>THANK YOU, DEFINITELY AGREE.
WITH SOMETHING COMPLEX AS OA, WE
NEED TO TAKE A SYSTEMS BASED
APPROACH, JOHNNY HAS DONE SOME
CLINICAL TRIALS WHERE HE TRIED
TO DO SOME COMBINATION THERAPIES
AND HE HAS HIS HAND UP.
>>I AGREE WITH JENNIFER, WE
TALK ABOUT CARTILAGE BUT I THINK
A LOT OF WORK BEING DONE AT
CELLULAR SENESCENCE HAVE SHOWN
SENESCENCE CELLS ARE DETRIMENTAL
FOR CARTILAGE AND MAYBE IN THIS
CASE ELIMINATE THEM AND THIS IS
KIND OF WHEN WE THINK ABOUT
(INAUDIBLE) WE THINK ABOUT PRP
OR BMAC OR STEM CELLS SINOLITIC
DRUGS CAN BE USED TO SENESCENCE
CELLS. THEY DON'T HAVE TO BE USE
ALONE, THEY CAN BE USED IN
CONJUNCTION WITH STEM CELLS. AND
ALSO I WANTED TO SAY FIBROSIS
HAS BEEN A BIG PROBLEM FOR
SKELETAL MUSCLE BUT TURNS OUT
CARTILAGE REPAIR LEAD TO FIBER
CARTILAGER WE THINK IS FIBROSIS
AND CARTILAGE NOW APPROACH BLOCK
TGF BETA 1 REDUCE TGF BETA 1 NOT
ELIMINATE BUT REDUCE IT IN
CARTILAGE REPAIR. SO WHAT WE
HAVE STARTED, IN THE CLINIC, I
WANT TO MAKE FINAL POINT ABOUT
THE FACT WHEN A PATIENT COME AND
SEE A SURGEON AND HE IS THINKING
ABOUT JOINT REPLACEMENT, IT IS
NOT BECAUSE HE DOESN'T HAVE ANY
CARTILAGE IN HIS KNEE. IT IS
BECAUSE HE HAS PAIN. WE NOW KNOW
STEPS CLEARLY YOU DON'T TREAT
KNEE OA YOU TREAT THE PAIN. THEY
WOULD LITTLE CARTILAGE SOMETIMES
AND HAVE NO PAIN. SO WHAT HE
WHICH TRUE TO DO, IS DELAY JOINT
REPLACEMENT AS LATE AS POSSIBLE
BECAUSE WE ALL KNOW THAT IF YOU
GET A JOINT REPLACEMENT AT 55
YOU'RE GOING TO NEED ANOTHER
NEED OR HIP AT 75. SO FOR US WE
ARE TRYING TO SAY WELL, CAN WE
CUT THE PAIN, CAN WE DEVELOP A
CONSERVATIVE TREATMENT TO TRY TO
DEAL AS LONG AS POSSIBLE THE
KNEE OR THE HIP REPLACEMENT.
THIS IS WHAT WE HAVE DONE SO WE
MOW BMAC IS NOT STEM CELL
THERAPY, IT CONTAINS SOME STEM
CELLS AND CONTAIN A LOT OF
FACTORS SO WHAT WE DID IS
COMBINE DM AC TO REDUCE SCAR BUT
AT THE SAME TIME WE EWE
XENOLYTIC AGENT TO REDUCE
SENESCENCE SO WE REDUCE
INFLAMMATION IN THE CONTEXT OF
OA, REDUCE IT WITH SINOLITIC
TREATMENT, WE INJECT DMAC WITH
FACTORS IN IT AND AFTER THAT
BLOCK THE FIBROSIS. THE GOAL IS
TO TRY TO DELAY LONG AS POSSIBLE
JOINT REPLACEMENT. THAT IS
SOMETHING VERY IMPORTANT BECAUSE
PEOPLE DOESN'T COME AND SEE YOU
AND SAY I DON'T HAVE CARTILAGE
IN MY KNEE, CAN YOU PUT IT BACK
IN? THAT WOULD BE AWESOME BUT
RIGHT NOW PEOPLE ARE TRYING TO
DELAY THIS JOINT REPLACEMENT AS
LONG AS POSSIBLE.
>>I WOULD AGREE WITH THAT. I'M
ON MUTE.
>>WE CAN HEAR YOU.
>>I HAVE HAD TWO KNEES THAT
EAST LASTED 28 YEARS. THE FACT
THAT I'M FIVE FOOT ONE, VERY
PETITE, ASIAN, AS YOU MIGHT
THINK, AND DON'T EAT A LOT OF
DAIRY, NO ONE TOLD ME EARLY ON
EVER THAT NUTRITION THAT MY
JOINTS AND MY BONES NEEDED ALONG
THE WAY. I THINK THAT IN TODAY'S
HOPEFULLY FAMILY STANDARDS
THAT'S DIFFERENT BECAUSE WE ARE
VERY NUTRITIONALLY CONSCIOUS NOW
SO THAT CAN BE USED TO OUR, I
SAY OUR, THOSE WHO TRY TO KEEP
PEOPLE MEDICALLY STRAIGHT, IF
YOU WILL AND HEALTHY THAT IS ONE
OF MY BIG ISSUES DOING SPEECHES
JUST TO PATIENTS, IS EVERY
ASPECT THOSE KINDS OF THINGS
THEY CAN CONTROL, LIFESTYLE, YOU
EATING SLEEPING STRESS
MANAGEMENT, YOUR WORK LIFE YOUR
FAMILY LIFE YOUR CHILDREN,
CHILDREN'S LIVE, HOW YOU ARRANGE
YOUR DAY, ET CETERA, ET CETERA.
IF DR. CHU WERE TO ASK ME AND
DR. RODEO ASK ME AMYE, WHAT ARE
EMERGING OPPORTUNITIES TO GO
INTO FROM A PATIENT PERSPECTIVE?
I WANT TO AVOID HAVING TO GO TO
DR. HUARD TO GET A JOINT
REPLACEMENT BUT I DON'T KNOW I
WAIT TOO LONG BY THE TIME THAT
HAPPENS. BECAUSE WHEN PAIN
EMERGES IT IS SEVERE. I WOULD
LIKE TO KNOW EARLIER ON FROM A
SELF-ASSESSMENT, THIS CAN BE
WRAPPED AROUND JOINT YOUR
FINGER, WRAPPED AROUND YOUR
WRIST ELBOWS SHOULDERS ANKLE, I
HAVE HAD JOINT REPLACEMENTS IN
ALL THOSE THAT TELL ME YOU ARE
WAITING TOO MUCH ON THE LEFT
SIDE OF YOUR LEGS VERSUS THE
RIGHT SIDE YOU ARE USING YOUR
LEFT ARMOR THAN USING THE RIGHT
ARM. THERE IS BODY MECHANICS
ACTIVITIES THAT MAY OR MAY NOT
BE, HAS TO BE PROVEN FIRST, MAY
OR MAY NOT BE HELPFUL BUT
TECHNIQUES AND STRATEGIES CAN
HELP THE PATIENT DETERMINE HOW
SOON OR LATE THEY CAN COME TO
YOU FOR THAT KIND OF HELP. FROM
ORTHOPEDIC STANDPOINT I NEVER
ENCOUNTERED THAT. EVERY TIME I
DO IT IS ALWAYS YOU WAITED LONG
ENOUGH TO GET HER HERE. THAT WAY
CHOICE BECAUSE OF WHAT YOU SAID
THEY DON'T LAST THAT LONG SO YOU
WANTED TO GET AS GREAT MILEAGE
AS YOU CAN. SO DELAY AS MUCH AS
POSSIBLE. WHICH ARE TALKING
QUALITY OF LIFE, THE ABILITY FOR
ME TO ACCOMPLISH MY GOALS AND
OBJECTIVES IN LIFE. THAT IS WHAT
I WISH.
