GOOD MORNING.

AND WELCOME.

MY NAME IS IS PAM ROBY FROM THE

NATIONAL INSTITUTE OF DENTAL AND

CRANIOFACIAL RESEARCH.

YOU WOULD LIKE -- I WOULD LIKE

TO WELCOME YOU TO OUR WORKSHOP

TODAY AND TOMORROW THE

PLURIPOTENT STEM CELL AND

TRANSLATION PRE-CLINICAL

CONSIDERATIONS.

THIS IS ACTUALLY THE SECOND

WORKSHOP IN A SERIES.

WE HAD A PREVIOUS WORKSHOP LAST

MAY, APRIL, SORRY.

WHERE WE TALKED ABOUT EARLY

DECISIONS AND IN THIS PARTICULAR

WORKSHOP WE'RE GOING TO GO

FURTHER AND TALK ABOUT

APPROXIMATE MALL MODELS AND PR

CLINICAL KINDS OF DECISIONS THAT

WE HAVE TO MAKE.

I WOULD LIKE TO INTRODUCE OUR

FIRST SPEAKER, DR. WALTER

KOROSHETZ, THE DEPUTY DIRECTOR

OF NINDS.

HE IS STANDING IN FOR STORY

LANDIS WHO UNFORTUNATELY

COULDN'T BE WITH US TODAY.

HE'S INTIMATELY INVOLVED IN MANY

NINDS CLINICAL ACTIVITIES AND IN

PARTICULAR HE HAS BEEN WORKING

WITH THE CENTER FOR NEUROSCIENCE

AND REGENERATIVE MEDICINE, A

COLLABORATIVE PROGRAM BETWEEN

NIH AND THE DEPARTMENT OF

DEFENSE, FOR THE TREATMENT OF

TRAUMATIC BRAIN INJURY.

THANK YOU FOR JOINING US.

I WANT TO THANK EVERYONE FOR

COMING.

IT'S INCREDIBLY IMPORTANT

MEETING TO START TALKING ABOUT

PRE-CLINICAL CONSIDERATIONS WITH

REGARD TO STEM CELL PLURIPOTENT

CELLS.

THE PROBLEMS THAT YOU'RE GOING

TO BE TALKING ABOUT, SOME WILL

BE UNIQUE BUT THE PROBLEM OF

MOVING PRE-CLINICAL TO CLINICAL

IS DIFFICULT ONE NO MATTER WHAT

AREA YOU'RE IN, WE RECENTLY HAD

A MEETING ON THIS TOPIC BECAUSE

AS YOU KNOW IN THE SMALL

MOLECULE FIELD WE HAVE FACED A

LOT OF HURDLES IN TRYING TO

OPTIMIZE PRE-CLINICAL RESEARCH

AND ACTUALLY AN INTEREST AT NIH

TO LOOK IN THAT FEELTD, RAJESH

RAGANATHAN IS HERE TO TELL YOU

ABOUT SOME OF THE LESSONS

LEARNED, AS YOU MOVE FORWARD

INTO THIS REALLY FRONTIER SPACE

YOU'RE ENTERING NOW.

WE'RE TALKING P TOPICS IN THE

MIDDLE OF THE SLIDE.

PROAF CUSSLY THE GROUP DISCUSSED

PLURIPOTENT STEM CELL SOURCES

AND BANKING.

WE PROGRAMMING AND CONTROLLING

CELL PROPERTIES AND CELL

CHARACTERIZATION.

IT SHOULD DETERMINE A LOT OF

PRE-CLINICAL SCIENCE SO ONE

ERROR THAT HAS BEEN ACKNOWLEDGED

BY US AND PHARMACEUTICAL

COMPANIES IS OFTENTIMES THE

DEVELOPMENT PROCESS, GOES ON IN

THE ABSENCE OF FEEDBACK FROM THE

CLINICAL PROCESS AND THERE'S A

BIG HURDLE TO BE OVERCOME IN

TRYING TO THINK ABOUT WHAT IS

THE CLINICAL MODEL AND HOW THAT

DETERMINES YOUR PRE-CLINICAL

MODEL.

YOU NEED TO KNOW THAT AS SOON AS

YOU CAN.

UNIQUE TO THIS AREA IS CELL

DELIVERY AND TRACKING, WHAT ARE

THESE CELLS DOING, WHERE ARE

THEY GOING, HOW LONG THEY'RE

STAYING THERE.

ON THE ENDOCRINE OR

MICROENDOCRINE SIDE.

THE SAFETY AND PRE-CLINICAL STU

DOES DESIGNS ARE OF COURSE

SPECIAL IMPORTANCE TO THE FDA,

AS THEY AS THEY TRY TO NEGOTIATE

WITH THE SIGNTIS THE NEW SPACE

TRYING TO MOVE PROMISING NEW

THERAPIES INTO AN AREA THAT HAS

NEVER BEEN DONE BEFORE AND

KEEPING A REALLY STRONG EYE ON

SAFETY.

ONE DOES NOT HAVE TO LOOK FAR TO

SEE WHERE TROUBLES CAN HURT A

FIELD, ONE LOOKS BACK AT

TROUBLES GENE THERAPY HAD AND

MANY WILL ASCRIBE TO THE VIEW

THAT THOSE TROUBLES THAT CAME

WITH REGARD TO SAFETY STOPPED

THE PROGRAM BUT SIGNIFICANT

IMPACTS ON APPROXIMATE ENTIRE

FIELD.

THAT'S SOMETHING YOU WANT TO BE

EXTREMELY CAREFUL OF BECAUSE

THERE ARE SAFETY CONCERNS THAT

COME UP SO YOU WANT TO BE

CAREFUL WITH THE FDA TO GO INTO

THE CLINIC THESE SAFETY ISSUES

ARE REALLY LOOK AT CAR FRIDAY

FOR YOUR PROJECT AND ALSO THE

ENTIRE FIELD.

COMBINATION PRODUCTS, WHEN WE

TALK ABOUT SOME OF THE DISEASES

THAT WE'RE TRYING TO WORK ON FOR

MANY, WE HAVE WORKED WITH A

SINGLE TARGET MOLECULE AND

FAILED.

ANOTHER TARGET AND FAILED,

ANOTHER TARGET AND FAILED AND

THERE IS A CONSENSUS THAT SOME

DISORDERS YOU NEED COMBINATION

THERAPIES TO MAKE A DIFFERENCE.

WITH CELLAR THERAPY YOU MAYBE

WORKING WITH CELLS L THAT ARE

TRANSPORTING MOLECULES OF

INTEREST, GENES OF INTEREST EBB

TO AN AREA SO YOU'RE LOOKING AT

TWO EXPERIMENTAL PARADIGMS AT

ONCE.

AGAIN, MUCH MORE DIFFICULT AREA,

ONE CERTAINLY THAT FARM SUECAL

COMPANIES HAVE SHIED AWAY FROM

BUT BIOLOGICALLY MAKES THE MOST

SENSE.

SO HOW TO MANEUVER THAT SPACE IN

DISCUSSIONS WITH THE FDA IS

INCREDIBLY IMPORTANT.

THEN EMERGING AREAS CLEARLY IN

THIS AREA SUCH A NEW AREA, WITH

SUCH POTENTIAL, I'M SURE THE

THINGS WE'RE THINKING OF NOW,

PEOPLE CHUCKLE AT IN 50 YEARS

BECAUSE THEY SEE WE WERE JUST

REALLY LOOKING AT A PIECE AND

THERE'S SOMETHING MUCH BIGGER

THAT WILL EXPLODE OVER TIME.

THE KEY THEMES ARE CONTINUING

THE PRODUCT DEVELOPMENT LINE,

UNDERSTANDING AND DISCUSSING HOW

THE NIH AND FDA CAN COLLABORATE

WITH THE SCIENTISTS AND MOVE THE

FIELD FORWARD.

AND TO TAKE LESSONS FROM REAL

WORLD EXPERIENCES.

THE CORE PLANNING COMMITTEE AND

EXOFFICIO COMMITTEE, THAT DEBT

OF GRATITUDE TO PEOPLE THAT DID

THE HARD WORK BEHIND THE SCENES

TO MAKE THE MEETING HAPPEN AND

WE'LL BE WORKING TO MAKE SURE

IT'S PRODUCTIVE AS WE MOVE

ALONG.

STORY WANTED ME TO MENTION A

COUPLE OF THINGS IN TERMS OF THE

NATIONAL INSTITUTE OF HEALTH,

SOME IS BACKGROUND, BUT THOUGHT

IT WAS RELEVANT TO YOUR

DELIBERATIONS TODAY.

NIH'S MISSION IS TO SEEK

FUNDAMENTAL KNOWLEDGE ABOUT THE

NATURE AND BEHAVIOR OF LIVING

SYSTEMS AN APPLICATION OF

KNOWLEDGE TO ENHANCE HEALTH,

LENGTHEN LIFE AND REDUCE BURDENS

AND DISABILITY.

KIND OF THIS ONE INTEGRATED

SCIENTIFIC PATH WE'RE ON AND

CERTAINLY IN THE STEM CELL FIELD

PEOPLE LEARNING AMAZING BASIC

SCIENCE COLONELS OF KNOWLEDGE

IMPORTANT FOR DEVELOPMENT

DEGENERATION.

AS WELL AS THE IDEA THAT NEW

TECHNOLOGIES ARE HELPFUL FOR

THERAPEUTIC DEVELOPMENT AND CELL

REPLACEMENT THERAPY.

SO I THINK THAT IT IS REASONABLE

TO THINK OF THIS EFFORT AS ONE

THINKS OF THE NIH MISSION AS

MULTI-FACTORIAL AS YOU MOVE

AHEAD.

AND TO TRY TO ALWAYS INTEGRATE

THE NEW FINDINGS FROM THE BASIC

SCIENCE WITH THE -- YOUR EFFORTS

TO MOVE THINGS TRANSLATIONALLY.

SO THE DIFFICULT THING ABOUT NIH

IS IT'S COMPOSED OF 27

INSTITUTES AN CENTERS THE GOOD

THING IS IT'S COMPOSED OF 27

INSTITUTES AND CENTERS SO PEOPLE

GREAT EXPERTISE IN PARTICULAR

AREAS AND TO TAP INTO THAT

EXPERTISE AND THAT MISSION IS

IMPORTANT.

BUT THEN IT'S ALSO PUTS

RESPONSIBILITY ON THE NIH ITSELF

WHEN SYSTEM OF THESE PROBLEMS

WHICH ARE GENERAL RAKE PROBLEMS

THAT -- GENERIC PROBLEMS TO FORM

GROUPS SUCH AS THE ONE PUTTING

ON THIS MEETING SO THAT THE

INSTITUTES ARE NOT ACTING AS

SILOS BUT WORKING TOGETHER.

WE FUND ARE SEARCH IN DIFFERENT

AREAS, DIFFERENT STOUTS ARE

SOMEWHAT DIFFERENT IN MECHANISMS

THAT THAT YOU HAVE BUT WE HAVE

PRIMARILY GRANTS WHICH WE GIVE

TO INVESTIGATORS MOST OF OUR

RESEARCH GOES TO INVESTIGATOR

INITIATED RESEARCH SO IDEAS THAT

COME IN, GET PEER ARE VIEWED,

GET SCORES, GO TO THE INSTITUTES

AND STARTS PAYING THE SCORES

UNTIL THEY RUN OUT OF MONEY SO

IT'S NOT LIKE WE DON'T LIKE YOUR

GRANT TO GET FUNDED BUT IT'S

JUST FELL ABOVE WHERE WE HAD

ENOUGH MONEY TO HAVE ENOUGH

MONEY TO DO SOMETHING SO KNOWING

HOW THE SYSTEM WORKS FOR SYSTEMS

IS IMPORTANT.

SYSTEM OF PEER REVIEW HAS

CERTAIN VAGARIES TO IT.

IT CAN MAKE PEOPLE FRUSTRATED

BUT IF YOU GO AROUND THE WORLD

YOU SEE IT'S REALLY THE BEST

SYSTEM IN THE WORLD.

IT IT'S THE ONLY PLACE WHERE

SOMEONE WITH GOOD IDEA CAN COME

IN AND GET AN HONEST LOOK AT THE

IDEA PAY LINE GET FUNDING FOR

RESEARCH.

WE FUND THROUGH CONTRACT

MECHANISM COOPERATIVE AGREEMENTS

AND SPECIAL CIRCUMSTANCES WHERE

THERE'S A MISSION THAT NEEDS TO

BE ACCOMPLISHED AND A MUCH MORE

CE FINED MILESTONE DRIVEN

PROCESS TO GET THROUGH.

FOR INSTANCE AS RAJESH WILL TALK

ABOUT HOW WE WORK ALONG

MILESTONES TO DEVELOP NEWTHER

THERAPIES TO THE FAD FOR IND

OVER A FIVE YEAR PERIOD.

COOPERATIVE AGREEMENTS WORKING

ON MILESTONES, RELEASING FURTHER

MONEY IF MILESTONES ARE HIT.

THEN SOME INSTITUTES WILL ALSO

DO CONTRACTS FOR PARTICULAR

PRODUCTS THAT THEY NEED TO GET

DONE.

WE FUND BASIC TRANSLATIONAL

CLINICAL RESEARCH UP TO CLINICAL

TRIALS.

AND MENTIONED THE PEER REVIEW

SYSTEM.

STEM CELL RESEARCH IS WELL

REPRESENTED IN OUR PORTFOLIO.

IT'S ESTIMATED THAT ABOUT

1.2 BILLION OF THE NIH MONEY

WENT TO RESEARCH THAT WAS

RELEVANT TO STEM CELL BIOLOGY,

ABOUT 3.5% OF THE TOTAL BUDGET

WHICH IS $31 BILLION.

WE SUPPORT ALL TYPES OF STEM

CELL RESEARCH HUMAN AND

NON-HUMAN, EM EMBRYONIC,

NON-EMBRYONIC, PAY SICK AND

TRANSLATIONAL AND THE

FUNDAMENTAL CATEGORIES WITH

DETERMINE -- ARE DETERMINED BY

PEER REVIEW.

IT'S NOT PEOPLE SITTING AT THE

TOP SAYING WE WANT THIS PERCENT

OF MONEY IN PLURIPOTENT CELLS

AND THIS FROM HUMAN EMBRYONIC

CELLS.

WHAT HAPPENS IS A TESTAMENT TO

THE GOOD IDEAS COMING INTO PEER

REVIEW THAT DRIVE HOW MUCH MONEY

GOES INTO DIFFERENT AREAS.

FROM OUR INSTITUTE WE ARE STILL

ON THIS PROBLEM OF AS AN EXAMPLE

OF TRYING TO REPLACE DOPAMINE

NEURONS IN PATIENTS WITH

PARKINSON'S DISEASE.

AS YOU MAY KNOW PARKINSON'S

DISEASE IS DUE TO DEATH OF

CERTAIN SEGMENT OF NEURONS IN

THE NERVOUS SYSTEM, ONE SEGMENT

IS THE DOPAMINE PRODUCING NEURON

AND THE MODE OF MANIFESTATION OF

PARKINSON'S, MANY CAN BE EARLY

STAGES, CAN BE TAKEN AWAY BY

DOPAMINE AGONIST SO WE KNOW

PHARMACO LOGICALLY THAT BY

GIVING PEOPLE SENTEMED CAR

BYDOPA, THESE CELLS THAT ARE

SICK AND TUL REMAINING, 80% ARE

DEAD BY THE TIME THEY FIND

SYMPTOMS THE REST THE 20% WE CAN

SUPPLY DOPAMINE SUBSTRATE, THE

SYMPTOMS CAN DISAPPEAR IN THE

EARLY STAGES OF THE DISEASE.

UNFORTUNATELY, THOSE CELLS

CONTINUE TO DIE AS YOU GET DOWN

TO FEWER AND FEWER THE DRUGS

DON'T WORK ANY MORE AND YOU GET

BASICALLY A SEVERELY DISABLED

PERSON.

BUT IT ALSO HAS BEEN A HOOK THAT

IF WE CAN JUST KEEP THIS

DOPAMINE SYSTEM ALIVE AND EVEN

AT 20% LEVEL WITH THE DRUGS

THESE PEOPLE WILL DO VERY WELL

FOR LONG PERIODS OF TIME.

SO THAT'S BEEN KIND OF THE THING

THAT'S DRIVEN US TO TRY TO WORK

ON REPLACING THE CELLS AND AS

YOU MAY KNOW, 20 YEARS AGO OR SO

WE FUNNED A TRIAL HUMAN

EMBRYONIC STEM CELLS TO REPLACE

CELLS IN PATIENTS WITH

PARKINSON'S.

THAT TRIAL DIDN'T GO SO WELL, IT

WAS EARLY DAYS, CELLS WE NO ONE

KNEW HOW TO CONTROL THEM,

PATIENTS HAD SIDE EFFECTS DUE TO

CELLS RELEASING TOO MUCH

DOPAMINE SO IN SOME PATIENTS

THERE WAS NO EFFECT, SOME

PATIENTS IT WAS LIKE AN OVERDOSE

EFFECT.

AND SO THAT TRIAL WAS STOPPED.

STILL SOME THINK THIS MAYBE A

MINORITY OF PATIENTS WHICH

THINGS HIT SWEET SPOT AND 20

YEARS LATER THE PATIENTS ARE

DOING WELL BUT THAT'S WE'RE

TALKING TWO OR THREE PATIENTS

AND I DON'T THINK THAT'S

PUBLISHED.

STILL, WE HAVE THAT HOOK THAT

MAYBE THIS REALLY IS A VIABLE

WAY TO GO FORWARD BUT MAYBE WE

NEED NEW TECHNOLOGY, CELLS THAT

INTEGRATE BETTER, CELLS THAT ARE

MUCH MORE NORMAL IN ACTION TO

AVOID THIS OVERDOSE RELEASE.

SO WE'RE INTERESTED, THIS IS

JUST AN EXAMPLE OF PEOPLE

LOOKING AT WAYS OF TAKING THE

PLURIPOTENT STEM CELLS AND

DEVELOPING PARTICULAR WAYS OF

TWEAKING THOSE CELLS TO GET THAT

PARTICULAR TYPE OF DOPAMINE

CELL, IN THE PAST IT WAS ANY

DOPAMINE CELL WOULD WORK AND WE

WOULD SETTLE FOR THAT BUT HERE

INVESTIGATORS ARE REFINING THE

ACTUAL DOPAMINE CELLS L BY

FORCING THEM IN A PATHWAY THAT

HAS GOOD BIOLOGICAL REASONS TO

ASSUME A MORE NORMAL PATHWAY.