>>THANK YOU. SYSTEMS BASED
APPROACH, LOOKING AT SYSTEMIC
FACTORS, LIFESTYLE, LOOKING AT
XENOLYTICS, COMBINATION THERAPY.
WHAT ELSE? ALONG THE LINES OF
NEW APPROACH?
>>JOHNNY, NICE COMMENTS ABOUT
COMBINATION APPROACHES,
COMBINING XENOLYTICS OR TGF BETA
INHIBITION WITH OUR BIOLOGIC DU
JOUR. THREE HANDS RAISED, WE'LL
START WITH DR. BARRY.
>>THANKS. I WANTED TO MENTION
CONTEXT OF EMERGING TECHNOLO
TECHNOLOGIES, USE OF INDUCED
PLURIPOTENT STEM CELLS AS
MODALITY TO EXPLORE, MANY
PROBLEMS THAT WE TALKED EARLIER
IN TERMS OF CONSISTENCY AND
CHARACTERIZATION OF CELLS, MANY
PROBLEMS COULD POTENTIALLY GO
AWAY IF WE START USING INDUCE
PLURIPOTENT STEM CELLS AS
THERAPEUTIC. WE ARE EARLY DAYS
OF THAT YET. ALSO THE USE OF
IPSCs IN MODELING HASN'T
HAPPENED NEARLY AS MUCH IN
ORTHOPEDIC FEE AS IT HAS IN
NEUROLOGY AND THERE'S TREMENDOUS
OPPORTUNITIES FOR DEVELOPING NEW
ASSAYS AND NEW MODELS, DISEASE
SPECIFIC MODEL USING IPSC WE CAN
EXPLORE
>>IPS INDUCED PLURIPOTENT
CELLS, SCALABILITY,
MANUFACTURING SCALABILITY, ALL
THESE THINGS.
>>FIRST THEY PLURIPOTENT,
SECONDLY POTENTIALLY HAVE
POPULATION THAT WILL GO ON AND
ON AND YOU IN PRINCIPLE WON'T
HAVE THE PROBLEMS OF SENESCENCE
TRANSFORMATION OR CHROMOSOMAL
ABNORMALITIES YOU HAVE WITH
PRIMARY CELLS, THESE ARE
ADVANTAGES, NOT ALL FULLY
EXPLOITED YET BUT POTENTIAL IS
THERE.
>>NOT TO JUMP IN BUT MOST
SCALABLE OF CELLS, FOR REASONS
FRANK JUST DESCRIBED.
>>I AGREE WITH ALL THESE
COMMENTS ABOUT IPS AND LARGE
PART IS GETTING CONTROL OVER
VARIATION. THAT WE HAVE. SO IPS
IN CULTURE EXPANDABLE CELLS AND
ENGINEERS CELLS, THESE ARE
CLONAL CELLS FROM SINGLE GENOMIC
BACKGROUND, START FROM SINGLE
CELL, CHARACTERIZE AND MON FOR
OVER TIME AND THAT THEY ARE NOT
ALL STABLE AND THERE ARE
DUPLICATIONS AND MUTATIONS IPS
CELLS, NOT AS CLEAN UP PLATFORM
AS WE LOVE BUT IT WILL IMPROVE.
THE COMMENT I WILL MAKE WAS
TWOFOLD. ONE WAS WHERE WE ARE
LIMITED IN A PLACE WE HAVE
OPPORTUNITIES IS -- I DON'T
THINK WE WILL MOVE FORWARD VERY
MUCH. WITH PRP AS A THERAPY,
UNTIL WE HAVE STANDARDS FOR IT.
IF WE DID A STUDY WITH THIS OR
THAT CENTRIFUGE, I MAY OR MAY
NOT WORK. ONE CENTRIFUGE DOESN'T
WORK BUT WE DELIVERED A WIDE
VARIETY OF -- CENTRIFUGE BECAUSE
EVERY PATIENT DIFFERS. UNTIL WE
HAVE A WAY TO MAKE A PRP
PREPARATION WHERE WE DEFINE WE
WANT CONCENTRATION IN THIS
RANGE, WE WANT TO ELIMINATE A
CERTAIN GROUP CYTOKINES ARE
WITHIN THIS RANGE, WE WANT TO
ELIMINATE NUCLEATED CELLS OR RED
CELLS WITHIN THIS RANGE SO WE
HAVE THAT CONTROL, THERE IS
HONESTLY NO WAY OR REASON FOR
PROSPECTIVE RANDOMIZE TRIAL, NOT
GOING TO MEAN ANYTHING EVEN IF
SUCCESSFUL OR FAIL BECAUSE ONLY
PROVE ONE AND ONLY ONE THING
THAT WE WILL WANT TO CHANGE IN
THE FUTURE. SO I'M NOT A GREAT
FAN OF INVESTING LOTS OF ENERGY
DESIGNING A PROSPECTIVE
RANDOMIZE PRP TRIAL UNLESS ALL
THOSE VARIABLES. THIS SPEAKS TO
SOMETHING AMYE BROUGHT UP, WE
ALSO STRUGGLE WITH PICKING THE
RIGHT PATIENT AND CONTROLLING
THE PATIENT VARIABILITY. WE HAVE
NO CONTROL OVER PATIENT
VARIABILITY. BUT ALL OUR
PATIENTS PRESENT WITH NOT JUST
ARTHRITIS IN ONE JOINT, IT COULD
BE MEDIAL LATERAL SIDE, FEMORAL
IN CASE OF KNEE AND NOT INVOLVE
MEDIAL LATERAL SIZE, THOSE ARE
DIFFERENT PROBABILITIES OF
FAILURE ALREADY, WE KNOW THAT
FEMORAL DISEASE AT LEAST IN OUR
PRACTICE IS A NON-RESPONDER NO
REASON TO OFFER SOMEBODY WITH
PRIMARY FEMORAL DISEASE PRP
INJECTION WE HAVEN'T SEEN
RESPONSES IN THOSE PATIENTS.
BUT PATIENTS PRESENT WITH
OBESITY OR NOT SYSTEMIC
INFLAMMATORY MARKERS ARE NOT
OSTEOPOROSIS ARE NOT, WE ARE NOT
COMPARTMENTALIZING THOSE
PATIENTS OR CATEGORIZING OR EVEN
COLLECTING DATA IN A WAY
SYSTEMATICALLY ALLOWS US TO DO
RETROSPECTIVE ANALYSIS IF THERE
IS A COHORT OF PATIENTS WE ARE
PARTICULARLY GOOD OR BAD AT
ALREADY. OR VITAMIN D DEFICIENT
OR NOT, THIRD OF MY PATIENTS
UNDERGOING THE ARTHROPLASTY WHEN
WE SCREEN THEM OR VITAMIN B
DEFICIENT BEFORE WE COME IN AND
WE HAVE TO CORRECT THAT BEFORE
SURGERY. SO WE HAVEN'T TAKEN THE
SYSTEMIC APPROACH, AS ONE JOINT
AT A TIME APPROACH, THAT IS A
MISTAKE.
>>RIGHT ON.
>>GEORGE YOU HAVE THE DATA AT
THE CLEVELAND CLINIC. YOU HAVE
BEEN DOING THIS SINCE I WAS
THERE. ALL THIS DATA IS RIGHT
THERE. YOU CAN DO THIS
RETROSPECTIVE ANALYSIS, YOU HAVE
EVERY PATIENT THERE WITH ALL
THAT DATA.
>>IT IS DESIGNED WELL, THERE IS
PLACE WHERE PATIENTS ENTER DATA,
PLACE WHERE PHYSICIANS ENTER
DATA WE CAN CAPTURE THAT DATA
BUT HALF THE PATIENTS DON'T COME
BACK. WE DON'T HAVE A HIGH
QUALITY STUDY WE GET MORE
PATIENTS TO COME BACK AND
PROVIDE OUTCOMES SO WE CAN
REPORT ON PATIENTS THAT DO COME
BACK BUT THERE ARE PATIENTS THAT
DON'T COME BACK IN THE SYSTEM.
WE DON'T NECESSARILY
COMPARTMENTALIZE INFLAMMATORY
MARKERS OR WE HAVE MEASURES OF
OBESITY. WE KNOW IF THEY HAVE
ONE OR BOTH THESE INVOLVED BUT
WE DON'T HAVE NECESSARILY
SYSTEMATIC INFORMATION ON ALL
THOSE, ALL THOSE OTHER PARSING
PHENOMENON BUT WE ARE TRYING, I
THINK THAT IS THE POINT. WE DO
THAT DATA, I HAVE DATA CONNIE
HAS DATA. WE ALSO HAVE A GOOD
WAY TO SYSTEMATICALLY MERGE DATA
INTO SOMETHING WHERE WE COULD
MAKE IT MORE POWERFUL.
>>BUT THAT WOULD BE IMPORTANT.
IT REALLY LOOKING AT THE
SYSTEMIC ASPECTS, THAT MAJOR
THING TO HIGHLIGHT FROM OUR
DISCUSSION HERE DANIEL WHITE HAS
HID HAND UP FOR A WHILE.
>>THANK YOU. ANDREAS AS WELL.
>>FROM MY PERSPECTIVE AS
PHYSICAL THERAPIST EMERGING
LITERATURE ABOUT UNDERLOADING
BEING A RISK FACTOR FOR THE
DEVELOPMENT OF OSTEOARTHRITIS
AND PATELLA FROM OSTEOARTHRITIS
AND THAT HIGHLIGHTS THE NEED FOR
PAYING ATTENTION TO THE LOADING
ENVIRONMENT AND HOW IMPORTANT
THAT IS. ALL MAJOR MEDICAL
ASSOCIATIONS RECOMMEND SORT OF
STANDARD EXERCISE AND BEING
PHYSICALLY ACTIVE FOR KNEE OA. I
THINK AN IMPORTANT AREA TO
CONSIDER ARE INTERVENTIONS YOU
TALK ABOUT CAN BE DONE IN
CONJUNCTION WITH AN EXERCISE
PROGRAM SO THAT YOU ARE
LEVERAGING THE BENEFITS OF BOTH
EMERGING THERAPY AS WELL AS
TRIED AND TRUE OPTIMIZE PATIENTS
SORT OF HEALTH STATUS. GIVING
THE FAR REACHING BENEFITS OF
EXERCISE AND PHYSICAL ACTIVITY
FROM EVERYTHING FROM MOOD AND
PSYCHOSOCIAL STATUS TO PAIN AND
HEALTH RELATED QUALITY OF LIFE,
WHY NOT LEVERAGE THAT IN
ADDITION TO MERGING APPROACHES
AND COOL APPROACHES THAT FARSHID
WAS TALKING ABOUT WITH THE TRIED
AND TRUE. MY THOUGHTS USING A
MULTI-MODAL APPROACH FOR
INVESTIGATING USE IN THOSE
AREAS.
>>GOOD POINTS. ANY THOUGHTS HOW
THIS DATA CAN BE COLLECTED IN A
SYSTEMATIC AND FASHION EASY TO
USE?
>>FROM GENERAL ACTIVITY LEVEL,
OBJECTIVE MONITORS USED WELL
ESTABLISHED TO RECORD PEOPLE'S
PHYSICAL ACTIVITY AS WELL AS A
BIG EMERGING AREA IS SEDENTARY
BEHAVIOR. MOST OF US ARE SITTING
RIGHT NOW AND HOW MUCH SITTING
WE ARE DOING AND HOW THAT --
WHAT THE RATIO OF SITTING TO
WALKING TO STANDING ARE. USING
RESEARCH GRADE MONITORS WELL
ESTABLISHED PROTOCOLS ARE SIMPLE
WAY THEY CAN BE INCORPORATED AT
A MINIMUM AS OUTCOME MEASURE
INTO ANY STUDY. HOPE THAT
ANSWERS YOUR QUESTION.
>>THANK YOU. ANDREAS. I THINK
MAYBE ALSO BRIEFLY INTRODUCE
YOURSELF.
>>ANDREAS, HHS, I'M A CLINICIAN
-- I
>>I KNOW YOU I WANTED TO MAKE
SURE EVERYBODY HAD A CHANCE TO
HEAR YOU.
>>WE HAVE KNOWN EACH OTHER FOR
20 YEARS. I THINK WHAT CONFUSES
ME AS A CLINICIAN THE MOST, THIS
IS PICKING UP A POINT GEORGE
MADE IN TERMS OF HOW IT DOESN'T
RESPOND TO PRP INJECTIONS. I SEE
PATELLA FEMORAL ISSUES AFTER A
ACL. TEN YEARS AGO HAD ACL BUT
NOW A LESION. DOESN'T MAKE SENSE
BUT PICKS UP ON WHAT DANIEL SAID
IN TERMS OF MAYBE CHANGES IN
QUAD STRENGTH, MAYBE PEOPLE
BECOME MORE HAMSTRING, THAT
LEADS TO ARTHRITIS. BUT
ARTHRITIS IN PEOPLE WHETHER
PLAYED BASKETBALL SINCE THEY
WERE FOUR SO THAT'S REPETITIVE
MICROTRAUMA AND I SEE THAT IN
PEOPLE WITH PAT LA ALL THE TIME,
-- PATELLA ALL THE TIME AND
DON'T MECHANICALLY HAVE GOOD
TRACK AND THEN I SEE TIP OF
ICEBERG IN PATIENTS WHO HAVE
JOINT DISEASE. ON X-RAY THEY
MIGHT LOOK THE SAME AND WE ALL
THEM ARTHRITIS BUT THEY HAVE
DIFFERENT CHALLENGES AND AS LONG
AS WE THROW EVERYONE IN THE SAME
POT, SAY LET'S TREAT THIS
ARTHRITIS PATIENT THE RESULTS
AND THAT IS WHAT WE HAVE, ARE
VERY CONFUSING. AS CLINICIAN NOT
CALL PEOPLE ARTHRITIS BUT GET
SUBCATEGORIES AND GET BETTER, I
THIS I THEN OUR TRIALS WOULD BE
BETTER.