CLAIMING THESE EXPERIMENTS IF

YOU LOOK AT FOR INSTANCE THE

DIAGRAM ON THE RIGHT HERE, WHERE

THE PHENOTYPE HERE IS WHEN YOU

GIVE ANIMALS WHO HAD THEIR

DOPAMINE CELLS REMOVED ON ONE

SIDE OF THE BRAIN WITH THE

TOXIN, THAT'S OUR MODEL.

THEN YOU TRANSPLANT YOUR

PLURIPOTENT CELLS PUSHED TOWARD

DOPAMINE PHENOTYPE INTO THE

BRAIN AND YOU GIVE ANIMALS

AMPHETAMINE, IN THE

UNTRANSPLANTED AT A TIME THEY

RUN AROUND IN CIRCLES

CONTINUOUSLY.

THE NORMALIZATION EFFECT IS FOR

THAT TURNING BEHAVIOR TO STOP.

YOU CAN SEE HERE WHEN THEY LOOK

AT ROSETTE DERIVED T H POSITIVE

DOPAMINE CELLS VERSUS THEIR

TWEAKED PATHWAY TOWARDS WHAT

THEY CALL FOUR PLATE DERIVED

CELLS WHICH HAVE BIOLOGICAL

PROPERTIES THAT SEEM MORE NORMAL

FOR THESE DOPAMINE CELLS YOU CAN

SEE THAT SOME INITIAL

IMPROVEMENT BUT THEN IT WAS LOST

IN THE FOUR PLATE DERIVED YOU

GET A COMPLETE NORMALIZATION OF

ABNORMAL TURNING BEHAVIOR WHICH

IS A CRUDE PHENOTYPE BUT IS ONE

COMMONLY USED TO SHOW THAT YOU

HAVE CURED THE MOTOR PHENOTYPE

IN THESE ANIMALS.

SO THIS WAS BASICALLY THEY KID

IT IN MICE, IN RATS, IMMUNE

SUPPRESSED AND DID IT IN A

NUMBER OF MONKEYS.

SO MULTIPLE DIFFERENT SPECIES,

REPLICATING AT EACH STEP.

SO THE QUESTION NOW IS IS THIS

READY FOR PRIME TIME, WHAT DO

YOU NEED TO GET PRIME TIME AND

THESE DISCUSSIONS WITH THE FDA

COME TO A HEAD.

THE ISSUES OF TOW MORE FORMATION

OVERGROWTH OF NEURAL CELLS HAVE

TO BE WORKED OUT.

$123 MILLION ASSIGNED NON-HUMAN

EMBRYONIC STEM CELL RESEARCH,

165 MILLION, HUMAN INDUCED

PLURIPOTENT STEM CELLS,

124 MILLION IN NON-HUMAN IPS

CELL, 37 MILLION.

THE INITIAL INVESTMENT 170 LINES

OF HUMAN EMBRYONIC STEM CELLS

APPROVED FOR FEDERAL FUNDING AND

COUPLE OF THINGS HAVE CHANGED,

THAT WILL BE BROUGHT OUT TODAY.

THOSE ARE THE FACT THAT IN THE

LAST YEAR NIH HAS STARTED THIS

NIH CENTER FOR REGENERATIVE

MEDICINE WHICH MAHENDRA RAO IS

HERE TO TALK ABOUT AND ALSO A

NEW TRANSLATIONAL CENTER CALLED

NCATS.

CENTER FOR REGENERATIVE

MEDICINE.

I WON'T GO INTO IN DETAIL.

AS MAHENDRA WILL THE REST OF THE

DAY.

NCATS IS AN INSTITUTE TRYING TO

SOLVE PROBLEMS OF TRANSLATION.

WE OPENED DISCUSSION TODAY

TELLING YOU ABOUT THE SMALL

MOLECULES SURE PEOPLE ARE WARE

OF THEM AS WELL AS PROBLEMS

YOU'RE FACING AND OTHER CLINICAL

TRANSLATIONAL AREAS THAT ARE

BRAND NEW FACING.

SO OUR HOPE IS THE INSTITUTE

WILL ENGINEER SOLUTIONS TO THE

PROBLEMS THAT WE HAVE BEEN

HITTING.

SO WITH THAT, I'M GOING TO CLOSE

AND WISH YOU THE BEST FOR THE

MEETING.

AND THANKS TO EVERYBODY ELSE FOR

COMING AND THANKS FOR THE

COMMITTEE FOR DOING THE HARD

WORK.

THANKS.

[APPLAUSE]

>> THANK YOU, DR. KOROSHETZ.

OUR NEXT SPREAR IS DR. CELIA

WITTEN, DIRECTOR OF THE OFFICE

OF CELLULAR TISSUE AND GENE

THERAPY AT FDA CENTER FOR

BIOLOGICS EVALUATION AND

RESEARCH, OTHERWISE KNOWN AS A

CBER.

SHE'S GOING TO GIVE YOU A SHORT

RECAP OF OUR FIRST WORKSHOP SO

THAT EVERYBODY IS STARTING OFF

ON THE SAME PAGE.

THANK YOU.

>> THANK YOU, I WOULD LIKE TO

WELCOME EVERYBODY TO THIS

WORKSHOP WHICH I HAVE BEEN

WORKING ON PLANNING FOR AND

LOOKING FORWARD TO FOR A WHILE.

SO I'M GOING TO GIVE A BRIEF

OVERVIEW OF MY OFFICE AND WHAT

WE DO AND ALSO TALK BRIEFLY

ABOUT PAST WORKSHOP AND WHAT WE

HOPE TO GET OUT OF THIS

WORKSHOP.

JUST TO MAKE A COMMENT ABOUT OUR

MISSION, EVERYBODY THINKS OF FDA

AS BEING THE ORGANIZATION

RESPONSIBLE FOR REGULATION AND

PROTECTING PUBLIC HEALTH BY

LOOKING AT SAFETY AND EFFICACY.

WE ALSO DO HAVE AS PART OF OUR

FORMAL MISSION STATEMENT

ADVANCING PUBLIC HEALTH BY

HELPING TO SPEED INNOVATIONS AND

OUR EFFORTS WITH GROUPS LIKE

THIS ONE THAT HAVE DIALOGUE WITH

THE SCIENTIFIC COMMUNITY AS PART

OF OUR WAY OF ACCOMPLISHING THAT

INNOVATIONS PART OF OUR MISSION.

FDA AS MANY OF YOU KNOW HAS A

NUMBER OF CENTERS THREE WHICH

DEAL WITH MEDICAL PRODUCTS AND

OUR OFFICE IS IN THE CENTER FOR

PIE LOGICS, ONE OF THREE OFFICES

THAT DOES PRE-MARKET REVIEW.

I HAVE HERE EXAMPLES OF THE

PRODUCTS IN OUR OFFICE, OFFICE

OF CELLULAR TISSUE AND GENE

THERAPIES.

AND SOME OF THESE ARE OVERLPING

CATEGORIES.

SO WF STEM CELL AN STEM CELL

DERIVED PRODUCTS.

SOMATIC CELL THERAPY, CANCER

VACCINES AN ACTIVE

IMMUNOTHERAPIES GENE THERAPY AND

A FEW DEVICES AND COMBINATION

PRODUCTS.

THE ACTIVITIES IN OUR OFFICE

INCLUDE REGULATORY REVIEW,

POLICY AND REGULATORY GUIDANCE

DEVELOPMENT AND I'M GOING TO

GIVE A COUPLE OF EXAMPLES,

OUTREACH, MEETINGS LIKE THIS,

ADVISORY COMMITTEE MEETINGS

OTHER TYPES OF INTERACTIONS WITH

THE PUBLIC, PUBLICATIONS AND WE

HAVE AN ACTIVE GROUP THAT DOES

MISSION RELATED RESEARCH THAT

SOME ARE FAMILIARk#Nh WITH ON
THE

NIH CAMPUS IN BUILDING 29.

HERE THIS SLIDE TELLS YOU A BIT

ABOUT THE VOLUME OF NEW STUDIES.

SO TES ARE INVESTIGATIONAL

STUDIES.

I DON'T HAVE A SEPARATE SLIDE

ABOUT LICENSING.

WE LICENSED CORED BLOOD AND

OTHER APPLICATIONS THIS YEAR.

BUT THIS IS AN IDEA HOW MANY NEW

INVESTIGATIONAL NEW DRUG OR

DEVICE EXEMPTION STUDIES THAT WE

REVIEW ANNUALLY.

THE DEVICES ARE ONLY A SMALL

PORTION OF THIS.

WE SEEM TO HAVE HAD A UPTICK IN

INTEREST IN THE LAST YEAR, 2011

WHICH SEEMS TO BE CONTINUING

THIS YEAR SO I HOPE THAT SPEAKS

FAVORABLY ABOUT STATE OF THE

SCIENCE AND CLIMATE FOR

DEVELOPMENT OF SOME OF THESE

APPROACHES.

AS I MENTIONED ONE OF THE TYPES

OF OUTREACH AND COMMUNICATION WE

DO IS PUBLICATION OF GUIDANCE.

THESE ARE SOME OF THE GUIDANCE

WE HAVE PUBLISHED MANY THE LAST

YEAR AND A HALF, WHAT I WANT TO

HIGHLIGHT IS THIS, OUR PROGRAM

PRIORITY, THE HIGHEST PROGRAM

PRY YOUR TU FOR THIS YEAR IS

PUBLISHING A DRAFT GUIDANCE OF

CELLULAR AN GENE THERAPY

PRODUCTS SO I HOPE THAT WE -- I

CAN MAKE MO PROMISES ABOUT

TIMING BUT I HOPE WE'RE ABLE TO

COME UP WITH THAT SOMETIME THIS

THIS CALENDAR YEAR.

WE HAD A NUMBER OF ADVISORY

COMMITTEE MEETINGS THAT WOULD BE

OF INTEREST IN THIS GROUP AND

THIS IS THE LAST YEAR AND A HALF

WORTH OF ADVISORY COMMITTEE

MEETINGS.

ONE IS TO UPDATE POLICIES ON TO

ASK THE AD SIZERY COMMITTEE FOR

INFORMATION RELATED TO POLICIES

ON TESTING FOR REPLICATION OF

COMPETENT RETROVIRUS AN

LENTIVIRUS IN GENE HER PI

TRIALS.

WE HAD AN ADVISORY COMMITTEE

MEETING ON CELL THERAPY TRIALS

IN RETINAL DISEASE TO ASK ABOUT

PRE-CLINICAL AND PRIMARILY

CLINICAL DEVELOPMENT STRATEGIES

FOR THESE PRODUCTS AS WELL AS A

MEETING ABOUT CORED BLOOD, A

DEVICE FOR CELL SORTING AND BLA

FOR DENTAL USE.

WE HAVE INTERNATIONAL

ENGAGEMENTS, AS I KNOW EVERYBODY

HERE IS AWARE, THERE IS ACTIVITY

INTERNATIONALLY IN THE STEM CELL

AREA AND SCIENCE IS CERTAINLY

INTERNATIONAL, SO THEREFORE, WE

ALSO HAVE INTERNATIONAL

REGULATORY ACTIVITIES AND WE'RE

ASKED WHAT KIND OF DIALOGUE WITH

OUR INTERNATIONAL PARTNERS.

WE HAVE A REGULATOR FORUM BEING

DEVELOPED LOOSELY ASSOCIATED

WITH ICH THAT'S NOT A FORMAL ICH

EFFORT.

WE HAVE A FORMALIZED CLUSTER

MEETING WITH EMA, ADVANCED

THERAPEUTIC MEDICINAL PRODUCT.

WE SPEAK TO THEM AND WE ALSO

HAVE HAVE SOMETIMES PARALLEL

ADVICE IF A SPONSOR WANTS TO

KNOW GET ADVISE SIMULTANEOUSLY

FROM US AN EMA WE'LL HAVE A

ADVICE MEETING.

AND WE HAVE ACTIVITIES ALSO WITH

THE APAC GROUP AND INTERNATIONAL

ACTIVITIES ON ALTERNATIVE

METHODS TO ANIMAL TESTING.

SO THE WORKSHOPS REFERRED TO

INCLUDE THE WORKSHOP IN MARCH ON

PLURIPOTENT STEM CELLS AN

TRANSLATION EARLY DECISIONS.

THE PREVIOUS WORKSHOP PREVIOUS

TO THIS ONE.

THAT COVERED A NUMBER OF TOPICS

INCLUDING PRODUCT CHARACTER

SAWX, SOURCE CONTROL AND

EMERGING SECONDNOLOGIES.

I WON'T GO INTO IT IN ENORMOUS

DETAIL SINCE I THINK THERE'S

QUITE AN OVERLAP BETWEEN THIS

AUDIENCE AND THE AUDIENCE AT

THAT MEETING BUT I WILL JUST

MENTION SOME HIGHLIGHTS WHICH

WAS THE DISCUSSION OF SOURCE

CONTROL ATTRACTED INTEREST

BECAUSE I BELIEVE IT WAS VERY

GOOD FORUM FOR A MEETING OF MIND

IN TERMS OF HOW DONOR

ELIGIBILITY RULES NEED TO BE

LOOKED AT SEPARATELY FROM NIH

PROCESS FOR LOOKING AT CELLS AND

APPROVING CELL LINES FOR USE.

SO INFORMATION ON SOURCE CONTROL

AND DONOR ELIGIBILITY ROLES IN

PARTICULAR WAS A GOOD DISCUSSION

AT THIS MEETING.

THERE WAS A DISCUSSION ON

EMERGING TECHNOLOGIES AND THESE

ARE EXAMPLES THAT RELATE

DIRECTLY TO THIS MEETING IN THE

SENSE THAT SOME QUESTIONS YOU

WANT TO ASK HAVE TO BE RELATED

LINK Electronics, Inc.

MODEL NUMBER: PDR-885

SOFTWARE VERSION: 3.0A

TEST TEST TEST TEST TEST TEST

TEST TEST TEST TEST TEST TEST

TEST TEST TEST TEST TEST TEST

TEST TEST TEST TEST SO AGAIN, I

WANT TO RE-EMPHASIZE THERE'S

SEVERAL -- THE FDA HAS

EXPERIENCED SEVERAL CURRENT

TRIALS RELATED TO STEM CELLS AND

PRIMARY CELLS THAT ARE ON GOING,

SEVERAL KINDS OF EFFORTS.

AND ALL SORT OF PHASES OF

APPROVAL PROCESSES THAT WE JUST

HEARD ABOUT.

JUST WANT TO SWITCH THEN TALKING

ABOUT WHAT'S HAPPENING WITH WHAT

WE CAME UP AS TAKE AWAYS FROM

THE FIRST MEETING.

THERE WAS A BIG ISSUE WITH

CONSENT AND I WANT TO REMIND

PEOPLE WHO ARE HERE THAT THE

CONSENT ISSUE WITH RESULTS

RELATED NOT JUST TO THE FACT

THAT WHAT'S THE LANGUAGE IN

CONCEPT BUT THE TIMING OF

CONSENT AND THE RECONSENT ISSUES

AND WHAT YOU CAN DO WITH STOOL

SAMPLES OR SAMPLES FROM DISEASE

PATIENTS WITH YOU MIGHT ONLY USE

FOR A PARTICULAR PURPOSE, WHAT

YOU HAVE TO DO IF THERE ARE

DIFFERENT CONSENT FORMS,

ADDITIONAL REQUIREMENT IN TERMS

OF HOW YOU CHECK THE TISSUE.

THERE'S A WHOLE LIST OF ISSUES

THAT CAME UP AT THAT MEETING AND

THERE WAS RESPONSES BY THE FDA

AND THE NIH IN TERMS OF BEING

ABLE TO MOVE FORWARD.

I WOULD ENCOURAGE YOU AVAILABLE

DRAFT RULES PROPOSED FOR CONSENT

BASED ON DISCUSSIONS HAD BY

VARIETY OF STAKEHOLDERS.

THE FIRST MEETING THERE WAS

SEVERAL ISSUES COVERED.

I'M NOT GOING TO TRY TO DISCUSS

ALL OF THEM BUT TRY TO HIGHLIGHT

THEM WITH STANDARD MODEL, YOU

HAVE THE THINK ABOUT GOING

TOWARDS THE CLINICAL TRIAL IN

TERMS OF MANUFACTURED PRODUCT,

IN TERMS OF THINKING ABOUT

SOURCING, DERIVATION OF THE

CELLS, MAKING SHOOR YOUR

TIRCHIATE AND -- SURE YOU

DIFFERENTIATE AND MANUFACTURE

THEM, SORT THE CELLS, ENGINEER

THE CELLS DEPENDING ON WHAT THE

END GOAL IS AND PERFORM

PRE-CLINICAL STUDIES, CLINICAL

STUDIES AN APPLY FOR LICENSE

INSURE OF NEW DRUG.

THE IMPORTANT THING IS WHY I PUT

ANYTIME A LINEAR FASHION, IT'S

IMPORTANT TO DO PRE-CLINICAL

STUDIES WITH THE PRODUCT YOU'RE

GOING TO FINALLY MANUFACTURE BY

THE PROCESS YOU HAVE ALREADY

MANUFACTURED SO THERE'S A LINEAR

SEQUENCE.

YOU CAN'T RUSH TO DO YOUR PRTS

WITH A SIMILAR -- PRE-CLINICAL

STUDIES AND STILL EXPECT TO GET

APPROVAL UNLESS IT WAS SIMILAR.

LIKEWISE WHEN YOU DO YOUR

PRE-CLINICAL STUDIES YOU BETTER

HAVE THE MECHANISMS LATER IN THE

RELEASE CRITERIA SECTOR WORKED

OUT SO THAT WHEN YOU PERFORM

YOUR CLINICAL STUDIES YOU

MATCHED OR YOU HAVE DATA AS TO

WHY YOU LOOK AT IT, YOU KNOW

WHAT THE DOSE IS THAT YOU'RE

GOING TO USE AS WELL.

THAT'S A REALLY IMPORTANT LINEAR

SERIES, THAT'S WHY THE MEETINGS

WE LOOKED AT WERE DESIGNED THAT

WAY.

SO MANY ISSUES WERE COVERED IN

THE FIRST MEETING, WHERE YOU

HAVE THE MANUFACTURE THE CELLS

IN GFP AND CAN ENTER THE GMP

REQUIREMENT AND TUSH SHOE

DERIVATION, THE APPROPRIATE

CONSENT WHO OWNS THE MATERIAL,

WHAT IS THE SIZE TO MAKE AND HOW

YOU MAKE WORKING BANKS.

IF IT'S A PRIMARY CELL PRODUCT

HOW YOU REPLENISH THAT SEED BANK

AND WHAT YOU DO IN TERMS OF

QUALITY CONTROL AND TESTING FOR

NEW SEED BANK THAT YOU MAKE.

IS THERE SOMETHING LIKE A

RESEARCH PRODUCT TESTING TO

REDUCE THE TIME THAT YOU LOOK AT

IF YOU PERFORM ENGINEERING

THERE'S SCIENCE ISSUES AND

REGULATORY ISSUES WHEN YOU CAN

DO THAT ENGINEERING.

IF YOU HAVE TO SHIP CELLS, IS

THERE A RIGHT PROTOCOL YOU CAN

USE FOR LIVING CELLS P AND WILL

YOU TRACK OR TRACE THE CELLS NOT

IN VIVO BUT DURING THE

MANUFACTURING PROCESS.

LIKEWISE ISSUES WITH THE SITE

THAT YOU USE, I WON'T READ THEM

ALL LIEU BUT THERE'S SEVERAL

THINGS DISCUSSED AT THE LAST

MEETING.

LIKEWISE ISSUES RELATED TO

ENGINEERING, THAT YOU HAVE TO

LOOK AT BECAUSE THAT NOW IS LIKE

GENE THERAPY, SO THERE ARE

SPECIFIC REGULATIONS RELATED TO

GENE THERAPY TO WORRY ABOUT THAT

HAD TO BE INCORPORATED INTO ANY

MANUFACTURING DESIGN PROCESSES.

AND THAT WOULD BE IMPORTANT AS

WELL.

LIKEWISE THERE WERE SPECIFIC

ISSUES BROUGHT UP WITH SORTING

BECAUSE THERE WASN'T YET

CLINICALLY APPROVED FACT SORTER

AVAILABLE AND THERE ARE SEVERAL

COMPANIES TRYING TO GET

VALIDATION ON THOSE SORTS OF

SORTING.

PROCESSES AND IT'S IMPORTANT TO

UNDERSTAND WHERE THE FEEL WAS AT

AND ISSUES RELATED TO REGULATORY

COMPLIANCE TO USE SORTING OF

SELECTION AS METHOD.

YOU HEARD FROM CELIA THERE WAS A

SPECIAL MEETING BY THE FDA IN

TERMS OF LOOKING AT THE SORTING

PROCESS FOR CD34 POSITIVE CELLS

AND THAT'S AN L IMPORTANT

ALTERNATIVE TO FACT SORTING

APPROVED FOR MAKING SURE WE HAVE

CLINICAL PRODUCTS.

A LOT OF THIS ONE GOAL AS YOU

HEARD, NOT JUST TO HAVE A

MEETING BUT ALSO TO TAKE THE

RESULTS FROM THAT MEETING MAKE

SURE THEY'RE AVAILABLE AND ONE

WAY IS TO HAVE MEETING REPORTS

OR SUMMARIES OR WORK WITH OTHER

STAKEHOLDERS LIKE SOCIETY

SECTORS TO PUT THAT OUT THERE SO

THAT YOU HAVE SUMMARY AN ACCESS

TO INFORMATION.

SO WHILE WE POST THINGS ON THE

WEBSITE AS WELL, WE ALSO TRY TO

SUBMIT THESE AS MANUSCRIPTS OF

MEETING REVIEWS IN VARIOUS

JOURNALS, THIS IS AN EXAMPLE OF

WHAT HAPPENED AFTER THE FIRST

MEETING IN TERMS OF BEING ABLE

TO ISOLATE AND PRODUCE CELLS FOR

CELL THERAPY SPONSOR BY THE

ISCCR FOR THE VARIOUS MEETINGS

HELDEN COLLUDING THE ONE --

INCLUDING THE ONE HELD BUT NIH

AND THE FDA.

SO I WANT TO GO TO WHAT I THINK

ARE GOALS OF THIS MEETING AND TO

GO BACK AND QUICKLY SAY ONE

MEEDZ TO UNDERSTAND WHAT WE USE

ANIMAL MODELS FOR.

IT'S NOT JUST FOR EFFICACY,

WHICH IS WHAT MOST ACADEMIC

IMPORTANT FOR.

IT'S MUCH MORE THAN THAT.

YOU NEED TO UNDERSTAND THE

MECHANISM OF ACTION, LOOKING AT

ADOPTION OF PRODUCT, TRIX OF

PRODUCT, METABOLISM OF PRODUCT,

EXCRETION OF PRODUCT AND

TOXICITY OF THAT PRODUCT.

THAT'S AN IMPORTANT SET OF

THINGS DESIGNED FOR SMALL

MOLECULE THERAPY.

AND IT WAS DONE IN ANIMALS AND

WE HAVE TO GET SOME MODEL OR

EQUIVALENT MODEL OF DOING THAT

FOR CELL BASED THERAPY AS WELL.

WE HAVE TO LOOK AT THE

ASSOCIATED DEVICE OR DELIVERY

STUDIES THAT NEED TO BE DONE

BECAUSE YOU'RE GOING TO DELIVER

CELLS AND YOU HAVE TO VALIDATE

SOME OF YOUR SURROGATE MEASURES

OF MANUFACTURING IN PRE-CLINICAL

ANIMAL STUDIES SO YOU JUSTIFY

WHY YOU CAN RELEASE YOUR PRODUCT

AND YOU KNOW IT'S USEFUL IN SOME

FASHION.

SO YOU NEED DO THAT IN YOUR

ANIMAL STUDIES.

THERE ARE SPECIFIC ISSUES THAT

ARISE WHEN WE TRY TO TRANSLATE

THIS INTO USING ANIMAL CELLS --

MODELS FOR CELL BASED THERAPY.

WE HAVE DOSING ISSUES BECAUSE WE

CAN'T REALLY GET A MAXIMUM DOSE,

THERE'S A MAXIMUM FEASIBLE DOSE,

TERMINOLOGY WE HAVE TO THINK

ABOUT, THERE ARE ISSUES HOW WE

TRACK CELLS, ISSUES WITH

FOLLOW-UP OF CELLS, ISSUES WITH

TUMORIGENICITY ASSAYS, ISSUES OF

MECHANISM OF ACTION, ESPECIALLY

LOOKING A MIXED PRODUCT OR WHEN

THE MECHANISM OF ACTION NOT

KNOWN WHICH IS VERY COMMON WITH

CELL BASED THERAPY INCLUDING

MSCs, THAT PEOPLE HAVE BEEN

USING.

WE HAVE ISSUES HOW TO DESIGN THE

APPROPRIATE DEVICE VALIDATE TO

BE USED WITH CELLS.

AND WE DON'T QUITE KNOW WHAT ARE

THE SURROGATE MEASURES OF

POTENCY THAT WE CAN USE FOR CELL

BASED THIFT WHEN THE MECHANISM

OF ACTIVITY IS NOT KNOWN AND WE

HAVE TO FIGURE A WAY TO JUSTIFY

WHAT WE ARE DOING.

LAST ACCURACY OF DISEASE MODELS

AND ONE CRITICAL GENERAL ISSUE

AND THAT IS HOW DO YOU STUDY

IMMIEWB ISSUES IN A XENO MODEL.

I WANT TO EMPHASIZE THAT NEXT

PART OF MY TALK.

SO THAT'S IMPORTANT ANIMAL

STUDIES, WE HAVE TO WORRY ABOUT

THEM AND I TRIED TO LIST THEM

THE SAME WAY.

THE IMPORTANCE IS WE HAVE TO

SOLVE THESE BEFORE WE GO FORE TO

DOING PRE-CLINICAL TRIAL AND

MATCHING WITH YOUR PRE-CLINICAL

CELL BASED MANUFACTURE

EXPERIMENTS THAT YOU DESIGN.

AGAIN I WANT TO EMPHASIZE WE

DONE WANT TO REDISCOVER THE

BHEEL, I WANT TO EMPHASIZE TWO

THINGS, YOU HAVE THIS IN YOUR

HAHN OUTS THAT YOU GOT AT LEAST

AS PDF FOR PEOPLE REGISTERED.

AND THIS WAS MANUSCRIPT

SUBMITTED BY JOYCE FRAY ANDk-

OTHERS HERE IN THE MEETING, YOU

CAN TALK TO HER, THIS IS

SPONSORED BY THE CALIFORNIA

INSTITUTE OF REGENERATIVE

MEDICINE AND EMPHASIZE THE

ISSUES YOU HEAR AT THE MEETING,

YOU HAVE TO PERSPECTIVE FROM THE

MEETING THERE WAS A SECOND

MEETING YOU GOT THE MEETING

RESULTS AS WELL, THAT MEETING

WAS SPONSORED BY THE NINDS BUT

BY A DIFFERENCE IC THAN WHAT

YOU'RE HEARING TODAY.

YOU HAVE A SUMMARY OF THAT AND

THE PROGRAM OFFICE WHO LED THIS

WAS (INDISCERNIBLE) AND SEVERAL

PEOPLE SPEAKING TODAY HERE

EMPHASIZE THINGS ABOUT ISSUES

RELATED TO SMALL AND LARGE

ANIMALS, TRACKING ISSUES WHICH I

WOULD ENCOURAGE YOU LOOK T AT AN

INFORMATION PIECE AS WELL.

SO THE NEXT TWO OR THREE MINUTES

I WILL EMPHASIZE ISSUES WE HAVE

WITH THE IMMUNE SYSTEM.

PRODUCTS PROVOKE IMMUNE RESPONSE

BECAUSE YOU'RE USING FETAL CELLS

AND ANTIGEN WAS NEVER EXPRESSED

LATER IN DEVELOPMENT SO IT'S A

NEW ANTIGEN THOUGH IT'S AN

AUTOLOGOUS CELL.

THE XENOCOMPONENTS USED IN

MANUFACTURING CAN PROVIDE IMMUNE

RESPONSE, ANCILLARY COMPONENTS

MAYBE PRESENT BECAUSE OF THE THE

MANUFACTURING PROCESS OR BECAUSE

YOU'RE USING SCAFFOLDING SECTOR,

THERE MAYBE A MISMATCH ANTIGENS

TISSUE AND CELL PRODUCTS CAN

ALSO MODULATE AN IMMUNE RESPONSE

SO THAT'S AN IMPORTANT THING TO

RESPOND THAT THEY CAN CHANGE THE

IMMUNE RESPONSE SO YOU HAVE TO

TEST THESE THINGS AND THE HOST

CAN RESPOND DIFFERENTLY

DEPENDING ON THE HOST IMMUNE

STATUS OR WHAT THE PREVIOUS

EXPOSURE TO ANTIGEN AND WE KNOW

-- THIS CAN BECOME IMPORTANT

DOING SINGLE CELL INJECTION,

REPEAT INJECTIONS IN TERMS OF

THERAPY SECTOR.

SO ALL THESE BECOME REALLY

IMPORTANT IMMUNE ISSUES WE HAVE

TO WORRY ABOUT WHEN YOU PERFORM

PRE-CLINICAL ANIMAL MODELS AND

WE HAVE TO LOOK AT SOLUTIONS

THAT WE HAVE.

AND WE DONE REALLY HAVE A LOT OF

SOLUTIONS THAT WE CAN LOOK AT

BUT THESE ARE THINGS THAT PEOPLE

HAVE BEEN LOOKING AT, IMMUNE

SITES IN ANIMALS, HUMANIZED

ANIMAL MODELS, IMMUNE

COMPROMISED ANIMAL MODELS OR IN

VITRO EXPERIMENTS RATHER THAN IN

VIVO WHERE YOU CAN TO THIS OR

HOMOLOGOUS SPECIES EXPERIMENTS

BUT YOU HAVE ISSUES WITH THAT AS

WELL.

THE SECOND IMPORTANT ISSUE OTHER

THAN THE IMMUNE ISSUE DOING THAT

IS REPORTER ISSUES.

THERE ARE SEVERAL REPORTER

ISSUES.

THE REPORT ITSELF ENGINEERED TO

THE CELL, WE HAVE TO WORRY

WHETHER ENGINEERING CHANGED THE

CELL ITSELF OR THE REPORT ITSELF

MIGHT CAUSE AN IMMUNE RESPONSE,

THE SENSITIVITY ISSUES WITH THAT

TRACKING AND TRACING ISSUES THAT

WE HAVE TO WORRY ABOUT AND

DIVIDING CELLS THAT CHANGE THE

RESULT IN TERMS OF BEING ABLE TO

DO THAT AND WHEN WE USE CELLS

THAT'S WHAT WE'RE OFTEN DOING.

SILENCING ISSUES THAT WE HAVE TO

WORRY ABOUT WITH CELLS.

THE OTHER PART TO REMIND YOU OF

IS WHEN CELLS ARE NOT AN ISSUE.

THEY'RE GENERALLY NOT AN ISSUE

WHEN LOOKING CELLS WHICH ARE

WHAT'S CALLED THE HIT AND RUN

HYPOTHESIS IN TERMS OF TREATING

CELLS, YOU HOPE THE CELLS DIE,

GO AWAY AND USING THEM ONLY

TRANSIENTLY.

THEN YOU ONLY WORRY ABOUT THAT.

YOU HAVE TO ASK YOURSELF

QUESTIONS WE DONE KNOW, IS THIS

AN ISSUE WITH AUTOLOGOUS CELLS,

A SPECIAL PROBLEM YOU HAVE TO

WORRY ABOUT AND THE MULTI-SITE

SPECIFIC PROBLEM AS WELL.

THE LAST TWO SLIDES THAT I WANT

TO SHOW YOU ARE TRYING TO

EMPHASIZE ONE MORE PIECE, TO

REMIND YOU WE ARE GOING TO TRY

TO HAVE A MEETING IN THE FUTURE

ON THE CLINICAL TRIAL STUDIES AN

ISSUES RELATED TO THAT ALL I

WANT TO TRY TO EMPHASIZE TODAY

IS THAT TO STUDY ANY OF THESE

ISSUES YOU HAVE TO HAVE A

COMPLETE SET OF PRE-CLINICAL

DATA ABOUT YOU HAVE TO HAVE

APPROPRIATE MANUFACTURING

PRODUCT PROCESS NAILED DOWNU
 IN

SOME FASHION AT LEAST CLOSE TO

FINAL AS POSSIBLE, THOUGH WE

HAVE DIFFERENCES BETWEEN EUROPE

AND THE U.S. IN TERMS OF WHAT WE

CAN AND CANNOT DO.

IT'S VERY IMPORTANT TO GET AS

CLOSE AS POSSIBLE, OR YOU MAY

HAVE TO REPEAT STUDIES AGAIN.

I'LL SKIP THIS, THIS IS JUST THE

SORT OF IMPORTANTISH U SHOES WE

HOPE TO RAISE AS ISSUES.

AND I WANT TO INVITE EVEN IF

THERE ARE SPECIFIC ISSUES FOR

THIS MEETING FUTURE YOU SHALL

SHOES WE CAN INCORPORATE INTO

PLANNING BECAUSE THESE MEETINGS

TAKE TIME TO PLAN.

SO I'LL END HERE BY SAYING THESE

ARE GOALS.

WE NEED TO UNDERSTAND WHAT THE

NIH NEEDS TO DO AND PRIORITIZE

IT, WE WANT TO INTEGRATE

FEEDBACK FROM THIS MEETING WITH

OTHER MEETINGS, THAT THE NIH

ORGANIZED TO COME UP WITH A PLAN

AND WORK WITH THE FDA AND OTHER

STAKEHOLDERS TO ENSURE

HARMONIZATION.

THE MAJOR ISSUES WE SEE, WHAT

YOU HAVE ALREADY SEEN LISTED

HERE, I HOPE THAT THIS MEETING

WE'LL COME THROUGH WITH SOME

SORT OF CONCLUSION ANSWERS TO

THE QUESTIONS THAT I HAVE

RAISED.

THANK YOU.

[APPLAUSE]

(OFF MIC)

>> SPEAK LOUDER.

>> I THINK IT'S ON.

HI.

JOY (INDISCERNIBLE) ACCESS BIO.

I REALLY THOUGHT THAT CELIA'S

SLIDE PRESENTATION WAS

ASTOUNDING, THAT SLIDE YOU

REFERENCED, THE PERCENTAGE OF

RESEARCH BASE VERSUS COMMERCIAL

BASED.

I WOULD -- I THINK THE 2011 HAD

LIKE 140.

I THINK ANOTHER SPECTACULAR

FOLLOW-UP SLIDE WOULD BE HOW

DIFFERENT ALL THOSE PRODUCTS

ARE.

BECAUSE I THINK THAT'S HUGELY

CHALLENGING.

I GUESS MY QUESTION TO YOU IS IN

TERMS OF THE GOAL OF NIH WITH

RESPECT TO THE CLINICAL PIECE,

THE TRANSLATION, CLINICAL

INVESTIGATION VERSUS CLINICAL

DEVELOPMENT AND EXPECTATION OF A

PRODUCT, SO WITHIN A PERCENTAGE

OF TRANSLATING HOW MUCH

INVESTIGATORS REALLY WANT TO

TRANSLATE INTO A PRODUCT VERSUS

TRANSRATE TO CLINIC TO DO

INVESTIGATION.

PUZ FOR ME I THINK OFTEN THE

CHALLENGE IS YOU'RE CONSTANTLY

TWEAKING YOUR PRODUCT AS A

CLINICAL INVESTIGATOR TO MAKE IT

BETTER.

ONCE IN CHAL DEVELOPMENT THERE'S

NO OPPORTUNITY FOR THAT, YOU

HAVE TO DECIDE AND MOVE FORWARD.

CAN YOU GIVE A SENSE OF HOW MUCH

YOU WANT TO DO CLINICAL

INVESTIGATION VERSUS ACTUALLY

DEVELOP A PRODUCT?

>> IT'S AN IMPORTANT POINT.

IF YOU LOOK AT SMALL MOLECULE

DEVELOPMENT WHAT HAPPENEDDED

WHEN YOU LOOK AT CLINICAL

TRIALS, MOST OF THE TRIALS

TAKING ALREADY APPROVED PRODUCTS

WHICH ARE THEN TWEAK OR YOU LOOK

AT COMBINATIONS OR DOSING

CHANGES, ET CETERA.

THAT'S BEEN THE BIG FOCUS OF

CLINICAL TRIALS BEING DONE IN

THE ACADEMIC ARENA.

MOST SORT OF NEW DRUG

MANUFACTURING TRIALS WERE ALWAYS

DONE BY PHARMA.

HOWEVER, WITH CELL BASED

THERAPY, THERE AREN'T THAT MANY

APPROVED SETS.