>>WE TALKED THE NEED TO
PHENOTYPE PATIENTS AND
TREMENDOUS HETEROGENEITY IN
PATIENT PHENOTYPE.
>>MULTI-DISCIPLINARY MODELING
OF THE DIFFERENT OA SUB TYPES.
SO WE WILL DEFINITELY HIGHLIGHT
THOSE ARE AREAS OF -- THANK YOU,
ANDREAS. SHALL WE MOVE TO THE
NEXT TOPIC?
>>LARISSA'S POINT WEIGH IN ON
THIS FROM THE REGULATORY.
>>I JUST WANTED TO COME BACK TO
THE COMMENTS ABOUT THE
IMPORTANCE OF HAVING A STANDARD
DEFINING HOW YOU MAKE THESE
PRODUCTS WHETHER PRP CELL
THERAPY, STEM CELLS, MESENCHYMAL
STEM CELLS, MEDICINAL SIGNALING
CELLS, WHAT ARE ARE WE TALKING
ABOUT HOW ARE WE MAKING THEM,
THERE HAVE TO BE MORE OR LESS
DEFINED APPROACH. BEFORE WE GO
INTO CLINICAL TRIALS WE HAVE TO
LOOK AT THE QUALITY AND
CONSISTENCY HOW THESE TREATMENTS
ARE MADE. MAYBE AS A GROUP MAYBE
ONE OUTCOME OF THIS DISCUSSION
WE COULD FIND WAYS TO TRY TO
CONTRIBUTE TO DEVELOPMENT OF
STANDARDS HOW THESE PRODUCTS
COULD BE POTENTIALLY MADE BEFORE
THEY TRIED. THAT IS ONE
COMMENT. THE OTHER IT WAS
STRIKING TO SEE IN THE
PRESENTATIONS, HOW SOMEBODY
LOOKED AT CLINICALTRIALS.GOV AND
DIFFERENT TYPES OF THERAPIES
WHEN THEY START WITH THOUSANDS
OF TRIALS AND WHEN PRODUCT GO
INTO PHASE 3 THERE ARE FEW LEFT.
I WANTED TO MAKE A POINT THERE'S
PROBABLY A REASON FOR WHY THERE
ARE FEW LEFT. BECAUSE IF THEY
WERE PROPERLY INVESTIGATED, THEY
DIDN'T WORK. SO THAT IS ANOTHER
CONTEXT FOR OUR BELIEFS IN
THINGS WE ARE TRYING TO BUY
OURSELVES INTO. AGAIN IT IS
REALLY IMPORTANT TO HAVE QUALITY
INVESTIGATIONS DONE WITH THESE
PRODUCTS AND BE A LITTLE MORE
SKEPTICAL BEFORE WE JUMP INTO
BELIEVING THINGS WILL WORK.
>>I HAD TO SUMMARIZE ONE THING
THAT'S COME OUT OF SIX HOURS,
PRIORITIES FOR MOVING FORWARD
CONTACTIZATION. STANDARDIZATION
AND CHARACTERIZATION VARIOUS
WAYS GEORGE MENTIONED WITH PRP.
RECOGNIZE LIMITATIONS BUT
CLEARLY EVERYTHING STARTS THERE.
A ROT STARTS TH LOT OF IT STAR
>>YES.
>>GO TO NUMBER 3, CHALLENGES
AND GAPS, LOT OF THIS COME OUT.
>>BACK TO AMYE, THE QUESTION I
ASKED AT THE VERY BEGINNING AND
YOU ANSWERED NICELY, THE
BARRIERS TO CLINICAL TRIALS.MENT
SO SAY WE HAVE A PREPARATION WE
CAN STANDARDIZE. WE CAN
CHARACTERIZE IT. WE RUN A
CLINICAL TRIAL IN A REALISTIC
FASHION, HOW DO WE DO
MULTI-CENTRIC TRIALS. RHETORICAL
QUESTION CHALLENGE BUT THESE ARE
THE CHALLENGES.
>>I HAD ADDRESS TO ONE OF THE
QUESTIONS THAT WAS SUBMITTED TO
ME WAS HOW TO ATTRACT MORE
PEOPLE AND CONSISTENTLY IN
PEOPLE MORE THAN SEVERAL TIMES
WHERE PEOPLE START OUT IN
CLINICAL TRIALS BUT CHOOSE NOT
TO FURTHER PARTICIPATE. IT WAS
VERY CLEAR, I WAS SURPRISED THAT
THERE IS EVEN A CHOICE BECAUSE
IT WASN'T DEFINED CLEARLY ENOUGH
PATIENT IN TERMS OF THAT CHOICE
OR AT LEAST OPPORTUNITY FOR
FURTHER EDUCATION AND
EXPLANATION MAYBE SOME WIGGLE
ROOM, CAN'T DO TOO MUCH BUT I
THINK THAT PARTICULARLY IN AREA
OF CARTILAGE ANYTHING ABOUT
CARTILAGE HERE IS MY QUESTION TO
THE ILLUSTRIOUS PANEL FOR THOSE
THAT CONDUCTED STUDIES, WHAT
NOT, HOW DO YOU EXPLAIN IT TO A
PATIENT? THEY GET THE IDEA IT IS
CARTILAGE, I USED EDUCATIONAL
PATIENT LECTURERS, I USE THE
CHICKEN BONE AS A PERFECT
EXAMPLE. ARE YOU STILL DOING
THAT? SEEMS HIGHLY EFFECTIVE.
EVEN VEGANS KNOW WHAT A CHICKEN
BONE WITHOUT THE MEAT LOOKS
LIKE. AND THAT'S A GREAT START.
YOU HAVE TO GIVE THE PATIENT A
LEAP OF FAITH TO OKAY THAT IS
WHAT THE CARTILAGE IS, WHAT WE
ARE DOING OUR STUDY ON. NOW WE
WANT TO TEST YOURS OUT. SO THEN
ALL THE FEAR, ARE YOU GOING TO
HURT ME, PUT SOMETHING UNUSUAL
IN ME THAT I'M NOT GOING TO
CONTROL. THERE'S ALL THE
QUESTIONS AND IF YOU DON'T
ANSWER UP FRONT WILL ABSOLUTELY
FILTER UP, MAYBE NOT DURING
THEIR -- YOUR SESSION WITH THEM
OR YOUR NURSE PRACTITIONER
SESSION SESSION WITH THE PATIENT
BUT CERTAINLY WILL FILTER UP,
HAVING SOME SESSIONS IN SOME WAY
COLLECTIVELY SUPPORTED CONVENED
BY THE FDA BY LARISSA MIGHT BE
HELPFUL IN AREAS WHERE CLINICAL
TRIALS HAVE TO BE DONE ON PARTS
OF PEOPLE'S BODIES THAT JUST
SCARE THE HOLY BEJESUS OUT OF
THEM, THAT IS MY QUESTION TO YOU
HOW SUCCESSFUL HAS IT BEEN,
REPEAT SCENARIO WHAT IS YOUR
EXPERIENCE AND SHARING WHAT
WORKS. SHARING WHAT DOES DID NOT
WORK IS VALUABLE TOO.
>>CLINICAL TRIALS ARE HARD
BECAUSE PATIENTS COME IN
BELIEVING THE STUFF ALL WORKS
AND DON'T WANT RANDOMIZE, THEY
WANT THE ACTIVE TREATMENT, IT IS
AN AREA WE AS PHYSICIANS NEED,
PATIENTS THINK ITAS. THAT IS ONE
MORE -- IT DOES. THAT IS ONE
MORE CHALLENGE especially
relevant to regenerative
medicine due to aggressive
marketing and everything out
there.
>>DANIEL, I DON'T KNOW IF YOU
CAN SEE ME I HAD TO MOVE TO MY
CAR FROM MY OFFICE I'M SORRY.
I'M QUITE COMFORTABLE ADDRESSING
SOME OF THOSE QUESTIONS BECAUSE
YOU AND OTHERS PROBABLY KNOW WE
HAVE DONE A COUPLE OF TRIALS
THAT LED TO THE REGISTRATION OF
THESE PROJECTS AND I EVEN HAD TO
TALK TO PATIENTS TO RANDOMIZE
AGAINST MICROFRACTURE FOR THE
SECOND TIME IN A SECOND
MULTI-CENTER TRIAL AND IT COMES
DOWN TO BEING HONEST AND
TRANSPARENT ABOUT WHAT WE KNOW
AND WHAT WE DON'T KNOW. AND IT
COMES DOWN TO THE PATIENT DOCTOR
TRUST AND IF THEY TRUST YOU THEY
WILL TRUST YOU ARE DOING THE
TRIAL FOR A GOOD REASON.
CONTRARY WHAT I HEAR PEOPLE SAY
I HAVE NOT FOUND A SINGLE
PROBLEM WITH RANDOMIZATION OF
THE PATIENTS. UNLESS THEY GET
THE IDEA THEY ARE USED FOR
MARKETING PURPOSES. THOSE
STUDIES DON'T DO WELL, BUT IF
THERE IS REAL SURGICAL EQUIPOISE
OR SCIENTIFIC UNCERTAINTY
PATIENT WILL FOLLOW WHAT DOCTOR
EXPLAINS TO THEM, IF THEY
EXPLAIN IT UNDERSTANDABLE TERMS
THAT IS MY EXPERIENCE.
>>FARSH.
>>I HAVE A QUESTION ABOUT THE
CLINICAL TRIALS ISSUE. LACK OF
GOOD CONTROL GROUP, THERE IS A
HUGE PLACEBO EFFECT IN OA
STUDIES PARTICULARLY IF THE KNEE
HAS INJECTION IN IT OR ANY
INJECTION OCCURS, 20 TO 40%
PLACEBO EFFECT. IF YOU HAVE A
TRIAL WITHOUT THAT IT IS NOT
GOING TO BE MEANINGFUL. YOU SEE
AN EFFECT. THE OTHER IS I HAVE
BEEN REVIEWING CLINICAL TRIALS
ON MSC AND I WOULD SAY A GOOD
NUMBER ARE NOT TRIALS, THEY ARE
JUST REGISTERED WITH NUMBER OF
PATIENTS FOR VARIOUS OF THESE
FLY BY NIGHT CLINICS TO SAY WE
HAVE A TRIAL ONGOING. THEREFORE
NEVER REPORTED. ANOTHER GROUP
NOT REPORTED BECAUSE THEY HAVE
NEGATIVE FINDINGS OR
INCONCLUSIVE FINDINGS, BECAUSE
OF THAT THERE IS INCREDIBLE
STATISTICAL BURDEN ON THE TRIALS
THAT ARE RUN PROPERLY. SO THINK
IF AS A LABORATORY YOU JUST
TOSSED 50% OF YOUR DATA BECAUSE
IT WASN'T SIGNIFICANT, AND YOU
JUST REPORTED THE POSITIVE SIDE
WHAT DOES THAT MEAN? TERMS OF
THE STATS FOR YOUR POSITIVE
FINDINGS? AS A FIELD WE HAVE
DONE THAT. SO IF WE HAVE
CLINICAL TRIALS NOW WE HAVE A
BETTER FINDING FOR IT TO BE
MEANINGFUL BECAUSE HALF THE
BATTLE IS THROWN OUT WHETHER YOU
THROW IT OR NOT, IT IS A BIG
STATISTICAL PICTURE OF WHERE WE
ARE AS A FIELD. BETTER OVERSIGHT
ON THIS AND THE REPORTING. IT IS
A BRAIN DUMP AND WE NEED BETTER
CLINICAL TRIALS, NOT JUST MORE
CLINICAL TRIALS.
>>AGREED. ALSO TO SPECIFY AHEAD
OF TIME THE PRIMARY OUTCOME WE
TALKED THROUGH THIS MEETING
ABOUT HOW STRUCTURAL OUTCOMES DO
NOT RELATE TO PAIN OR SYMPTOMS
OR EVEN FUNCTION UNTIL LATE IN
THE DISEASE IF SOMETHING IS
SPECIFICALLY TO REPAIR THE
CARTILAGE I WOULD SUBMIT PRIMARY
OUTCOME SHOULD NOT BE PATIENT
REPORTED PAIN, THAT IS STILL AN
IMPORTANT OUTCOME BUT IF YOUR
THERAPY IS GEARED TOWARDS
REPAIRING AND REGENERATIVE
CARTILAGE, IT IS ALSO VERY
IMPORTANT TO HAVE A STRUCTURAL
OUTCOME HOW LONG IT DID THA THA.
NOT SAYING TO IGNORE PATIENT
REPORTED OUTCOME BECAUSE AS WE
TALKED ABOUT THAT'S THE MAIN
REASON THE PATIENT SEEKS
TREATMENT BUT SYMPTOMS MAY AS WE
KNOW SYMPTOMS IN OA DEVELOP
LATER, TYPICALLY LATER THAN
STRUCTURAL DISEASE SO IF WE ARE
TRYING TO OPT FOR EARLY
TREATMENT,S THE CARTILAGE REPAIR
PROCEDURES ARE TO ALTER
PRESUMABLY IMPROVE STRETCHER SO
THERE NEEDS TO BE MORE
ACCEPTANCE IN THE CLINICAL
TRIALS, WHAT STAGE OF OA ARE WE
TALKING ABOUT AND WHAT ARE THE
IMPORTANT OUTCOMES FOR THAT
STAGE. END STAGE DISEASE YES AS
JOHNNY AND OTHERS MENTIONED. IF
YOU ARE TRYING TO GET PEOPLE TO
HAVE LESS PAIN SO THAT THEY CAN
FUNCTION BETTER AND STAVE OFF
THE JOINT REPLACEMENT, THEN THAT
IS ANOTHER OUTCOME BUT EARLY ON
I DON'T THINK THAT CAN BE THE
PRIMARY OUTCOME LIKE TO ASK
CAROLYN LUTZKO.