SO ANY CLINICAL TRIAL THAT'S

BEING DONE EVEN BY ACADEMIA IS

BEING DONE WITH A CELL PRODUCT

THAT IS UNAPPROVED IN SOME

FASHION FOR -- SO THE KIND OF

CLINICAL TRIAL A CLINICIAN WILL

DO IS DIFFERENT FUNDAMENTALLY

BETWEEN WHAT YOU WOULD HAVE DONE

WITH SMALL MOLECULE.

THAT'S BEEN THE PROBLEM.

THERE IS THIS FUNDAMENTAL

DIFFERENCE BUT THE CLINICIANS,

THOUGH THEY HAVE A LOT OF

EXPERIENCE IN RUNNING CLINICAL

TRIALS, AND EXPERTISE IN LOOKING

AT PATIENTS, DON'T HAVE THAT

EXPERIENCE IN MATCHING THE

CLINICAL TRIAL AND THE GOALS OF

THE CLINICAL TRIAL WITH THE

ISSUES WITH WHAT WOULD BE A NEW

PRODUCT.

SO THAT'S BEEN WHAT'S MISSING.

THAT'S WHY FOR EXAMPLE MOST

CLINICIANS DONE WORRY ABOUT THE

PRE-CLINICAL ANIMAL STUDIES WHEN

LOOKING AT A PRODUCT BECAUSE

THAT'S ALL BEEN DONE.

THEY HAVE AN APPROVED PRODUCT

THAT'S GONE LIEU THE FDA PROCESS

BUT WITH CELLS, YOU HAVE TO

WORRY ABOUT IT.

AND YOU HAVE TO WORRY NOBT JUST

ABOUT MECHANISM OF ACTION WHICH

IS WHAT MANY DID BUT YOU HAVE TO

WORRY ABOUT SAFETY STUDIES WHICH

PHARMA USED TO DO WITH SMALL

MOLECULE.

THAT'S THE FUNDAMENTAL

DIFFERENCE.

IT IT'S CLEAR PATIENT WHOSE WANT

THE MOVE FORWARD WITH CELL BASED

TRIALS, WANT TO GET A NEW

PRODUCT WIDELY AVAILABLE, JUST

THERE IS THIS GAP IN TERMS OF

HOW TO DO OUT AND WHAT THE COST

WILL BE, AND FOR NIH, THAT'S THE

BIG PROBLEM WHO WILL FUND THAT

BUT CERTAINLY THE PO-1 LARGE

GRANTS ARE SUFFICIENT MAGNITUDE

OR SUFFICIENT TIME LINE TO DO

THAT.

SO IT'S A BIG PROBLEM THAT THE

NIH IS GRAPPLING WITH IN TERMS

OF= M ABLE TO DO THAT.

>> THANK YOU, MAHENDRA.

>> CAN I MAKE ONE COMMENT

>> I'M MERCEDES (INDISCERNIBLE)

WITH OFFICE OF TISSUE GENES.

ON TOP OF WHAT MAHENDRA JUST

SAID WE HAVE MOUs IN NINDS AND

NHLBI AND OTHERS AND SO IT'S

IMPORTANT TO THIS ASPECT OF

TRANSLATIONAL AND THERE'S CROSS

TALK BETWEEN FDA AND NIH.

>> I THINK IT'S AN IMPORTANT

POINT AND WE HAVE BEEN ABLE TO

GET HELP FROM THE FDA AND YOU

HEARD FROM CELIA AS WELL YOU CAN

APPROACH THE FDA EARLY IN THE

PROCESS BECAUSE THE FDA

RECOGNIZE EARLY THE ACADEMICS

ARE MOVING FORWARD AND DOING

MORE WORK THAN WHAT PHARMA WAS

DOING AND YOU SAW IN THAT RATIO

THEY NEED HELP EARLY ON THE IN

FUNDAMENTAL PROCESSES BUT YOU

CAN TAKE ON IN ALL THESE TRIALS.

>> VERY GOOD POINTS, TAKES A

TEAM THE GET THIS BALL ROLLING.

OUR NEXT SPEAKER IS IS DR. PETER

COFFEY WHO HAS SPEARHEADED THE

LONDON PROJECT TO CURE BLINDNESS

AND HE HAS WORKED FOR MANY YEARS

ON THE THE USE OF EM WREE I

DON'T KNOWIC -- EMBRYONIC STEM

CELLS FOR THE TREATMENT OF EYE

DISEASE.

HE WAS THE FIRST AUTHOR ON VERY

SEMINOLE PAPERS IN TERMS OF

BEING ABLE TO USE THESE CELLS

FOR TREATMENT OF BLINDNESS.

>> THANK YOU VERY MUCH FOR THE

INVITATION.

I THINK I HAVE BEEN INVITED

BECAUSE I'M A BRITT AND

THEREFORE TO STAY AWAY FROM ANY

CONTROVERSY WITH THE U.S. FDA.

IN THE UK, WE WOULD HAVE TO GO

THROUGH NEARLY FIVE REGULATORY

BODIES BEFORE WE ACTUALLY GO TO

CLINICAL TRIAL.

SO I THINK WITH THE FDA IS A ONE

STOP SHOP, A GREAT OPPORTUNITY

AS OPPOSED TO ACTUALLY WHAT WE

DO FACING EUROPE AND EVEN

LICENSING THEN HAS TO GO TO

EUROPE TO THE EUROPEAN MEDICAL

AGENT.

SO WHAT I WANT TO DO IS SET THE

CONTEXT HOPEFULLY FOR THE NEXT

TWO DAYS AROUND WHAT ARE THE

PROBLEMS, THE REAL WORLD

PROBLEMS WHICH TWO COMPANIES

FACED RECENTLY IN TAKING A

PLURIPOTENT CELL TO THE CLINIC,

THAT WAS GERON AND ACT.

SO FIRST LET'S LOOK AT A CHAL

PROBLEM AND TRY AND SOLVE IT

WITH CELL THERAPY.

SO I WILL TALK ABOUT EYE, NOT

SURPRISINGLY MY AREA OF

RESEARCH.

SPEFGLY DISEASES WHICH AFFECT

THE BACK OF THE EYE.

SO A GREAT ADVANTAGE IN MY AREA

BUT ONE AREA WHICH IS A TOPIC IN

THE NEXT TALK IN TERMS OF

CLINICAL TRANSLATION AND

CLINICAL MONITORING IS THE

ABILITY TO LOOK INTO THAT ORGAN,

VERY EASILY TO LOOK THROUGH THE

FRONT OF THE EYE AND BACK OF THE

EYE WHICH PEOPLE DO WHEN THEY GO

THE OPTOMETRISTS, AND AN AREA

WHICH INVOLVES THE ABILITY WHAT

WE DEFINE AS SEEING, WHICH IS A

REGION OF LESS THAN 10% OF THE

EYE WHICH IS KNOWN AS THE

MACULAR.

IN FACT, A SMALLER REGION WHERE

FOCUS VISION IS WHERE WE USE

THAT INFORMATION TO RECOGNIZE

FACES TO DRIVE AN AREA OF LESS

THAN A MILLIMETER.

OUT'S A GREAT ADVANTAGE IN THIS

AREA FOR ME IN THAT WHEN WE'RE

THINKING OF LICENSED PRODUCTS

WHERE WE'RE THINKING BEYOND

GOING INTO THOSE CLINICAL

TRIALS, BUT PRODUCING A

THERAPEUTIC, THE SCALE UP TO

THIS TYPE OF THERAPY IS MINIMAL.

WE NEED TO SAVE AN AREA IN TERMS

OF MILLIMETERS AND TO BE ABLE TO

DO THAT WE NEED FEW CELLS.

WE NEED HUNDREDS OF THOUSANDS OF

CELLS.

SO THE MACULAR REGION IS WHERE I

WANT TO FOCUS OUR ATTENTION

TODAY.

A REGION BELOW THE SCENE PARTLY,

THE AREA KNOWN AS THE RETINA

WHICH CONTAIN THE CELLS THAT

PROCESS VISION, NOT THE AREA WE

WANT TO FOCUS OUR ATTENTION,

IT'S THE LAYER BEHIND THAT, AND

THAT'S A SINGLE LAYER OF CELLS

KNOWN AS THE RETINAL PIGMENT

EPIHELIUM AND MIND THAT IS A

BLOOD SUPPLY.

THAT RETINAL PIGMENT EPITHELIUM

IS TOTALLY IMPORTANT FOR GOOD

VISION IT SUPPORTS THE SAME PART

OF THE EYE, IT GIVES NUTRIENTS,

IT'S ACTUALLY INVOLVED IN

RECYCLING SOME OF THE CHEMICALS

INVOLVED IN VISION.

SO THAT MIDDLE LAYER HAS TO BE

HEALTHY FOR VISION FOR YOUR

VISION.

AND FOR THE MAJORITY OF THE LIVE

THAT'S WHAT HAPPENS.

ON THE LEFT SIDE ARE SEE A

PKTURE OF A COUPLE OF BOYS, ON

THE RIGHT USING SIMPLE CAMERAS

WE CAN LOOK TO THE BACK OF THE

EYE IN BEAUTIFUL DETAIL, AND

THAT SPOT THERE IS WHERE THE

INFORMATION LEAF IT IS OPTIC

NERVE AND THAT PREGNANT

PIGMENTED AREA KNOWN Z THE

MACULA WHERE THAT VISION IS SO

IT LOOKS NICE FOR THE MAJORITY

OF OUR LYES.

AS WE AGE -- LIVES.

AS WE AGE, MOST AROUND 45 TO 65,

CERTAINLY FIND IT DIFFICULT TO

READ MENUS IN RESTAURANTS

BECAUSE WE START SUFFERING FROM

A LENS PROBLEM, WE CAN SOLVE

THAT, WE JUST NEED TO WEAR

FLASESES.

SO THIS PROBLEM WE CAN'T SOLVE

BY WEARING FLASES.

YOU START TO LOSE YOUR CENTRAL

VISION BECAUSE WHAT HAPPENS IN

THE AREA OF THAT MACULA, THE RP

STARTS TO FAIL.

THEY START TO DIE.

AS A COPS QENS, THIS TOP LAYER

-- CONSEQUENCE THAT TOP LAYER TE

TIER YOUR RATES AS WELL.

80% OF THE PATIENTS THAT PRESENT

WILL SUFFER FROM THIS FORM OF

THAT DISEASE KNOWN AS DRY AGE

RELATED MACULAR DEGENERATION.

AND AT PRESENT NOTHING CAN BE

DONE FOR THESE PATIENTS.

THE WET FORM ACCOUNTS FOR 10%

BECAUSE THAT BIG BLOOD SUPPLY IN

THE BACK OF THE EYE FORCES

VESSELS THROUGH THE MIDDLE LAYER

OF THE RPA AND IT BECOMES LEAKY,

DEPOSITS BLOOD BETWEEN THE TOP

LAYER AND THE MIDDLE LAYER, AND

AS A CONS CONSEQUENCE IT STARTS

TO PUSH THE SAME PART OF THE EYE

AWAY FROM ITS SUPPORT AND THE

SAME PART OF THE EYE DIES.

FORT IN THELY 6, 7, 8 YEARS AGO,

DRUGS WERE INTRODUCED WHICH CAME

FROM CANCER WHICH STOP THESE

BLEEDS.

THOSE INJECTIONS HAVE TO BE

GIVEN EVERY MONTH FOR THE REST

OF THE LIFE OF THAT PATIENT AND

INJECTED TO THE BACK OF THE EYE.

THE BIGGEST EYE HOSPITAL IN UK

AND EUROPE, 20 NEW PATIENTS

COMING IN A WEEK TO ACTUALLY

HAVE THOSE INJECTIONS.

WHICH HAVE TO COME BACK EVERY

FOUR WEEKS.

IT'S A HUGE CLINICAL PROBLEM, AT

LEAST THERE IS A TREATMENT.

SO OVER 8 YEARS AGO, WE EXAMINED

THE POSSIBILITY OF IS THERE ANY

WAY WE CAN IN SOME WAY PUT THAT

CARPET OF CELLS BACK TO STOP THE

SAME PART OF EYE DYING.

SO THE (INAUDIBLE) IS DYING

BECAUSE THE MIDDLE LAYER STARTS

TO DETERIORATE AND DAY.

CAN WE PUT THOSE CELLS BACK?

SO IN WET WHERE YOU GET THE

BLEED OR IN TRY WHERE YOU HAVE

THE RP FAILING CAN WE PUT CELLS

BACKEN TO THAT MIDDLE LAYER?

THAT'S WHAT WE TASKED OURSELVES

WITH NEARLY EIGHT YEARS AGO.

THE WHICH WE LOOKED AT FIRST WAS

BY USING THE PATIENT OWN CELLS.

THIS IS A VIDEO JUST SHOWING THE

FIRST OPERATIONS.

SO WE RAISER OUT AN AREA OF RP

AWAY FROM THAT CENTRAL VISUAL

AREA.

YOU'LL SEE IT IN A SECOND.

PERIPHERAL AREA OF RPA.

THERE IS THE OPTIC NERVE HEAD

AND WE'LL TAKE THE TOP LAYER OFF

WHICH IS THE SAME PART OF THE

EYE, THE NEURAL RETINA, AND THEN

REMOVE THE RPA AND PLACE IT

UNDER THE MACULAR.

LET THAT RUN A COUPLE MORE

SECONDS, WE'RE ACHING OUT THE

RPA.

THE REASON FOR THIS WAS TO SHOW

THAT PROOF OF CONCEPT, PU CELLS

BACK UNDER THAT MACULA, CAN YOU

STOP SOMEONE'S VISION FROM

GOING, FROM A PERSON FROM GOING

BLIND.

AND DONALD WAS ONE OF THE

PATIENTS WHO WENT THROUGH THAT

OPERATION WHEN HE CAME INTO THE

CLINIC, COULDN'T READ THE BIG A.

HE DID HAVE THE WET FORM, AND IF

UP FORTUNATELY AT THE TIME IT

WASN'T LICENSED IN THE UK IF HE

HAD GOT THAT INJECTION IT WOULD

HAVE GOT THREE LINE IMPROVEMENT

AND ACTUALLY FOLLOWING THAT

SURGERY IS DOWN AT 612 WHICH IS

24/40.

AT 618 IS THE LEVEL OF RITION

YOU NEED THE DRIVE IN THE UK.

HOWEVER THESE WERE DIFFICULT

OPERATIONS, THERE WERE AT LEAST

TWO HOURS TO DO THE OPERATION IT

INVOLVED FURTHER PROCEDURES AS

IN YOU HAVE TO REMOVE THE BACK

OF THE EYE BECAUSE YOU'RE

PUSHING THE RETINA BACK TO THE

BACK OF THE EYE AND YOU HAVE TO

OPERATE ON THE MUSCLES TO ENSURE

AN ALIGNMENT WITH THE EYE.

SO IT COULDN'T BE SEEN AS

OUTPATIENT PROCEDURE.

WHAT WE WANT TO DO IS PRODUCE A

PATCH A FACT TOTOR OF RPA OF 6

BY 3 MILL E METERS.

RESURFACE THE ONE DOE OPT EYE,

THE WORK OF MIGUEL

(INDISCERNIBLE) BEING UNIQUE IN

THIS AREA FOR OCULAR DISEASE.

THERE ARE MANY SOURCES, THAT'S

WHAT WE WERE ASKED TO DO,

THERE'S MANY SOURCES OF CELLS

MR. IPS OR -- WHETHER IPS OR,S.

WHAT WE'RE USING IS LINES

PRODUCING SHE FIELD IN THE UK,

IMAGINATIVELY CHEF 1 WAS THE

NAME OF THE CELL LINE, THAT

PARTICULAR LINE WAS AN EMBRYONIC

LINE.

A MAJOR RESEARCHER AS WE ALREADY

HEARD TRACKING THE TRACEABILITY

OF THAT CELL, ESPECIALLY NOW

WITH THE NEW ATMP OUTLINE FROM

EUROPE IS ESSENTIAL.

SO EVEN FROM THE START THE

PERSON DONATING THAT CELL HAS TO

GIVE PERMISSION FOR THIS TO BE

USED AS A LICENSED THERAPEUTIC.

THAT WAS NOT THE CASE FOR CHEF 1

WHEN IT WAS INITIAL HI DERIVED.

WE KNOW A LOT ABOUT BIOLOGY,

DEVELOP MENTAL BIOLOGY OF RPA.

IMMEDIATELY, ONE OF THE THINGS

THAT WE MANAGED TO GET WAS THE

CELLS TO DIFFERENTIATE INTO RPA.

WE DIDN'T WANT A STEM CELL, WE

WANTED RPA.

IMMEDIATELY IN THE PRODUCTION OR

IN THE PRE-CLINICAL WORK, THIS

GIVES ONE HANDLE ON DEFINING

WHAT THE CELL TYPE IS.

SO ONE OF THE CRITERIA EVEN IN

OUR PRE-CLINICAL WORK IS

PIGMENTATION ABOUTEN COBBLESTONE

MORPHOLOGY IN A WAY OF ACTUALLY

DEFINING THE CELL TYPE THAT YOU

WANTED TO USE.

YOU THEN HAVE TO GO THROUGH A

WHOLE PROCESS IN THE

PRE-CLINICAL BUILD UP TO

IDENTIFYING PARTICULAR MARKERS

WHETHER THREW PCR, WHERE IT BE

THROUGH ANTI-BE DIS, TO ACTUALLY

INDICATE THE IN PROCESS

VALIDATION OF YOUR

DIFFERENTIATION.

ALL THIS HAS TO BE DONE AS WAS

ALREADY MENTIONED, HAS TO BE

DONE ON THE THERAPEUTIC CELL

LINE YOU'RE USING.

THOSE PROTEIN MARKERS IN SOME

WAY NEED NEED TO DEFINE YOUR

CELL TYPE.

SO WE HAVE TO BE CLEAR WHAT WE

WERE GOING TO USE FOR THOSE

INDICATORS.

WE ALSO HAVE TO WORK ON VARY LT

OF THOSE INDICATOR --

VARIABILITY TO BUILD UP THE

PRE-CLINICAL PACKAGE OF IS THIS

REALLY, WHAT DOES THIS CELL DO?

WHAT ARE YOU ACTUALLY SAYING IT

DOES, HOW ARE YOU GOING TO

IDENTIFY IT?

ONE POTENCY ASSAY WE LOOK AT

AGAIN TO SAY WHETHER IT WAS

REALLY AN RP CELL OR NOT WAS ONE

FUNCTION OF THESE CELLS WHICH IS

PHAGOCYTOSED THE 8 LITTLE DISCS

WHICH WERE SHED FROM THOSE PHOTO

RECEPTOR CELLS.