>>YOU MAY RECALL, SO MY
INTEREST IS IN DEVELOPMENT AND
MANUFACTURING OF CELL BASED
THERAPIES. SO IN LISTENING
THROUGH THE DISCUSSION, MOST OF
MY WORK IS BLOOD AND GENETICS
RELATED. THE MOVEMENT TOWARDS
ALLO TRANSPLANTS OR ALLO
THERAPIES IS GOING TO HELP THAT
REALLY GETTING AT THE QUESTION
BECAUSE YOU CAN CENTRALIZE YOUR
MANUFACTURING AND IF YOU HAVE
MORE LIKE INVESTIGATIONAL
PHARMACY AT MANY SITES,
ENROLLMENT MAYBE DIFFERENT AT
LEAST YOU CAN TACKLE THAT,
WHETHER IT'S MSCs, EVEN PRP,
IT WOULD BE FROZEN,NA IPS ARE
GREAT WAY TO DO THAT. I THINK IT
COULD -- YOU CAN GET IT SOME OF
THESE DIFFERENTLY AS WE -- IF WE
CAN AND AS WE MOVE TO ALLO
THERAPIES.
>>THANK YOU.
>>GEORGE MUSCHLER.
>>I WAS GOING TO COME BACK TO
COMMENT MADE IN ADDITION TO
BEING ABLE TO SELECT PATIENTS TO
BE PARTICIPANTS IN THESE STUDIES
GETTING THEM TO COME BACK FOR
FOLLOW-UP AND REMAIN YOU MADE
THE STATEMENT YOU CAN'T BELIEVE
THAT IS AN OPTION TO NOT
FOLLOW-UP. SO THAT IS -- WE FEEL
THAT WAY TOO BUT THE ONLY POWER
THAT CLINICIANS HAVE IS TO BUILD
TRUST AS SHANE MENTIONED AND
DANIEL MENTIONED AND TO SHOW THE
PATIENT YOU CARE ABOUT THEM
COMING BACK. CLINICAL
COORDINATORS ARE ESSENTIAL IN
THAT PROCESS. TO THIS DAY BUT
STILL PATIENTS HAVE OPTIONS. AND
ONE OF THE LEVERS THAT HAS NOT
BEEN APPLIED TO THESE STUDIES
AND THERE MAYBE AN OPPORTUNITY
TO DO THAT IS TO PARTNER WITH
PAYERS BECAUSE YOU CAN IMAGINE A
PATIENT WHO WOULD LIKE TO HAVE
ACCESS TO THESE THERAPIES AND
LIKE TO BE PARTICIPANT IN A
STUDY, A PAYER WHO WOULD LIKE
KNEE REPLACEMENTS AND HAVE
CHEAPER OPTION BUT WOULD
REIMBURSE A PATIENT ONLY IF THEY
CAME BACK TO FOLLOW-UP. AS PART
OF THE STUDY. THERE IS AN
OPPORTUNITY THERE. WE GOT A
LITTLE WAY DOWN THE ROAD WITH
MEDICAL ABOUT SIX OR EIGHT YEARS
AGO AND SOME LEADERSHIP CHANGED
BUT THERE IS AN OPTION WHERE FOR
ANY OF US WHO LIVE IN AN
ENVIRONMENT WITH COLLABORATIVE
PAYER TO IMPROVE PATIENT
PARTICIPATION.
>>THANK YOU. I THINK DAN'S
COMMENT HIGHLIGHTED THE
IMPORTANCE OF BUILDING TRUST IN
TRANSPARENCY AND IF YOU HAVE THE
PAYERS INVOLVED ARE YOU
CONCERNED GEORGE, THERE MAYBE
EFFECT ON HOW PATIENT VIEWS
THEIR TREATMENT?
>>HOPEFULLY NOT, HOPEFULLY THEY
-- IN OUR CASE WHERE OUR OPINION
IS THAT WE USE SIX MONTH
FOLLOW-UP AS WINDOW SO NOT A
LONG FOLLOW UP, WE KNOW IT IS
WITHIN A YEAR PATIENTS ARE
THINKING OF US, THEY HAVEN'T
CHANGED THEIR ADDRESS OR PHONE
NUMBER. NOT CHANGED JOBS SO IT
IS POSSIBLE TO REACH THEM. THEY
STILL HAVE THE SAME PAYER DURING
THAT TIME. THERE IS NO REASON TO
MAKE THIS CO-WE ARESIVE, WE WANT
TO KNOW, ARE YOU BETTER, WORSE,
DO YOU CLIMB STAIRS, NOT CLIMB
STAIRS B ARE YOU STILL WORKING,
STILL PLAY SPORTS, THERE IS A
LIMITED NUMBER OF QUESTIONS AND
WE DON'T HAVE TO DESIGN IT IN A
WAY TO PHYSICALLY COME BACK
UNLESS WE HAVE IMAGING TO DO OR
INFLAMMATORY MARKERS TO DO OTHER
THINGS BUT WE CAN MAKE IT EASY
ENOUGH TO PATIENTS TO DO IT. I
THINK IT IS -- THERE IS NO
REASON WE SHOULDN'T HAVE 80 TO
90% FOLLOW-UP ON THESE STUDIES
IF WE CAN ALIGN PROCESS AND MAKE
EASY FOR PATIENTS TO COMMUNICATE
WELL BUT ALSO MOTIVATE THEM SO
THEY ARE NOT INCLINED IF THEY
ARE UNCERTAIN ABOUT OUTCOME OR
ANOTHER SHINEC OBJECT SHOWS UP
ON COMPUTER SCREEN AND THEY WANT
WANT THE TRY SOMETHING ELSE,
THEY FEEL GUILTY BECAUSE THEY
DID SOMETHING ELSE, WE DON'T
WANT THEM TO FEEL GUILTY ABOUT
THAT. THERE IS HOPE IN
COMMUNICATING BUT I DON'T
PRETEND IT IS EASY BUT ONE EXTRA
LEVER. I DON'T THINK IT WOULD
COME, WE ARE NOT ASKING THEM --
NOT PUTTING THEM AT RISK.
>>WE COULD ALWAYS CONSIDER
PCORI WAY WHICH IS PCORI
BASICALLY SAYS YOU WILL PAY
PATIENTS FOR THEIR
PARTICIPATION, YOU WILL PAY
PATIENTS WHO ARE SITTING ON YOUR
INVESTIGATION COMMITTEE. YOU
WILL PAY THE PATIENT OR TWO
SITTING ON EXECUTIVE PROJECT
COMMITTEE. THE PAYMENT IS VERY
-- IT IS UNDER $50. L IN SOME
CASES WE HAVE SEEN WHERE
PROBABLY OUT OF $50 PER PERSON
MAX OVER THE TIME -- NUMBERS OF
RESPONSES THAT THEY WILL NEED TO
GIVE, THEY WILL GIVE THEM A
LITTLE BIT MORE UP FRONT AND
FOLLOW-UP WITH A BIG HIT AT THE
END IF YOU WILL. YOU ARE TALKING
$35.
>>THIS IS DANIEL SORRY TO
INTERRUPT BUT I THINK THAT THE
ROLE OF THE CRC, STUDY
COORDINATOR OR DESK ATTENDANT
FIRST POINT OF CONTACT IS
IMPERATIVE. ALSO THE FIRST
DISCUSSION THAT WE HAVE HAD WITH
PATIENTS IN ALL THESE TRIALS IS
IS -- WE DON'T HAVE GOOD DATA WE
REALLY DON'T HAVE GOOD TRIALS,
THIS COULD BE A GOOD TRIAL BUT
WE NEED EVERYBODY TO PARTICIPATE
IN THE WHOLE TRAJECTORY SO THEY
ARE NOT JUST A SUBJECT, THEY ARE
A TEAM MEMBER. THE MOMENT THE
PATIENT UNDERSTANDS THEY ARE
PART OF THE TEAM DOING THE TRIAL
NOT JUST PART OF THE SUBJECTS
STUDIED, THE ENGAGEMENT IS MUCH
DIFFERENT. WE EVEN HAD PEOPLE
ASK TO CONTINUE TO FIVE AND TEN
YEARS AND HAVE A SURGICAL
ARTHROSCOPY, THESE ARE NOT CRAZY
PEOPLE, PEOPLE TRYING TO
CONTRIBUTE. THAT IS WHY U YOU
HAVE 98 AND 100% FOLLOW-UP IF
PATIENTS ARE ENGAGED IN RESEARCH
QUESTION, THEY ALSO IF THEY DROP
OUT IF THEY DON'T SEND IN THEIR
QUESTIONNAIRES ANY MORE, THE
STUDY WILL BE AT RISK AND SHARE
RESPONSIBILITY AND THAT IS ONE
ASPECT. AND THE OTHER ASPECT
THAT IS BENEFICIAL NOW IS THAT
THROUGH TELEHEALTH OPPORTUNITIES
HAVE EXPANDED THROUGH COVID
REGULATION, WE ARE ABLE TO DO
MORE FOLLOW-UPS THROUGH VIRTUAL
CONSULTATION AND NOT EVERY TIME
DO I NEED TO TOUCH THE PATIENT
MYSELF OR DO A KNEE EXAM MYSELF,
IF THE IMAGING PROTOCOL IS WELL
ESTABLISHED THEY CAN HAVE
IMAGING PROTOCOLS DONE LOCALLY
IN SCANNERS VALIDATED WITHIN THE
TRIAL. AND YOU CAN DO FOLLOW-UP
THROUGH QUESTIONNAIRES AND
VIRTUAL CONSULTATION WHICH
LIMITS THE TRAVEL RISK AND THE
DROP OUT SO EVOLVING
TECHNOLOGIES ARE TO OUR BENEFIT
I THINK. HIGH QUALITY FOLLOW-UP
IS IMPERATIVE FOR THE TRIAL. IF
YOU DROP BELOW 90% THE CHILD IS
AT RISK.
>>THANK YOU. SO WE ARE NOW AT
5:20. SO WE ARE SCHEDULED TO
HEAR FROM LINDSEY AND BOB
CARTER.
>>YES, THANK YOU. SO MUCH. I
WILL ASK BOB TO OFFER COMMENTS
FIRST THEN FOLLOW AFTER THAT.
>>THANK YOU.
>>THIS HAS BEEN A FANTASTIC
MEETING. REALLY APPRECIATE
THOUGHTFUL INPUTS FROM AND THE
TALKS WAROR WERE SUPERB. SO
THANKFUL FOR YOUR TIME AND
EFFORT. I DO THINK REGENERATIVE
MEDICINE IS FUTURE. I DO THINK
WE SOME DAY YOU CAN IMAGINE WE
WILL HAVE A THERAPY OR
COMBINATION OF THERAPIES THAT IN
SOME PEOPLE ARE GOING TO LEAD TO
HEALING OF CARTILAGE AND
ABEYANCE OF OTHER FACTORS THAT
LEAD TO REPETSIVE DEGENERATION
INFLAMMATORY CHANGES. SO WE ARE
AT THE VERY EARLY STAGE OF THIS.
WE ARE WORKING THROUGH THE
LOOKING GLASS TRYING TO FIGURE
HOW TO GET ON THE OTHER SIDE OF
IT. SO I DO THINK WE NEED A WIN
I THINK ALL THIS STUFF GOING ON
IN SOCIETY, FOCUS ON WHAT IS IT
GOING TO TAKE TO HAVE A
DEMONSTRATION THAT WE CAN
IMPROVE THINGS? WE ACTUALLY HAVE
GOOD DATA WE CAN REGROW
CARTILAGE WITH FGF 18, IT DID
REGROW IT ON LATERAL SIDE,
DIDN'T REDUCE PAIN SO PROGRAM
WAS STOPPED. WE DO KNOW FROM
THAT AND THE DISTRACTION STUDIES
THAT WE CAN LEAD TO REGROWTH OF
CARTILAGE IN PATIENTS WITH
ACTIVE OA IN HUMANS. HUMANS. SOE
STARTING POINTS REASONABLE TO
BELIEF WILL WORK BUT WE HAVE TO
GET A WIN TO SAY HERE IS A PLACE
WHERE IT WORKS. TO GEORGE'S
POINT, NOT ONLY HAVE TO BE
DEFINED IN TERMS OF
INTERVENTION, ALSO DEFINED ON
WHO THE SUBJECTS ARE.
PARTICIPANTS. PARTNERS IN THE
STUDY. DEFINING THE PEOPLE YOU
THINK MOST LIKELY TO RESPOND
DEFINING THE THERAPY IN TERMS OF
ALL THINGS YOU SAID IN TERMS OF
HOW TO CHARACTERIZE IT AND
FINDING A WAY TO GET A WIN, THIS
ACTUALLY WORKS WHETHER PRP OR
EXOSOMES OR CELLS. I DID GO
BACK ORS TALK TALK ABOUT THEIR
VERSION OF THE MEAN, DEGREE OF
REVERSION TO MEAN IN PATIENTS
WITH PAIN IS ASTOUNDING. IF THE
STUDIES ARE NOT WELL CONTROLLED,
THE REVERSION OF THE MEAN NOT TO
MENTION PLACEBO EFFECT, THE
VERSION OF THE MEAN IS OFTEN
MUCH GREATER. WE WHERE OVERWHELM
ANY SIGNALING WE HAVE SO WE HAVE
DEAL WITH THAT. ONCE WE HAVE THE
BIN WELCOME CHARACTERIZE
JOHNNY'S PART OF THIS, HIS CELLS
ARE SENT TO CENTER WHERE THEY
WILL DO IN DEPTH CELL CHARACTER
CAUTIONS AS PART OF REGENERATIVE
MEDICINE INNOVATION PROJECT, WE
DO NEED TO UNDERSTAND WHAT IS
GOING ON, I THINK TO THE POINT
DR. BARRY MADE ABOUT CURRENT
STANDARDS ARE NOT SUFFICIENT.