SO WE CAME UP WITH A WHOLE NEW

WAY OF FEEDING THESE RPE CELLS L

WITHOUT A SEGMENT, WITH BEADS TO

IN SOME WAY LOOK AT ASSAY, A

POTENCY ASSAY, WHICH REGULATORS

ACCEPT, WE HAVE COME UP WITH

DIFFERENT METHODS TO ACTUALLY DO

THIS.

YOU CAN USE VARIOUS SECRETIONS

OF COMPOUNDS FROM CELLS IN CELL

BUT AGAIN, NO ONE REALLY LOOKED

AT THIS CONCEPT OF POTENCY

ASSAYING -- ASSAYS.

HERE IS AN ATTEMPT TO SHOW ONE

OF THOSE OUTER SEGMENTS BEING

PHAGOCYTOSED BY THE RPA.

ONE MAJOR PROBLEM WHICH WE

CONSIDERED IN DELIVERING THE

CELLS, WE WOULD LIKE TO ACTUALLY

DELIVER THEM, TO ACTUALLY GO

BACK IN A VERY STRUCTURED

MANNER, THIS IS THE TOP OF THE

CELL, THE BOTTOM OF THE CELL,

IT'S A POLARIZED CELL.

WE WANTED TO DELIVER IT IN THAT

EXACT FORMATION IN A CARPET.

TO DO THAT WE IMMEDIATELY GO

INTO AN EVEN MORE DIFFICULT

ARENA WHICH IS WE HAVE A

COMBINATION PRODUCT.

BECAUSE WE'RE PRODUCING A

SUBSTRATE TO PUT ON ON TO THE
CELL,

PUT THE CELLS ON TO.

IN DOING THAT, FORTUNATELY AT

LEAST WITHIN THE UK UNDER THE

ATMP REGULAR LEARKS, THE

COMBINATION MEANS WE GO DOWN ONE

REGULATORY PATHWAY BUT IT'S A

DECISION WE NEED TO ASK

REGULATORS, ARE THEY GOING TO

SEE THIS AS A DEVICE AND ATHER

PRUTTIC -- THERAPEUTIC.

WE WERE TOLD NO, WE SEE THIS AS

COMBINATION, IT'S A COMBINED

THERAPEUTIC.

SO WE ONLY HAD ONE ROOT TO GO

DOWN.

THAT'S A DECISION SOME OF THE

SPEAKERS WILL DISCUSS TODAY.

SO WE HAVE AT LEAST ONE

COMBINATION PRODUCT ON A

SUBSTRATE, AN ARTIFICIAL

SUBSTRATE IN ITS OWN RIGHT HAS

TO BE EXAMINED FOR THE

REGULATORS.

WE HAVE TO G THROUGH MA'AMSA TO

LOOK AT THE BREAK TOWN,

EXISTENCE IN ANIMALS, THESE

PATCHES WERE IN ANIMALS FOR A

YEAR, IN LARGER ANIMALS FOR SIX

MONTHS.

AGAIN, WE HAVE TO GO THROUGH A

WHOLE PRE-CLINICAL BUILDUP OF A

PACKAGE TO DESIGN EXACTLY HOW

THESE CELLS LOOK ON THIS

MEMBRANE.

WE THEN PUT THESE IN ANIMAL

MODELS, WE TEST THEIR VISION.

AND THIS IS AN OPTIKINETIC, A

RAT IS KEPT IN A BOWL FOR A

PERIOD AND GRATINGS, ON THE

MONITOR, GRATINGS HERE ARE MOVED

AROUND.

IF THE ANIMAL CAN SEE THOSE

GRATINGS, THEN OBVIOUSLY IT'S

GOT GOOD VISION.

YOU MAKE THE GRATINGS FINER AND

FINER AND THAT DETERMINES HOW

FAR DOWN THE EYE CHART THEY GO.

OPT RIGHT HERE IS THE BLIND RAW

COLLAGEN SURGEONS WRAP AND ON

THE BOTTOM RODENTS, THESE

ANIMALS HAVE A PROBLEM IN THE RP

LAYER.

THEY DON'T PHAGOCYTOSE.

IT'S NOT AN EXACT MODEL OF AND

BUT A MODEL DYSFUNCTION OF RPA.

ANIMALS IN WHICH HUMAN RPA IS

PLACED BACKCK CAN ACTUALLY SEE
AND

CONTRACT THESE STIMULI.

IS IPS THE PANACEA TO THIS IN

TERMS OF REGULATORY PATHWAY?

NO.

IT MAY BE WORSE I THINK.

THOUGH WE'RE IMING THROUGH THESE

CELLS, YOU CAN PRODUCE CELLS, WE

DO USE IT, WE LOOK AT WHETHER

IT'S EQUIVALENT TO WHAT WE SEE.

IT EXPRESSES THE SAME TYPE OF

BIOLOGICAL MARKERS AND ALSO IN

TERMS OF EM.

WE CAN LOOK AT FACTORS USING,

THE MER TK OR RP-65 INVOLVED IN

THE PHOTO CYCLE AND IT EXPRESSES

THOSE.

WE USE THE SAME RELEASE

CRITERIA.

THE PROBLEM IS THE QUESTION WE

NEED THE ADDRESS HERE, ARE WE

GOING TO DO THIS FOR EVERY IPS

CELL?

WE'RE THEN GOING TO PUT IT INTO

A RAT MODEL OR ANIMAL MODEL

WHICH WE DID DO.

WE SAW THE SAME TRACKING

ABILITY.

WE DO SEE DIFFERENCES THOUGH,

THE CILIA IS SEEM LESS MATURE.

SO WE'RE LOOKING AT PARTNERSHIP

WITH NHS TRANSFUSION, LOOKING AT

NON-INTEGRATING NON-PLASMA GM

PRODUCTION, CLINICAL

MANUFACTURING FOR AGE DONORS NOT

AS EASY AS YOUNG DONORS DOING

THAT QC TO LOOK AT EQUIVALENCE

AND PROCESS VALIDATION.

BUT WE'RE LOOKING AT THE

POSSIBILITY OF LOOKING AT HLA

MATCHED IPS TO GET AROUND THE

PROBLEM OF HAVING TO DO THIS FOR

EVERY SINGLE IPS.

BUT WE HAVE TRIALED THE WHOLE

PROCEDURE IN A LARGE ANIMAL SO

WE HAVE THE SMALL ANIMALS TO

LOOK AT EFFICACY, LARGE ANIMALS

TO LOOK AT HOW WE DO IT

SURGICALLY IN A PATIENT.

SO WE HAVE GONE THROUGH THE

PROCESS AN THIS IS HOW WITH WE

DO IT IN THE PATIENT.

SO YOU TAKE THE VITREOUS OUT.

YOU ACTUALLY CAUSE A DETACHMENT,

AND YOU PUT THE PATCH IN.

SO THIS IS IN CARTOON, CAUSE

DETACHMENT, PUT THE PATCH IN,

PUSH IT BACK DOWN IN AND OUT.

WE HAD TO G THROUGH A WHOLE

TERATOMA STUDY TO LOOK AT MOUSE

IN THE OCULAR FINDING, LOOK AT

IMMUNOGENICITY.

THIS IS SOMETHING WHICH IS STILL

RELEVANT TO IPS.

THOSE CELLS HAVE BEEN TREATED IN

A CERTAIN WAY.

THE MINOR MAY HAVE CHANGED IN A

WAY WHICH WILL EFFECT THE

IMMUNOGENICITY OF THESE CELLS.

THIS IN VITRO STUDY IS VERY

IMPORTANT AND IN VIVO ASSESSMENT

NEEDS TO BE ADDRESSED AS WELL.

SO WE HAVE DONE TWO ANIMAL

MODELS WHICH IS -- WELL WE HAVE

DONE THREE, MOUSE, AND PIG TO

LOOK AT TUMORIGENICITY AND

BIODISTRIBUTION.

WE HAVE DONE RAT TO LOOK AT

EFFICACY AND IN FACT BEFORE WE

CAN PROBABLY COME TO THE FDA WE

HAVE TO DO A THIRD ANIMAL STUDY

WHICH WILL BE EUROPEAN.

SO WE WILL SEE HOW FAR WE GET

BEFORE COMING THERE.

SO WHAT IS IT THAT WE WANT TO

DO?

THIS IS THE HEADLINE PROBABLY

FOR THE NEXT TALK WHICH IS IN

TERMS OF THE TRANSLATION INTO

THE CLINIC WE DECIDED TO BE

BRITISH WORD CANY, WON WHETHER

-- I DON'T KNOW WHETHER IT'S

USED OFTEN IN AMERICA TO COMBINE

PHASE 1, 2 SAFETY WITH EF IS

EFFICACY OUTCOME.

THERE IS GROUP OF PATIENTS THAT

SUFFER RIPS OF THE RPA.

THEY HAVE WET SO THERE'S A BUILD

UP OF FLUID OF RPE.

SO WHAT YOU GET IS RED.

THE RED AREA HERE IS A HOLE IN

THE RPE.

THESE PATIENTS BEFORE THE --

COULD SEE, COULD DRIVE

EVERYTHING.

THEY HAVE GOT SIX WEEKS
AFTERq-"V

YOU CAN PUT THE PATCH BACK IN

THESE PATIENTS BEFORE THOSE SIX

WEEKS MAINTAIN THEIR VISION WE

WILL HAVE GOOD EFFICACY.

IN THAT FIRST TRIAL.

SO MAINTAINING VISION IS

IMPORTANT IN THESE PATIENTS.

SO WHAT WE CAN DO IS FOLLOW

THESE CELLS BY USING

AUTOFLUORESCENCE.

SO WHAT YOU CAN SEE ON THE LEFT

IS OUTLINE OF WHERE THE RP DIED

IN DOMED AND HEARSAY THE EIGHT

YEAR FOLLOW-UP WE DID A FEW

WEEKS AGO.

YOU CAN SEE THE PATCH OF RPE

TRANSPLANTED EIGHT YEARS AGO.

IF T WERE THE CASE THOSE DIVIDE

THOSE INDICATE WHERE THOSE

VISION WOULD BE AND FOCUS IN AN

AREA WHICH ALLOW YOU TO SEE A

BIG A ON EYE CHART IS NOW

FOCUSING HIS VISION OVER THE

PATCH OF RPE WE HAVE GIVEN HIM.

THAT'S WHY 8 YEARS LATER HE'S

STILL AT 612.

SO FLASHING RED.

SO I'LL FINISH.

THERE IS A HUGE GROUP OF PEOPLE

IN OPHTHALMOLOGY, PHENOM MALL

WORK -- PHENOMENAL WORK BY

(INDISCERNIBLE), THE EYE

COLLABORATION WITH BARBARA, IN

FACT ONE MAJOR REASON WE HAVE

MONEY TO GET THROUGH FIVE

REGULATORS IN THE UK IS BECAUSE

OF THE HEALTH OF PFIZER, AND

(INAUDIBLE) IN THE UK.

THANKS VERY MUCH.

[APPLAUSE]

(OFF MIC)

>> CAN YOU COMMENT ON THE IN

VIVO MECHANISM OF ACTION OF YOUR

RPE CELLS ASSUMENING THOSE RAT

MODELS YOU DID TRANSPLANT A

PATCH OF RPE DO YOU HAVE A SENSE

WHAT'S HAPPENING IN VIVO, MORE

LIKE THE ACP WHERE YOU HAVE

GROWTH FACTORS?

ARE YOU SEEING IT DOING MORE RPE

FUNCTIONS IN VIVO?

>> I THINK YOU'RE BEING HARSH ON

ATP AS WELL AND CLEARLY IN THE

CLINICAL SITUATION IN SOME -- WE

DONE KNOW YET, IN TERMS OF THE

ANIMAL MODELS THERE'S GOOD

EVIDENCE WHEN YOU GET THEM ON

THE BROOKS MEMBRANE AND YOU GET

THOSE MONOLAYERS.

THEY ACTUALLY FUNCTION AS PROPER

RPE REL SO THEY'RE PHAGOTIE TOAS

-- PHAGOCYTOSING AND THEY'RE

PRODUCING VARIOUS COMPOUNDS SO

IT'S MORE THAN JUST A SECRETION

OF THE NEUROTROPIC FACTOR.

THEY DO APPEAR TO TAKE UP THE

FUNCTION AGAIN.

IN TERMS OF ONE OF THE IMAGES I

DIDN'T SHOW YOU PICTURE IS WE

JUST COMPLETED A NEW IMAGING

TECHNOLOGY AND WENT BACK TO THE

AUTOLOGOUS PATIENTS WHICH WAS

FUNDED BY WHETHER THE SECTORS

ARE THERE AND THE PHOTO

RECEPTORS ARE THERE FUNCTIONING

IN TERMS OF PHAGOCYTOSENING THE

CELLS.

SO I WOULD SUGGESTION IF YOU GET

THEM ON THE CARPET, YOU WOULD

ACTUALLY BE A FUNCTIONING RPE

CELL, NOT JUST PRODUCING A

TROPIC FACTOR.

>> AND A A CONNECTED QUESTION IS

IN HUMAN RPE CELLS UNDO TEAR THE

MACRO LEVEL ON THE PERIPHERY OF

RPE ARE DIFFERENT.

DO YOU HAVE A SENSE OF WHAT KIND

OF RPE CELLS YOU'RE MAKING FROM

ES CELLS OR IPS CELLS?

Q.WE DO ACTUALLY.

WE DID QUITE A NICE LITTLE

STUDY, NOT PUBLISHED YET, WHERE

WE LOOKED AT THAT VERY QUESTION,

DOES IT LOOK LIKE MACULAR RPE OR

MORE LIKE PERIPHERAL RPE.

IT LOOKS MORE LIKE MACULAR RPE.

SO THE LAST THING I FORGOT TO

MENTION IN THE TALK, THOUGH THE

EYE IS IMMUNE PRIVILEGED SITE,

IN DISEASE IT'S NOT.

IT'S NOT A PRIF LIJED SITE AT

ALL.

IN FACT, I THINK THIS AGAIN IS

GOING TO BE ONE OF THE MAJOR

ISSUES FOR IPS AS WELL.

SURGICAL TRAUMA WHICH CREATES

PROBLEMS, NOT JUST FOR ES BUT

IPS AS WELL.

>> I WAS DECEMBER APPOINTED HEAR

WHAT YOU SAID ABOUT IMMUNE
t

PRIVILEGED.

WHEN YOU PUT NEW TISSUE IN WILL

IT BE DAMAGED BY THE IMMUNE

PROCESSES THAT LED TO DISEASE IN

THE FIRST PLACE?

>> IT'S TAKEN 75 YEARS FOR THAT

TO HAPPEN.

SO IF YOU'RE 75 WHEN YOU GET THE

TRANSPLANTS, IF YOU LIVE ANOTHER

75 YEARS GOOD ON P YOU.

NO, I DON'T THINK IT WILL COME

TO THE SAME PROBLEMS WHICH

ASSOCIATED WITH HOST RPA LASTED

(OFF MIC)

>> YES.

>> WHAT DO YOU WANT TO KNOW

ABOUT IT?

THE MATERIAL AT THE BACK IS

CRUCIAL BECAUSE THAT'S WHAT WE

MATURE THE CELL ON, THAT GIVES

IT ITS POLARIZATION, IT IS A

FOREIGN BODY TO THE EYE, WHICH I

THINK IS WHAT YOU'RE TRYING TO

ALLUDE TO BUT THE EYE IS

IMMUNOSUPPRESSED AS IN LOCALLY

SO IS THAT CUTS DOWN A LOT OF

REACTION TO THE SUBSTRATE

ITSELF.

>> THANKS VERY MUCH.

>> THANK YOU.

>> OUR NEXT SPEAKER IS PATRICK

AU FROM THE FOOD AND DRUG AD

MINUTE STRAIGHT, HE'S A

PHARMACOLOGY TOXICOLOGY REVIEWER

WHO IS ALSO A MEMBER OF THE CORE

PROGRAMMING COMMITTEE AN WORKED

VERY HARD TO PUT THIS MEETING

TOGETHER.

>> THANK YOU.

I WANT TO THANK DR. RAO AND

DR. COFFEY FOR THEIR

PRESENTATION, THEY PROVIDE A

NICE I DON'T HAVE VIEW OF THE

SCIENTIFIC CHALLENGES IN

BRINGING PLURIPOTENT STP

CRIMINAL DERIVED PRODUCT TO THE

CLINIC.

MY NAME IS PATRICK AU, I'M A

PHARMACOLOGY TOXICOLOGY REVIEWER

IN THE OFFICE OF CELLULAR TISSUE

AN GENE THERAPIES.

FOR THE NEXT 20 MINUTES EEL RYE

TO PROVIDE YOU WITH WHAT OUR

OFFICE EXPECTATION FOR THE

PRE-CLINICAL STUDIES THAT NEED

TO BE CONDUCTED TO SUPPORT A

PHASE 1 CLINICAL TRIAL.

SO HERE IS AN OVERVIEW OF MY

PRESENTATION FOR THIS MORNING.

I IMAGINE LOT OF YOU IN THE

AUDIENCE WORK IN THE AREA OF

BASIC RESEARCH AND YOU HAVE HERE

IN THE WORKSHOP AN INTEREST OF

DEVELOPING A CELL THERAPY

PRODUCT AND BRINGING IT TO THE

CLINICAL TRIAL FOR TESTING.

SO THE QUESTION IS YOU ARE IN

BASIC RESEARCH AND WE'RE TRYING

TO GET TO CLINICAL TRIAL SO HOW

DO YOU DO THIS?

SOMETIMES THIS CAN SEEM LIKE

BLACK BOX AND TODAY I'LL PROVIDE

YOU AN I DON'T HAVE VIEW OF AT

LEAST AT LEAST FROM THE

PRE-CLINICAL PERSPECTIVE ON

WHAT'S NEEDED.

SO IF SEE FROM THE SKIMATIC HERE

ANIMAL STU -- SCHEME ACTIONTIC

ANIMAL STUDIES IS AN IMPORTANT

CRITICAL COMPONENT BUT THERE'S

OTHER COMPONENT LIKE

MANUFACTURING AND SCALING UP AND

PRODUCT CAT IMOR SITION AND

ISSUE FOR DISCUSSING A PREVIOUS

WORKSHOP.

THE PRE-CLINICAL STUDIES, IT'S

POSSIBLE FOR ME TO PROVIDE YOU

IN THE 20 MINUTE ALL THE STUDIES

NEEDED AND THE DETHE TAILS.