ONCE WE HAVE A WIN WE CAN START
INVESTIGATING MECHANISMS IN
HUMAN AND BROADENING OUT -- THIS
IS THE POPULATION WE SEE -- WE
CAN BELIEVE. WHAT IS MORE
GENERAL YOU KNOW THIS IS A WIN,
PEOPLE WANT TO BE REIMBURSED BUT
AS SCIENTIST, OUR JOB IS TO
FIGURE OUT WHO RESPONDS TO WHICH
PREPARATIONS. I DON'T KNOW NIAMS
CAN FUND THE TRIAL WE NEED. IT
MAY LEAD TO BIG IN THE CELL
PREPS IF THAT IS WHERE WE GOING,
MAYBE TOO EXPENSIVE FOR US. WE
HAVE TO FIGURE HOW TO GET THAT
DONE AND IT MAY NOT BE ONE AND
DONE. THIS IS EXPENSIVE PATH.
WITH THAT, I THINK THERE IS
HONEHOPE. WE WILL GET THERE, MAE
TAKE FIVE YEARS, 50, A HUNDRED
BUT THIS IS THE FUTURE, WE ARE
JUST STARTING COULDN'T THE PATH,
WE ARE EXPLORE -- DOWN THE PATH.
WE WANT TO FIGURE HOW TO MAKE
THAT PATH STRAIGHT AS POSSIBLE.
THANK YOU FOR THE PARTICIPATION.
HAVING SAID THAT, I DON'T HAVE
TO PAY FOR IT, I'M GOING TO TURN
IT OVER TO LINDSEY.
>>SKIP THAT QUESTION NUMBER 4
WHAT DO WE NEED BESIDES MONEY,
RIGHT?
>>YEAH. NO. BOY, AM I GRATEFUL
TO THE EFFORT DEVOTED TO
ORGANIZING THIS AND TO ALL OF
YOU WHO SPENT SO MANY HOURS WITH
US, IT WAS A FASCINATING
DISCUSSION, I LEARNED A
TREMENDOUS AMOUNT, I WAS WRITING
DOWN HIGH LEVEL THEMES AS WE
REMEMBER GOING ALONG, BOB
TOUCHED UPON SO MANY OF THEM,
JUST CRITICAL IMPORTANCE OF
STUDY DESIGN, CHARACTERIZATION
AND STANDARDIZATION OF THE
PRODUCT, AND PROCESSES. T THE
HETEROGENEITY OF THE PATIENTS
FROM MINOR STRUCTURAL DEFECTS TO
GENERALIZED OSTEOARTHRITIS OF
DECADES AND DURATION AND THE
IMPORTANCE OF BETTER
UNDERSTANDING THE MECHANISMS. I
LOVED WHO WAS IT THAT SAID I'M
FORGETTING OFF THE TOP OF MY
HEAD, ONE OF OUR PARTICIPANTS
PERHAPS A GOAL TREESIS ON MOVING
FORWARD, BOY THAT WOULD BE
FANTASTIC, IF WE COULD GET TO A
WIN THAT WOULD BE AMAZING. HOW
TO GET THERE IS NOT CLEAR BUT
REALLY APPRECIATED THE
THOUGHTFUL DISCUSSION AND IN
TERMS OF THE NEW OPPORTUNITIES
MANY OF YOU TALKED ABOUT FUTURE
IN WHICH COMBINATION THERAPIES
ARE BEING APPLIED AND EXAMINED
IN RIGOROUS WAYS WE HAVE A LOT
OF WORK TO DO TO GET THERE. THE
COMMENTS ABOUT IPSCs WERE
INTERESTING AND I THOUGHT THAT
COMMENTS ABOUT SOME OF THE NOVEL
GENE THERAPY EDITING APPROACHES
WERE REALLY EXCITING. SYNTHETIC
GENE CIRCUITS, SO WE ARE ALREADY
SEEING REALLY EXCITING
INNOVATIVE APPROACHES IN THIS
AREA. THANK YOU AMYE FOR
BRINGING US BACK TO CENTER OF
THE UNIVERSE. PATIENT HERE. SO
IMPORTANCE OF PATIENT
ENGAGEMENT, GOOD PATIENT
COMMUNICATION CHARACTERIZED BY
TRANSPARENCY, THAT WAS
CRITICALLY IMPORTANT. LASTLY TOO
I WANT TO SAY HOW FORTUNATE WE
WERE TO HAVE LARISSA HERE FROM
THE FDA. I LEARNED A LOT FROM
THAT ONE PRESENTATION, HOPEFULLY
Y'ALL FOUND THAT HELPFUL AS
WELL. I DON'T KNOW WHAT ELSE TO
SAY EXCEPT THANK YOU, THANK YOU
THIS WAS REALLY GREAT DISCUSSION
ABOUT IMPORTANT COMPLICATED
TOPIC. SO THEN PERHAPS ONNA
NOTE, I DON'T KNOW WHETHER
JONELLE OR TED WERE PLANNING ON
LAST WORDS BUT REALLY ENJOYED
THIS.
>>JUST WANT TO THANK LEADERSHIP
FOR THE SUPPORT AND LONG TIME
SUPPORT ONE AND A HALF YEARS TO
MAKE THIS HAPPEN. THANKS TO
PARTICIPANTS TO FOR YOUR
CONTRIBUTIONS AND YOUR
COMPROMISE, YOU ARE WILLING TO
TAKE OUR ASSIGNMENT. AND I
APPRECIATE IT. I THINK THIS IS A
VERY GOOD ROUND TABLE
DISCUSSION. THANK YOU ALL.
>>THANK YOU, TED.
>>THANKS TO CONNIE AND SCOTT.
>>ABSOLUTELY. THANK YOU.
>>I THINK WHAT WE SHOULD DO
MOVING FORWARD IS TAKE A DAY OR
TWO A WEEK OR MONTH AND THINK ON
THIS AND COMMUNICATE VIA EMAIL M
IF SOMETHING DOES COME OUT OF
THIS PUT YOUR THOUGHTS DOWN AND
EMAIL TO THE GROUP. IF YOU HAVE
RANDOM THOUGHTS HOW WE MIGHT --
WHAT CONCLUSION REACHED HERE AND
IMPORTANTLY ACTION ITEMS, WHAT
ARE THE REAL PRIORITIES MOVING
FORWARD. WE TALKED ABOUT SOME
BUT ANY IDEAS THAT COME UP
PLEASE SHARE WITH US.
>>THANK YOU JONELLE.
>>THANK YOU TO EVERYBODY. I'M
SORRY, I CUT YOU OFF, DR. CHU.
>>DAVID AND EVERYONE, THANK YOU
SO MUCH.
>>I WAS JUST GOING TO SAY
MEETING IS ADJOURNED, HOPE
EVERYTHING HAS A PLEASANT
EVENING DEPENDING ON WHAT TIME
ZONE YOU ARE IN.
>>WE WILL SEND PICTURES.
>>THANKS FOR TECHNICAL SUPPORT
OF DAVID.
>>GOOD NIGHT. EVERYBODY.