NOT ONLY BECAUSE I DON'T HAVE 20

MINUTES BUT ALSO THERE ARE OTHER

SPEAKERS IN THE AUDIENCE WHO

WILL BE TALKING LATER WHO ARE

MUCH MORE EXPERIENCED AND HAVE

MORE KNOWLEDGE IN THESE AREAS.

SO WHAT I SPEND TO DO IN THE

NEXT 20 MINUTES OR SO IS TO

PROVIDE YOU WITH OUR THOUGHT

PROCESS AS A PHARMACOLOGY

TOXICOLOGY REVIEWER IND

SUBMISSION AND THIS SERVES TO

TBIED YOU IN DESIGNING YOUR PR

CLINICAL STUDY.

SO I WANT TO HIGHLIGHT IN THIS

SLIDE THE PRE-CLINICAL DATA

SUBMITTED FOR A GRANT AND

MANUSCRIPT IS ACTUALLY IN MANY

WAYS SIMILAR TO WHAT IS NEEDED

TO SUBMIT TO IND OR TO FDA

INVESTIGATION OF NEW DRUG CALLED

IND.

HOWEVER THERE ARE SOME

DIFFERENCES.

AND THIS IS IS DUE TO A CIMPT

EMPHASIS IN REVIEW OF THE DATA.

SO FOR SUBMISSIONS YOU HAD BEEN

SUBMITTING EFFICACY AND SAFETY

DATA.

HOWEVER, FOR A GRANT MANUSCRIPT

DE-EMPHASIS IS MORE TO WORK THE

EFFICACY YOU ALSO GET POINTS FOR

NOVELTY AND ALSO IDENTIFICATION

OF THE MOLECULAR MECHANISM OF

ACTION.

SO FOR FDA IND WE'RE INTERESTED

IN SEEING PROOF OF CONCEPT STUDY

DATA BUT OUR EMPHASIS, PRIMARY

REVIEW FOCUS IS ON THE SAFETY.

SO THE FDA EMPHASIS ON -- THE

EMPHASIS IN FDA IS ON SAFETY, IS

REALLY DUE TO SUPPORTED BY THE

IND REGULATION.

U I'M GIVING AN FDA TALK TO HAVE

A FEW SLIDES ON CODE OF FEDERAL

REGULATIONS.

SO 23 CFR (INDISCERNIBLE) FDA

PRIMARY OBJECTIVES IN REVIEWING

UND IN US A PHASES OF THE

INVESTIGATION TO ASSURE SAFETY

AND RIGHTS OF SUBJECTS.

SO THE QUESTION YOU MIGHT ASK IS

DOES THE REGULATION ANYTHING TO

SAY ABOUT WHAT TYPE OF

PRE-CLINICAL STUDIES NEED TO BE

SUBMITTED.

SO THE ANSWER IS ACTUALLY NO.

THE IND, THE REGULATION IS NOT

VERY SPECIFIC.

WHAT IS STATED IN IND

REGULATION, IS THAT THE KIND

DURATION APPROXIMATE SCOPE OF

APPROXIMATE MALL AND TEST

REQUIRED VARIES DURATION AND

NATURE OF PROPOSED DURATION.

SO THE FDA HAS FLEXIBILITY TO

FULFILLING WHAT'S REQUIRED IN

THE REGULATION AND I'LL EXPLAIN

IN A BIT WHY THIS FLEXIBILITY IS

NECESSARY.

HERE IS A BRIEF VEEFER YOU OF --

OVERVIEW OF CBER AND,ND, IT'S

NOT BY CLINICAL INDICATION.

IF A PRODUCT IS A CELL OR GENE

THERAPY YOU'LL BE E VIEWED BY

OUR OFFICE.

SO CEBR REVIEW, WE DON'T HAVE A

ONE SIZE FIT ALL REGULATORY

APPROACH, SO CURRENTLY THERE ARE

MANY DIFFERENT CELL THERAPY

PRODUCTS FOR DIFFERENT CLINICAL

INDICATION, IT WOULD BE

IMPOSSIBLE FOR ONE SIZE FIT ALL

APPROACH.

SO THE PRE-CLINICAL DATA

NECESSARY TO SUPPORT THE

DEVELOPMENT DEPENDS ON BIOLOGY

OF THE PRODUCT AND ALSO ON

TARGET DISEASE YOU SHOULD BE

NOTED PRE-CLINICAL STUDIES

DESIGNED TO SUPPORT THE USE OF

THE PRODUCT FOR SPECIFIC

CLINICAL INDICATION, AN EXAMPLE,

IF YOU HAVE PRE-CLINICAL DATA

SUPPORTING INTRAINJECTION IN TO

A CURE M RK AND NOW YOU WANT TO

USE THE SAME PRODUCT FOR

INTRAVENOUS ADMINISTRATION FOR

IQ STROKE IT'S LIKELY YOU NEED

TO CONDUCT ADDITIONAL STUDY TO

SUPPORT A NEW CLINICAL

INDICATION.

I WANT TO HIGHLIGHT THAT REVIEW

IS ON BALANCING RISK AND BENEFIT

EVEN AT THE IND STAGE.

SO PLURIPOTENT STEM CELLS HAVE

ATTRACTED A LOT OF INTEREST FOR

CLINICAL DEVELOPMENT BECAUSE OF

INHERENT BIOLOGICAL PROPERTIES,

THESE INCLUDE THE ABILITY FOR

CELL RENEWAL AND POTENTIAL FOR

THE CELL TO DIFFERENTIATE INTO

VERIOUS CELL TYPES.

SO THEY SERVE AS POTENTIALLY

UNLIMITED SOURCE OF CELL FOR

POTENTIAL CLINICAL USE, THEY

COULD REPLACE, RESTORE OR

REGENERATE DISEASE OR INJURY

TISSUES.

HOWEVER, THESE SAME BIOLOGICAL

PROPERTIES RAISE SAFETY CONCERNS

INCLUDING POTENTIAL FOR

INAPPROPRIATE DIFFERENTIATION

INTO ECTOPIC TISSUE OR POTENTIAL

FOR UNCONTROLLED GROWTH FORMING

TUMOR.

OTHER CONCERNS INCLUDE POTENTIAL

FOR DISTRIBUTION INTO NON-TARGET

SITE AND ALSO FOR THE INDUCED

IMMUNE RESPONSE.

WHAT IPS CELLS MAYBE POTENTIALLY

IMMUNE RESPONSE COULD BE REDUCED

BUT THAT'S PART OF THE

INVESTIGATION INVESTIGATION BY

DR. (INDISCERNIBLE).

I HIGHLIGHTED HERE THE

SCIENTIFIC REGULATORY CHALLENGES

INTO PRE-CLINICAL TESTING OF

STEM CELL DERIVED PRODUCT.

THE FIRST BULLET POINT DISCUSSED

IN PREVIOUS WORKSHOP, INCLUDING

HETEROGENEITY AND DYNAMIC NATURE

OF THE PRODUCT.

FOR SOME PRODUCT THAT'S UNCLEAR

MECHANISM OF ACTION AND

CURRENTLY FOR A LOT OF CELL

PRODUCT THAT'S NO GOOD IN VIVO

-- IN VITRO BIOMARKERS TO

RELIABLY PREDICT SAFETY AND

ACTIVITY.

THE LAST THREE POINTS ARE MORE

RELEVANT TO PRE-CLINICAL

TESTING.

I THINK CURRENTLY THERE IS, IT'S

VERY DIFFICULT TO TRACK THE CELL

IN VIVO ONCE YOU ADMINISTER,

THERE'S NO REAL TIME INFORMATION

ON WHERE THEY ARE, WHAT THEY ARE

DOING ONCE YOU INJECT THE CELLS.

ALSO MENTIONED BY DR. RAO,

IMMUNE RESPONSE IS VERY

CHALLENGING QUESTION TO ASK THE

ANIMALS.

SO IMMUNE RESPONSE OBSERVED IN

ANIMALS IS HARD TO TRANSLATE TO

THE CLINIC.

YOU MIGHT NOT SEE A IMMUNE

RESPONSE IN ANIMALS BECAUSE

THEY'RE IMMUNOCOMEMIZED ANIMAL.

IF YOU SEE A IMMUNE RESPONSE IN

PRE-CLINICAL STUDY, THAT'S DAW

TO XENOGENETIC RESPONSE WHICH

WOULD MIMIC THE SCENARIO, AN

ALLO GENETIC RESPONSE AND THERE

ARE LIMITATIONS TO THE ANIMAL

MODELS WHICH IS DISCUSSED BY

OTHER SPEAKERS IN THIS WORKSHOP.

SO MENTIONED EARLIER THAT'S NOT

A ONE SIESES FIT ALL APPROACH TO

-- ONE SIZE FI ALL APPROACH TO

PRE-CHAL TESTING, HOWEVER THERE

IS AN OVERARCHING GENERAL SET OF

QUESTIONS THAT INVESTIGATORS

SHOULD CONSIDER AS THEY DESIGN

THE PRE-CLINICAL STUDIES.

AND DUE TO THE DIVERSITY OF

POTENTIAL PRODUCTS THAT COULD BE

DERIVED FROM PLURIPOTENT STEM

CELLS, IT REQUIRE A CASE BY CASE

APPROACH SO WHAT DOES A CASE BY

CASE APPROACH MEAN PRACTICALLY?

CASE BY CASE APPROACH IS SCIENCE

BASED, DATA DRIVEN, THE

PRE-CLINICAL TEST IS TAILORED TO

THE SPECIFIC PRODUCT FOR THE

SPECIFIC CLINICAL INDICATION,

CASE BY CASE APPROACH IS

FLEXIBLE AND BASED ON

ACCUMULATED KNOWLEDGE.

SO WE AND BROADER SCIENTIFIC

COMMUNITY GAIN MORE KNOWLEDGE

AND EXPERIENCE.

SO THE TEST MAY BECOME

UNNECESSARY WHILE OTHER TESTS

BECOME NEEDED.

CASE BY CASE ALSO MEANS AN

ATTEMPT TO USE THE BEST ASSAY

USING THE BEST AVAILABLE

TECHNOLOGY.

FINALLY CASE BY CASE APPROACH

ALSO MEANS A JUDICIOUS USE OF

ANIMALS.

SO WHENEVER POSSIBLE USE THE

MINIMUM NUMBER OF NECESSARY

ANIMALS TO GET THE REQUIRED

DATA.

SO SPECIFIC STUDIES NEEDED AND

SPECIFIC DETAILS COVERED BY

DR. LANG IN HER TALK TOMORROW.

HOWEVER TO ORIENT YOU, WE WOULD

LIKE TO SEE PRF PROOF OF CONCEPT

STUDIES WHICH IS PROOF OF

CONCEPT DATA WHICH IS GENERALLY

CONDUCTED IN A RELEVANT DISEASE

ANIMAL MODEL AND ALSO SAFETY

STUDY WHICH IS USUALLY CONDUCTED

IN A HEALTHY ANIMAL AND FINALLY

THAT'S WHAT WE CALL A HYBRID

STUDY IN WHICH THE PHARMACOLOGY

AND TOXICOLOGY STUDIES COMBINE

TO A SINGLE STUDY AND THAT IS

CONDUCTED IN A RELEVANT DISEASE

MODEL SO DESIGNING A CLINICAL

DEVELOPMENT PROGRAM, WHAT

QUESTIONS SHOULD YOU BE ASKING?

SO I BREAK DOWN THE DIFFERENT

QUESTIONS TO DIFFERENT TOPICS

AND I ALSO HIGHLIGHTED ON THE

SLIDES HERE WHERE IN THE WASH UP

SOME OF THESE QUESTIONS WILL BE

MORE ADDRESSED IN DEPTH BY THE

OTHER SPEAKERS.

SO ONE FIRST QUESTION YOU SHOULD

BE ASKING IS WHAT IS THE

CLINICAL INDICATION, IF THE

PRODUCT USED FOR PREVENTION OR

FOR TREATMENT OF A DISEASE AND

IS IT GOING TO BE USED FOR

TREATMENT AT THE TREATMENT, IS

IT USED FOR ACUTE STAGE OR

CHRONIC STAGE OF THE DISEASE?

NEXT QUESTION, IS THERE ANY

DISEASE RELEVANT MODELS AND WHAT

IS FEASIBLE TO TEST A PRODUCT IN

THE ANIMALS IN THESE ANIMAL

MODELS.

AND ALSO WHAT IS THE PROPOSED

MECHANISM OF ACTION AND DO YOU

HAVE AVAILABLE DATA TO SUPPORT

YOUR HYPOTHESIS?

SO NEXT SET OF QUESTIONS, -- SO

YOU SHOULD DEFINE WHAT IS A

MINIMALLY EFFECTIVE DOSE LEVEL

AND WHAT DOSE RESPONSE

RELATIONSHIP AND FINALLY PLAN

FOR DOSE EXTRAPOLATION FROM

ANIMAL TO HUMAN.

THIS IS ESPECIALLY IMPORTANT FOR

LOCAL CELL DELIVERY AND I THINK

A LOT OF TIME TOAS IS NOT GIVEN

A LOT OF THOUGHT INTO THIS.

SO THE NEXT SET OF QUESTIONS IS

RELATED TO DELIVERY.

SO IN YOUR PRE-CLINICAL STUDY

YOU MIGHT EXPLORE WHAT IS THE

OPTIMAL DELIVERY SITE AND ROOT

OF DELIVERY.

AND OPTIMAL DELIVERY METHOD.

WHAT IS THE OPTIMAL TIMING OF

ADMINISTRATION RELATIVE TO STAGE

OF DISEASE BECAUSE THE PRODUCT

MIGHT WORK IN THE ACUTE SETTING

BUT NOT THE CHRONIC SETTING.

WILL IT REQUIRE TO BE DELIVERED

ON A SCAFFOLD OR REQUIRE

ENCAPSULATION.

SO THE NEXT SET OF QUESTIONS

RELATED TO THE IN VIVO CELL

STATES AND HOST RESPONSE, WHICH

I'LL COVER A LITTLE MORE IN

DEPTH.

SO FOR IN VIVO CELL STATE THE

FIRST QUESTION IS WHERE DO THE

CELL GO, DO YOU PLAN TO

ADMINISTER PRODUCT SYSTEMICALLY

VERSUS LOCALLY AND ALSO FOR

PRE-CLINICAL STUDY.

WHAT IS THE TIMING, WHAT ARE THE

TIME POINTS THAT YOU PLAN TO

ASSESS SITE DISTRIBUTION AND IN

THE DISTRIBUTION STUDY YOU MIGHT

WANT TO LOOK FOR WHETHER THERE'S

TARGET OR NON-TARGETED, WHETHER

THAT TARGETED CELL DELIVERY.

AND ATOMIC IS AN IMPORTANT

CONSIDERATION.

BECAUSE PROLIFERATION IS

ENCLOSED SPACE, WOULD CARRY A

HIGHER RISK AND HIGHER SAFETY

CONCERN.

FINALLY LOOK FOR WHETHER THERE'S

TOPIC TISSUE FORMATION.

SO ONCE YOU KNOW WHERE CELLS GO,

THE NEXT QUESTION IS HOW TO

CELLS PERSIST.

DISABILITY FOR TWO REASONS, FOR

ONE REASON HAVING A GOOD

UNDERSTANDING OF CELL

PERSISTENCE MAYBE PROVIDE

SUPPORT FOR YOUR PROPOSED

MECHANISM OF ACTION SO YOU CAN

KNOW WHETHER CELLS FUNCTION IN

POTENTIALLY BY BOTH MECHANISMS

AND SECOND REASON IS DUE TO

TUMORIGENICITY.

THE RISK OF TUMOR GENICITY, NOT

JUST THEORETICAL, SURE A LOT OF

YOU IN THE AUDIENCE ARE AWARE OF

THE PUBLICATION A FEW YEARS BACK

WHICH A YOUNG PATIENT RECEIVED

FETAL NEURAL CELLS AN FEW YEARS

LATER DEVELOPED TUMOR IN SPINAL

CORD AND ALSO IN THE BRAIN.

IT'S IMPORTANT TO KNOW FOR

TUMORIGENICITY TESTING, IN ORDER

TO BE MEANINGFUL THIS HAS TO BE

ADEQUATE CELL SURVIVAL IN THE

ANIMAL.

ONCE THE CELLS GO AN HOW LONG

THEY STAY, THE NEXT QUESTION IS

WHAT IS ACTUALLY HAPPENING TO

THE THE CELLS, HOW CELLS

DIFFERENTIATE, OR DEDIFFERENCE

RATE AND WHETHER ANY ANATOMICAL

INTEGRATION MORE IMPORTANTLY

WHERE FUNCTIONAL INTEGRATION AND

AS MENTIONED PREVIOUSLY,

PROLIFERATION OF ECTOPIC

FORMATION IS ALSO POSING

CONCERNS.

SO FINALLY YOU WANT TO ASK WHAT

HAPPENED TO THE HOST TISSUE,

WHETHER THERE'S PROCEDURE THE

RELATING EFFECT CAUSING LOCAL

SITE REACTION AND WHETHER

THERE'S AN M IMMUNE RESPONSE TO

THE ADMINISTERED CELLS AND

WHETHER THERE'S ANY -- WHETHER

THE CELLS CAUSES CHANGES IN THE

TISSUE ARCHITECTURE AND FINALLY

IT'S IMPORTANT FOR SAFETY

STUDIES TO IDENTIFY ANY

POTENTIAL TARGET TO GUIDE DESIGN

OF CLINICAL MONITORING PLAN.

SO I WANT TO HAVE A BRIEF WORD

ON ABOUT CHOOSING ANIMAL MODEL.

SO ACCORDING TO OXFORD ENGLISH

DICTIONARY, A MODEL IS A

REPRESENTATION OF REAL OR ACTUAL

OBJECT.

SO THE KEY WORD HERE IS

REPRESENTATION.

SO IDEALLY THE ANIMAL MODELS

WOULD MIMIC THE HUMAN DISEASE

BUT WE DONE EXPECT IT TO BE

IDENTICAL TO THE HUMAN DISEASE.

SO WHAT YOU NEED TO DO IS

IDENTIFY LIMITATIONS OF

APPROXIMATE MALL MODEL AND

PROVIDE ADEQUATE SCIENTIFIC

RATIONAL WHY YOU CHOOSE THE

ANIMAL MODELS FOR TESTING.

SO FOR THE REVIEW IN OUR OFFICE

WE DONE HAVE A DEFALL USE OF

NON-HUMAN PRIMATE.

ALSO TESTING PARADIGM FOR SMALL

MOLECULES WE DONE HAVE A DEFAULT

USE OF RODENT OR NON-RODENT

SPECIESER USE OF MULTIPLE

SPECIES.

IN SOME CASES IT MAY REQUIRE THE

USE OF MULTIPLE SPECIES USING

THE RHODEN NON-RODENT MODELS.

FOR EXAMPLE YOU MIGHT TEST

TUMORIGENICITY IN A MOUSE,

RATHER THAN IN A TEST OF

DELIVERABLE YOU USE LARGE

ANIMALS.

THE KEY IS YOU NEED TO

UNDERSTAND THE LIMB LIMITATION O

OF ANIMALS TO TARGET TO THE

QUESTIONS YOU WANT TO ASK AND

PROVIDE ADEQUATE SCIENTIFIC

JUSTIFICATION WHY YOU CHOOSE

THAT PARTICULAR ANIMAL MODEL.

HERE TO SUMMARIZE ABOUT THE

PRE-CLINICAL DEVELOPMENT

PROGRAM, WHEN YOU DEVELOP A

PRODUCT YOU WANT TO SELECT A

RELEVANT ANIMAL SPECIES MODELS

IN ORDER TO CONDUCT YOUR

PHARMACOLOGY AND SAFETY TEST --

STUDIES, TO GENERATE ADEQUATE

DATA TO SUPPORT AN ACCEPTABLE

RISK BENEFIT RATIO MOVING THE

PRODUCT TO THE CLINIC.

HERE IS A BOTTOM LINE WHAT I

CALL NEED THE KNOW ANANIAS TO

KNOW, SO YOU NEED TO HAVE

ADEQUATE SCIENTIFIC RATIONALE IN

THE PRODUCT TO TEST IN THE

CLINIC AND IDENTIFY A

BIOLOGICALLY EFFECTIVE CELL DOSE

RANGE AND ALSO HAVE SAFETY DATA

ON THE PRODUCT ITSELF AND --

HAVING AN UNDERSTANDING OF

MECHANISM OF ACTION IS NOT A

REQUIREMENT BUT IT DOES PROVIDE

A LOT OF HELP.

NICE TO KNOW ALSO REAL TIME

QUANTITATIVE CELL TRACKING TO

ANIMALS, THIS IS NOT A

REQUIREMENT BUT IT'S NICE TO

HAVE.

AND HERE IS A QUESTION WE ALWAYS

ASK WHEN WE HAVE IND, THAT'S A

QUESTION YOU SHOULD BE IS ASKING

TOO DOES THE IND CONTAIN

SUFFICIENT INFORMATION TO

IDENTIFY RISK TO THE SUBJECT AND

FROM POSED CLINICAL TRIAL -- AND

PROPOSED CLINICAL TRIAL?

SO (INDISCERNIBLE) TO ENGAGE

CBER AND OFFICE OTCG P, WE URGE

THEM TO HAVE EARLY INTERACTION

WITH US ESPECIALLY FOR A NOVEL

PRODUCT.

SO WE HAVE A PRE, PRE-IND

MEETING.

THIS IS A NON-BINDING INFORMAL

INTERACTION.

MORE A SCIENTIFIC EXCHANGE AN

DISCUSSION BETWEEN THE SPONSOR

AN OR OFFICE.

AND PRIMARILY BETWEEN THE FARM

TOX REVIEWER AND PRODUCT

REVIEWER.

THERE ARE CONTACT FOR THIS

MEETING IS (INDISCERNIBLE) WHO

IS THE BRANCH CHIEF OF THE

PHARMACOLOGY TOXICOLOGY BRANCH.

THE PRODUCT DEVELOPMENT HAS

BECOME MORE MATURED, WE WILL

RECOMMEND A PRE-IND MEETING, A

NON-BINDING FORMAL INTERACTION

AND WE PROVIDE YOU WITH MEETING

MINUTES AFTER THE MEETING.

IN THE PRIMARY MEETING YOU GET

ADVICE AND FEEDBACK FROM ALL

THREE DISCIPLINES CMC FARM TOX

AND CLINICAL.

I CANNOT OVERESTIMATE THE PRNS

OF COMMUNICATION INTERACTION

BETWEEN A SPONSOR AND THE FDA.

THE BENEFIT FROM DIALOGUE IN

RESPONSE TO ON GOING GUIDANCE

FROM CBER AND FOR US WE BENEFIT

FROM HAVING ABILITY TO PROVIDE

YOU WITH EARLY AND CONSISTENT

INPUT AND ADVICE ON THE

DEVELOPMENT OF THE PRE-CLINICAL

STUDY PROGRAM TO SPORE A

CLINICAL TRIAL -- SUPPORT A

CLINICAL TRIAL,ING TO WE CAN

FACILITATE THE PROCESS OF MOVING

THE PRODUCT TO CLINICAL TRIAL IN

A MANNER AS EFFICIENT AS

POSSIBLE BY HAVING A DESIGNING A

PRE-CLINICAL PROGRAM THAT

ADDRESSES SAFETY AND SCIENTIFIC

RATIONALE.

HERE IS MY CONTACT INFORMATION

AND OTHER PUBLIC ACCESS TO CBER.

OKAY.

THANK YOU.

[APPLAUSE]

>> WE HAVE TIME FOR SOME

QUESTIONS FOR PATRICK.

I TART BY TALKING A LITTLE BIT

ABOUT PLANS BETWEEN KNOWING AND

NOT KNOWING.

THE MECHANISM OF ACTION.

I THINK THIS IS ONE OF THE

HARDEST THINGS WE'RE FACING IN

CELL THERAPY.

IS THERE KIND OF LIKE A CUT OFF

THAT YOU HAVE IN TERMS OF YOU

DONE HAVE A CLUE HOW CELLS L ARE

WORKING NO GO OR IT'S A LITTLE

BIT MORE FREXABLE THAN THAT.

>> WE DON'T MEET MECHANISM OF

ACTION.

PEOPLE DOESN'T KNOW HOW

(INAUDIBLE) WORK.

THAT CASE.

I THINK I GUESS I PRIMARILY PO

FOCUS ON SAFETY BUT ALSO THE

PROOF OF CONCEPT DATA IS PART OF

THE RISK BENEFIT RATIO.

SOMEK NISM OF ACTION IS NOT --

SO THE MECHANISM OF ACTION IS

NOT REQUIRED.

IT INCREASES THE OFFICE INTEREST

IN PRODUCT DEVELOPMENT BECAUSE

YOU KNOW WHY YOUR PRODUCT WORK

AND HOW IT WORKS YOU CAN FURTHER

OPTIMIZE A PRODUCT FOR SPECIFIC

DISEASE OR IMPROVE YOUR PRODUCT.

WITHOUT IT IT BECOMES MORE

CHALLENGING.

MECHANISM OF ACTION HELPS YOU

DEFINE YOUR PROOF OF CONCEPT --

YOUR POTENCY ASSAY.

>> I WANT TO FOLLOW-UP ON ONE

ISSUE ONCE WE ARE PERFORMING THE

PRE-CLINICAL STUDY TO TRACK AND

TRACE, WE HAVE TO WORRY WHICH

EXPERIMENTS ARE SIMILAR ENOUGH,

IF YOU HAVE AUTOLOGOUS THERAPY,

WE HAVE TO DO ALL THE

EXPERIMENTS AGAIN, OR TRACKING

AND TRACING I HAVE TO PUT

ENGINEER REPORTER EXAMPLE, WE

CAN DO IT BUT TO DO IT IN EVERY

CELL IF YOU'RE TRYING TO DO THE

EXPERMITS -- EXPERIMENTS THAT'S

BECOMING EXPENSIVE AND TIME

CONSUMING AN TESTING REQUIRED TO

MAKE SURE THE REPORTER IS IN THE

RIGHT PLACE AND ALL THAT BECOMES

EXPENSIVE AS WELL.

SO IS THERE SOME POLICY OR ISSUE

OR THOUGHT PROCESS THE FDA HAS

GONE THROUGH IN LOOKING AT THAT

AS AN ISSUE SO TECHNICALLY WE

CAN LOOK AT WHAT WE SHOULD

DESIGN AS WE MOVE FORWARD?

>> I THINK THAT'S A VERY

EXCELLENT QUESTION.

HARD FOR US TO ANSWER BUT WHAT

WE'RE GOING TO SAY IS OUR

REGULATORY REVIEW APPROACH IS

NOT ONE SIZE FIT ALL.

IT DEPENDS ON THE PRODUCT.

SO WE HEARD FROM DR. COFFEY, AT

LEAST I UNDERSTAND AT THIS TIME,

LITERATURE AND MEETING IDs,

DIFFERENCE IS ANALYZED AS

NOTABLE DIFFERENCES INCLUDING

BOTH OPTIMAL DIFFERENCE

DIFFERENTIATION PROTOCOL CELL

YIELD IN EPIGENETIC SIGNATURES

SO WHAT I RECOMMEND A SPONSOR TO

DO IS TO CONDUCT STUDIES AN

GATHER DATA AND MAKE THE CASE,

PROVIDE JUSTIFICATION ON THE

PRE-CLINICAL DEVELOPMENT PLAN

AND THEN WE WILL ALL REVIEW A

SPONSOR DEVELOPMENT PROGRAM BUT

WE DONE NECESSARILY AGREE WITH

THE PROPOSAL BUT WE ALWAYS

REVIEW IT AND PROVIDE YOU WITH

FEEDBACK.

>> BRIAN (INDISCERNIBLE) U.S.

ARMY.

MUCH OF YOUR TALK, YOUR

REFERENCE DISEASE STATES, WE

NEED TO ACKNOWLEDGE THAT, SOME

OF THESE PRODUCTS MAY NOT BE

INTENDED TO ADDRESS DISEASE AT

ALL, RATHER TRAUMATIC INJURY.

AND ARE THERE IN THE EVENT OF

GROSS TISSUE LOSS OR DEATH DUE

TO TRAUMATIC INJURY, ARE THERE

NUANCES THAT MAYBE YOU WILL LIKE

TO BRING TO LIGHT BASED ON

MATERIAL YOU PRESENTD?

>> DISEASE MODEL IS NOT CHRONIC

INJURY, I CAN GIVE YOU SPECIFIC

PRE-CLINICAL

YOU ARE THE EXPERT.

YOU SHOULD PROPES TO US WHAT

ANIMAL MODELS YOU SHOULD LIKE TO

USE AND PROVIDE RATIONALE WHY

YOU BELIEVE IF AD QUAD TO MOVE

TO -- ADEQUATE TO MOVE TO

CLINICAL TRIALS.

SO IT'S IMPORTANT TO MOVE THE

PROPOSAL AND PROVIDE YOU WITH

FEEDBACK.

>> ROSE HUNDREDSUCKER FROM

NIBIB.

MINE IS MORE A COMMENT I'M

INTERESTED IN YOURS AND OTHER

RESPONSES DURING THE DAY.

I WOULD LIKE TO EXPLORE THE

MECHANISM OF ACTION CONCEPT.

WHEN YOU SAY I UNDERSTAND WHY

IT'S NOT REQUIRED IN QUOTE,

ESPECIALLY MIND SET TALKING MALL

MOLECULE OR BIOLOGIC, I CAN

RATIONALIZE WHY THAT MIGHT BE

SUCH A CRITICAL THING, IN THOSE

CONSIDERATIONS.

BUT WHEN YOU TALK ABOUT A CELL

BASED HER PI, A NEW FIRST IN

CLASS APPROACH, ONE THING WE RES

L WITH IS EFFECT DUE TO FACT YOU

HAVE CELL REGENERATION, OR

GROWTH FACTORS WHICH MAKE THE

HOST SOMETHING MAGIC AND COOL.

THAT'S IMPORTANT BECAUSE IF IT

TURNS OUT MOST SOME ENDOCRINE OR

PARAFFIN EFFECT, MAYBE IN THE

FUTURE AS YOU ARE PUSHING MORE

ON WHATEVER THE EFFECT IS YOU'RE

LOOKING FOR, WHAT YOU WANT TO DO

IS LOOK FOR SOME KIND OF SMALL

MOLECULE OR BIOLOGIC THAT MIGHT

ACCOMPLISH THAT EFFECT MT. HOST

AS OPPOSED TO IF YOU KNOW THE

MECHANISM OF ACTION IS CELL

REPOPULATION, ON THE NEXT

GENERATION EFFECT, PERFECTING IF

THAT'S A WORD YOURSELF.

SO IN THE CELL BASED ARENA, THE

MECHANISM OF ACTION QUESTION

BECOMES REALLY VERY IMPORTANT.

>> I AGREE PLEATLY.

AGAIN, FOR THE FDA WE WORK ON

THE REGULATION.

I SHOW YOU IN THE CFR PRIMARY

FOCUS ON SAFETY, BUT THEN I

THINK AS I MENTIONED PREVIOUS

RESPONSE, UNDERSTANDING

MECHANISM OF ACTION INCREASE

ASSESSING DEVELOPMENT PROGRAM.

>> DEBRA WEBSTER (INAUDIBLE)

ASSOCIATES IN LIGHT OF

INCREASING DISCUSSION HOW

IMPORTANT PROOF OF CONCEPT AND

EF CA I ISND MECHANISM OF

ACTION, ALSO IN LIGHT OF

POSSIBLE GREATER USE OF THE

ABOUT MALL YIEWL -- APPROXIMATE

MALL RULE, IS -- ANIMAL RULE, IS

THERE ANY PUSH FROM FDA TO

ENCOMPASS EFFICACY STUDIES AS

GLP?

HOW WELL THEY'RE CONDUCTED?

>> PROOF OF CONCEPT STUDY DOES

NOT NEED TO BE PERFORMED GLP.

SAFETY IDEALLY IT WOULD BE BUT

FOR THE PRODUCT THAT WE

REGULATE, A CELL THERAPY, THAT'S

BECAUSE WE UNDERSTAND IT IS

DIFFICULT TO PERFORM SOME OF

THESE ANIMAL DISEASE MODELS SO

WE DON'T REQUIRE SPONSORS TO

PERFORM SAFETY STUDIES PER GLP.

WHAT WE RECOMMEND A UPONSOR TO

DO HAVE -- SPONSOR TO DO IS HAVE

QUALITY ASSURANCE IN PLACE TO

STUDY TO COMPLY WITH THE FOOL

GLP.

Q.THERE'S NO PUSH FOR THAT?

>> NO FOR -- MERCEDES WILL

LIKELY SPEAK THE THAT.

GLP IF T ALL POSSIBLE, YES.

THAT'S NOT ADEQUATE.

GLP SHOULD BE DONE UNLESS THERE

ARE ABSOLUTE REASONS IE, THE CRO

YOU USE, IT'S A UNIQUE MODEL,

THEY CAN'T HANDLE THE MODEL IN

TERMS OF ANIMAL CARE ISSUE, ET

CETERA, AS SPECIFICS OF GLP IS

INCORPORATED AS PATRICK SAID

LIKE QUALITY ASSURANCE BY AN

INDEPENDENT MONITOR FOR EXAMPLE.

THAT DEFINITELY AN IMPORTANT

ISSUE.

THESE ARE REVISED AS I SPEAK.

SO I'M HOPING IN THE NEXT YEAR

THE REGULATIONS WILL BE OUT FOR

PUBLIC COMMENT AGAIN AND THIS IS

A BIG ISSUE WITH RESPECT TO A

LITTLE MORE BROT WITH RESPECT TO

GLP.

SO THE QUESTION OF EFFICACY --

>> IDENTIFY.

>> SORRY.

IDENTIFY YOURSELF.

>> OKAY.

NADIA (INDISCERNIBLE) NIDCR,

NIH.

YOU EMPHASIZED THE FOCUS OF FDA

IS PRIMARY SAFETY.

BUT YOU NEED SCIENTIFIC

RATIONALE.

SO I WANT TO ADDRESS SCIENTIFIC

RATIONAL.

ALREADY HAVE EVIDENCE WHAT THEY

PROPOSE PUT THROUGH FDA WORKS.

BUT THIS IS A GREAT AREA O SO I

WANT TO KNOW HOW MUCH+w�
SCIENTIFIC

RATIONAL IS REQUIRED.

WE KNOW FOR EXAMPLE, IT'S EASY

TO TREAT DIABETES IN MICE.

ALMOST NEVER WORKS IN HUMANS.

SAME STRATEGY.

IF SOMEBODY COMES WITH A MODEL

AND SAYS THIS ANTIBODY WORKS

GREAT AND WE WANT TO PUT IT

THROUGH SAFETY TRIAL, IT CAN BE

SAFEST PRODUCT IN THE WORLD AND

YOU GO THROUGH EXPENSIVE TESTS

BUT IT'S NOT A VERY GOOD

PRODUCT.

AND WE DO KNOW MOST OF THE --

MANY DRUGS WHICH GO THROUGH THE

REGULATORY PROCESS FAIL BECAUSE

THEY DON'T DO MUCH.

THE QUESTION IS HOW MUCH

SCIENTIFIC RATIONALE, EFFICACY

BASED, PROOF OF EFFICACY SHOULD

WE LOOK FOR BEFORE WE GO INTO

EXPENSIVE SAFETY TESTS.

I DON'T KNOW IF THERE IS AN

ANSWER TO THIS QUESTION.

>> VERY DIFFICULT QUESTION TO

ANSWER.

SPONSORS PERSPECTIVE, THEY WOULD

WANT STRONG PROOF OF CONCEPT

DATA, AND NOT SPEND ALL THIS

MONEY FOR CLINICAL TRIAL BUT I

THINK FROM THE FDA PERSPECTIVE I

DON'T THINK OUR BAR WILL BE THAT

HIGH.

BUT I THINK RISK BENEFIT RATIO,

IF YOU DONE HAVE -- IF YOUR

PROOF OF DATA IS NOT STRONG WE

WANT TO SEE THE PRODUCT IS SAFE.

BUT IF YOU HAVE STRONG ROBUST

PROOF OF CONCEPT DATA, THEN WE

UNDERSTAND IS THERE SAFETY

SIGNALS.

WE -- IT MIGHT BE POSSIBLE TO GO

TO CLINICAL TRIAL.

SO IF THE RISK BENEFIT -- IT'S A

RISK BENEFIT RATIO.

>> IT'S AN IMPORTANT ISSUE I

THINK.

>> MERCEDES, DO YOU WANT TO MAKE

A COMMENT?

>> WHY WOULD YOU COME TO US IF

YOU DON'T HAVE SOME IDEA OF WHAT

YOUR PRODUCT IS DOING?

>> THE QUESTION IS HOW STRONG IS

EVIDENCE?

DO YOU HAVE ANY KIND OF LEVEL

WHERE YOU -- YOU DONE GIVE

ADVICE.

WE THINK IT'S THERE IS EFFICACY

YOU CAN GO AHEAD AND

(INAUDIBLE).

>> AS YOU KNOW --

>> PUSH TO JUDGE.

>> IN SOME CASES NOT EVEN

AVAILABLE DISEASE MODEL SO IN

THOSE CASES WE ACCEPT IN VITRO

DATA ON PRE-CLINICAL FOR OTHER

INDICATIONS SO THAT NEED TO BE

SOME JUSTIFICATION, SOME

SCIENTIFIC RATIONALE.

SO IT'S NOT LIKE THEY CROSS

OVER, THEN -- SO IT'S ALL

NEGOTIATION BETWEEN SPONSOR AND

THE FDA.

SO THAT'S WHY COMMUNICATION IS

KEY.

>> ONE LAST COMMENT.

>> ONE LINER TO NADIA'S

QUESTION.

THE DISPOSITIVE WORDING -- I'M

MALCOLM MOOSE IN OCTG.

THE RESPONSIVE WORDING IN

REGULATION TO THIS POINT IS

WHETHER HUMAN SUBJECTS QUOTE,

ARE OR WOULD BE SUBJECT TO

UNREASONABLE AND SIGNIFICANT

RISK ILLNESS OR INJURY.

SO AS PATRICK SAID, IT'S A

SLIDING SCALE.

IF WE'RE TALKING ABOUT COSMETIC

INCASE, THE SAFETY DATA HAS TO

BE VERY TIGHT.

WE'RE TALKING STAGE FOUR

MELANOMA, THERE'S SAFETY SIGNALS

SO H'S A CASE BY CASE JUDGMENT

ON THE QUESTION, IS IT

REASONABLE?

THAT'S AS MUCH A MEDICAL AS

SCIENTIFIC AS A REGULATORY

QUESTION.

DOES THAT MAKE SENSE?

>> IT'S A TEAM BASED APPROACH,

WE TALK TO CLINICAL REVIEWER TO

GET TO COME TO SOME SORT OF

DIVISION TOGETHER.

NOT JUST A FARM TOK REVIEWER

MAKING A DECISION BY HIMSELF BUT

A TEAM BASED APPROACH.

>> THANK YOU, PATRICK.

THANK YOU TO ALL THE SPEAKERS

FOR THIS PART OF THE MORNING.

WE NOW HAVE COFFEY BREAK UNTIL

11 O'CLOCK.

THERE IS A LITTLE SHOP UPSTAIRS

WHERE WE CAN'T PROVIDE YOU WITH

REFRESHMENTS BUT THERE IS A SHOP

UPSTAIRS.

SO WE'LL MEET BACK HERE AT

11 O'CLOCK.

ALSO, IF THE SPEAKERS, AFTERNOON

SPEAKERS HAVE NOT LOADED THEIR

TALKS YET I WOULD LIKE TO ASK

THEM TO DO SO.

THANK YOU.

SO OUR NEXT SPEAKER IS ROBERT

DEANS, WHO IS EXECUTIVE VICE

PRESIDENT FOR REGENERATIVE

MEDICINE AT ATHERSYS.

HE'S WORKED WITH ANOTHER COMPANY

CALLED (INAUDIBLE) AND HAS SPENT

A GREAT DEAL OF WORK IN THE AREA

OF STEM CELL BIOLOGY,

DEVELOPMENT AND CELL THERAPIES.

>> THANK YOU,'S CERTAIN HI GREAT

TO BE HERE.

MY GOAL IS TO BEAT THE CLOCK,

IT'S ALMOST A GAME SHOW TO GET

THAT ACCOMPLISHED BUT MORE

IMPORTANTLY I HOPE THE COMMENTS

I CAN RAISE IN THE DISCUSSION WE

HAVE CONTRIBUTE TO THE OUTCOME

OF THE WORKSHOP, IT'S A

PROMISING AGENDA HERE.

I'M REPRESENTING A

COMPANY,@ERSYS STEM CELL

ISOLATEED FROM BONE MARROW,

WE'RE IN MID PHASE CLINICAL

DEVELOPMENT, WE COMPLETED TWO

PHASE 1 STUDY, ONE WITH CATHETER

DELIVERY TO THE HEART IN ACUTE

MI AND THE OTHER AS A

PROPHYLACTIC THERAPY IN

ALLOGENEIC BONE MARROW

TRANSPLANT TO LIMIT GBHD

INCIDENCE AND SEVERITY.

WE'RE ACTIVE IN TWO PHASE 2

STUDIES, ONE IN USING THE CELLS

AS AN IV PRODUCT IN ISCHEMIC

STROKE AND SECOND AS IV PRODUCT

IN ULCER RAYTIVE COLITIS SO I

REPRESENT THIS SO YOU UNDERSTAND

THE DISCUSSION FOR THIS TALK.

THIS SLIDE I WROTE YESTERDAY ON

THE AIRPLANE TRYING TO JUSTIFY

AS AN ADULT STEM CELL BIOLOGIST

I BELONGED AT A PLURIPOTENT STEM

CELL MEETING.

THAT'S TWO TAKE HOME POINTS

HERE.

THE FIRST, PLURIPOTENT STEM

CELLS CLEARLY AREN'T DIRECT

THERAPEUTIC PRODUCT AND IT'S THE

PROGENITORS ARE DERIVATIVE OF

THIS IMPORTANT CLASS OF CELLS

THAT ARE GOING TO BE

THERAPEUTIC.

AND IN THAT CONTEXT WITH ADULT

STEM CELLS PAVE THE WAY FOR

FINDING THE DEVELOPMENT PATH AND

IF YOU LET ME BE VERY SIMPLISTIC

TRANSITIONING OVER TO AN IPS OR

ES CELL THERAPEUTIC IS JUST

DERIVING A PROGENITOR FROM THE

DIFFERENCE TISSUE SOURCE.

SO THERE'S A LOT OF IMPORTANT

INFORMATION AND EXPERIENCE

GAINED BY ADVANCING ADULT STEM

CELLS.

THE SECOND THING IS THAT

PARTICULARLY WITH EXCEPTION OF

HEMATOPOIESIS, ADULT STEM CELLS

HAVEN'T BEEN EXCEPTIONALLY

POTENT IN TISSUE REGENERATION.

THAT'S OUTSIDE OF TISSUE

ENGINEERING.

BUT CERTAINLY WITH THE MSC FIELD

THE ADHERENT STEM CELL FIELD,

IT'S CLEAR THAT ORIGINAL STUDIES

THAT THOUGHT THESE CELLS COULD

REGENERATE TISSUES REALLY TOLD

US THAT THEY WERE BIOLOGIC DRUG

DELIVERY FACTORIES AND POTENTIAL

FOR TISSUE REGENERATION IS NOT

THERE BUT THERAPEUTIC BENEFIT

WAS DERIVED FROM TROPIC

INFLUENCE SO THIS SETS UP THESE

TWO MODELS OF CELL THERAPEUTIC

AS A TRANSPLANT PRODUCT WITH

LONG TERM REGENERATION OR CELL

THERAPEUTIC AS BIOLOGICS

DELIVERY VEHICLE.

SO IT'S CLEAR NOT ONLY ARE THE

CELLS DELIVERING BIOLOGICS BUT

IN A MULTI-MISSOURI DALTY

COMPLEX SO STIMULATE REGULAR

PAIR THROUGH MULTIPLE PATHWAYS

AND PAIR LEGAL.

SO YOU'RE SEEING A REDUCTION IN

INFLAMMATION, NEOANGIOGENESIS,

CYTOPROTECTION, RECRUITMENT OF

HOST PROGENITORS THAT

COMPLICATES PRE-CLINICAL MODELS

THAT DERIVES MECHANISM OF

BENEFIT BECAUSE YOU CAN'T KNOCK

DOWN ONE PATHWAYS ABOUT KNOCK

OUT THE RECOVERY BENEFIT.

THESE PATHWAYS ACT IN PARALLEL

AND CONTRIBUTENING PARALLEL TO

RECOVERY.

SO I WANTED TO TALK ABOUT THE

DIFFERENCES IN THIS TRANSPLANT

VERSUS BIOLOGIC PARADIGM.

WITH CELLS AS BIOLOGICS WITH OUR

UNDERSTANDING OF SHORT TERM

PERSISTENCE YOU HAVE ADULT FOCUS

ON SAFETYRYK SO THERE'S LESS

RISK BECAUSE CELLS ARE NOT

RETAIN LONG TERM WORRYING LONG

TERM ECTOPIC TISSUE, THERE IS

CONCERN AND RISK ABOUT THESE

CELLS GOING IN THROUGH TROPIC

PATHWAYS SUPPORTING ENDOGENOUS

TUMOR.

ONE THING IN COMPLICATION IN

THIS SPACE IS CELL PERSISTENCE

FALLS BELOW LEVEL OF PROTECTION

USING CURRENT QPCR OR IMAGE

BASED ASSAYS SO THOSE FAMILIAR

WITH ADHERENT STEM CELL SPACE

UNDERSTANDS THESE CELLS ARE

IMMUNE PRIVILEGED AND THEY

AREN'T READILY REJECTED OR

PROVOKING IN IMMUNE RESPONSE AN

YOU HAVE REQUIREMENTS FOR

IMMUNOLOGICAL MATCHING.

THAT MEANS YOU CAN STUDY THEM IN

IMMUNE COMPETENT ANIMAL SETTING.

IN PARTICULAR BECAUSE THESE

CELLS ARE KNOWN TO BE PRIMED

THIS THEIR RECOVERY RESPONSE BY

THE INFLAMMATORY ENVIRONMENT,

GAMMA INTERFERON GREATLY

INCREASES THE POTENCY OF THE

CELL POPULATION.

'S IMPORTANT TO MAKE EVALUATIONS

IN THE SETTING OF IMMUNE

COMPETENCY.

THE OTHER BENEFIT WITH THE

BIOLOGIC AND THIS CLASS OF CELLS

IS YOU CREATE A MASTER CELL BANK

WHICH LETS YOU USE SAME DONOR IN

REPEATED PRE-CLINICAL TESTING AN

ALLOWS DEEP TESTING AROUND

SAFETY AN EFFICACY.

IN CONTRAST TO THE TRANSPLAN

MODEL AND THROUGH TISSUE

REINRATION YOU HAVE ISSUES

AROUND -- REGENERATION YOU HAVE

ISSUES AROUND CELL SOURCE, THE

ES OR IPS RISK FOR CARRYING

TERATOMA THAT HAS TO BE TESTED.

AND OBVIOUSLY IF THE CELLS ARE

RETAINED LONG TERM YOU HAVE MORE

REQUIREMENTS TO TEST BOTH FOR

LACK OF ECTOPIC OR UNWANTED

TISSUE AN AS WELL YOU NEED A

SEPARATE BLOCK OF ASSAYS TO TEST

CELL FUNCTIONALITY IN SITU.

ANY TISSUES ARE DERIVED FROM ES

ORB IPS TRANSPLANT PRODUCT WILL

BE IMMUNE SENSITIZING AND THERE

WILL BE COMPLICATIONS IN

PRE-CLINICAL MODELS WHERE YOU

WILL NEED TO ABLATE THE IMMUNE

SYSTEM OR USE IMMUNOSUPPRESSIVE

DRUGSCH OBVIOUSLY IN THE

TRANSPLANT SETTING, PARADIGM

SETTING DONOR VARIABILITY IS A

BIG ISSUE AND IS COMPLY CATTED

NO JUST IN TERMS OF POTENCY

TESTING AT THE TIME OF PATIENT

USE BUT COMPLICATED IN TERMS OF

UNDERSTANDING THE VARIABILITY IN

POTENCY AMONG INDIVIDUALS IN

PARTICULAR INDIVIDUALS WITH

DISEASE ONE POINT THAT CAME UP

EARLIER IMPLIED THAT TOXICITY

TESTING OR EFFICACY TESTING IS A

LINEAR PATH TO FILING AN IND AND

ENTERING THE CLINIC.

WHAT WE WANT TO UNDERSTAND IN

BOTH SETTINGS IS IT'S NOT A

SINGLE STUDY AND NOT A LINEAR

PATH, IT'S REALLY A COMPOSITE

PRE-CLINICAL STUDIES CONTINUING

TO BE RUN DURING CLINICAL

DEVELOPMENT THROUGH PHASE 2ND

PHASE 3.

ALWAYS GETTING FEEDBACK ON

BIOMARKERS AND PATIENT RESPONSE

THAT YOU'RE TAKING BACK IN THE

PRE-CLINICAL SETTING TO BETTER

UNDERSTAND DOSE AND DOSE

REGIMENT, UNDERSTAND PATIENT

STRATIFICATION AND RESPONSES.

SO IN YOUR OVERALL POCKSISTY

PACKAGE VIEWED BY EXHUME

CUMULATIVE DATA YOU HAVE BUT

PRE-CLINICAL DATA SETS YOU HAVE

NOT LIMITED TO A SINGLE DISEASE

SETTING.

BUT I WANTED TO MAKE SURE THAT

WAS CLEAR.

SO THE OTHER POINT THAT WAS MADE

EARLIER, THAT VERY RELEVANT IS

WE DON'T GO THROUGH PR CLINICAL

TOXICITY TESTING TO REACH

MAXIMUM TOLERATED COAS IN PART

BECAUSE WE CAN'T GET THERE BUT

IN PARTu

ARE PROHIBITIVELY EXPENSIVE AT

THIS POINT AND REALLY TRYING TO

BRING AN ANIMAL TO A MAXIMAL

TOLERATED DOSE IS WAY OUT OF THE

SETTING OF CLINICAL REALITY.

MUCH TOXIS THETY TESTING WE HAVE

DONE IS DRAWN FROM PARALLEL WORK

IN DRUG AND BIOLOGICS.

I'M SHOWING YOU DATA WE HAVE

PUBLISHED IN G BHD PRE-CLINICAL

MODEL, A RAT MODEL FOR

ALLOGENEIC TRANSPLANT, IT'S

LETHAL IN BONE MARROW RESCUE AND

DELIVER ONCE OR UP TO FIVE

TIMES.

WHAT YOU'RE LOOKING AT THAT I

WANT YOU TO SEE ON THE LEFT SIDE

IS NATURE OF THE TEST WE RUN

BECAUSE THEY'RE STANDARD IN THE

DRUG WORLD, AROUND CLINICAL

HISTORY, HEMATOLOGY, RESPIRATORY

RATES OPT RIGHT SIDE.

WITH ANIMALS WITH SERIAL

INFUSIONS WE TRACKED THE HEART

BEAT DURING TIME OF INFUSION AND

LOOKED AT MLR AND T-CELL

SENSITIZATION AND A FULL PANEL

OF TISSUE HISTOPATHOLOGY.

SO WE HAVE A CORE BLOCK OF

BIOSAFETY DATA AROUND MASTER

CELL BANKS THAT REFLECTS MOSTLY

ON GENETIC ABILITY AND LACK OF

ECTOPIC OR TUMOR JE MISTY

TESTING AND THAT IS DEPENDENT --

TUMORIGENICITY TESTING IS ON

ROUTE OF THRIRY, IV, IM OR

SUBCUTANEOUS DELIVERY THERE.

WE HAVE BEEN ASKED BY THE

EUROPEAN REGULATORY AGENCIES TO

CARRY TUMOR TESTING OUT TO 24

MONTHS -- WEEKS AND WE HAVE BEEN

CONSCIOUS OF USING CELLS

EXPANDED WELL PAST THE CLINICAL

POPULATION WE HAVE KEPT ANIMALS

ON STUDY FOR A LONG TIME, AT ONE

POINT SEEMED LOGICAL TO SEE,

NEONATAL RATS AND ADULT RATS IN

ISCHEMIC INJURY IN THE BRAIN, WE

KEPT ANIMALS ON STUDY OVER 13

MONTHS.

WE HAD 65 ANIMALS IN EACH CLASS

AND TOOK ANIMALS DOWN AND DID A

FULL-BLOWN GLP HISTOPATHOLOGY.

WE HAVE ALSO LOOKED AT POTENTIAL

FOR IMMUNE SENSITIZATION BY

REINFUSING THE CELL PRODUCT,

USING PLEA KNOW SITES AS

CONTROL, WE LOOK FOR ALLOGENEIC

ANTIBODY AND EVIDENCE OF T-CELL

SENSITIZATION.

SO I THINK THE PATTERNS OR THE

MODELS PEOPLE USED IN EFFICACY

TESTING ARE CLEAR.

YOU START IN A SMALL ANIMAL AND

TROY TO UNDERSTAND THE

BIOLOGICAL IMPACT YOUR CELLS

HAVE.

SO IN THIS CONTEXT YOU DON'T

HAVE TO WORK IN A DISEASE

SETTING, JUST WORK IN A

BIOLOGICAL SETTING AND IT'S

CONVENIENT TO WORK IN MOUSE

MODELS WHERE YOU CAN USE KNOCK

OUT OR TRANSGENIC ANIMALS THAT

FOCUS ON SPECIFIC PATHWAYS.

WHAT WHAT YOU'RE DOING IS

UNDERSTANDING DO YOU HAVE A

BIOLOGICAL EFFECT CONSISTENT

WITH YOUR THERAPEUTIC

HYPOTHESIS.

SO IT ALSO LETS YOU USE A LARGE

NUMBER OF ANIMALS WHO GET

REASONABLE POWERING.

THERE ARE LIMITATIONS IN USING

SOME OF THE SMALL ANIMALS AND

THAT RELATES TO THE FREQUENCY

WITH WHICH YOU CAN COLLECT

TISSUE SUCH AS BLOOD AND INDUCE

SAMPLE SO YOU HAVE TO COMPROMISE

ANALYSIS THAT YOU WILL LIKE TO

SEE.

BUT HERE YOU'RE JUST ASKING DO I

HAVE A BIOLOGICAL EFFECT.

SO WITH THAT IN MIND, WITH THAT

ESTABLISHED YOU CAN OBVIOUSLY

MOVE AND PROBE DOSE RANGING AND

YOU CAN ALSO PROBE DOSE

REGIMENS, REPEAT DOSING.

SO THIS REALLY STAGES YOU TO GO

INTO A LARGE ANIMAL MODEL AS

NEEDED.

I'M NOT SOMEBODY THAT DOESN'T

KNEE -- DOES A KNEE JERK

RECOMMENDATION FOR LARGE ANIMAL

STUDIES SO THE LARGE MODEL WHERE

THE TISSUE PHYSIOLOGY REFLECTS

THE HUMAN SETTING IS AS ALICE

MENTIONED, REQUIRES THAT YOU

TEST WITH DELIVERY BY CATHETER

IN GEOMETRY OF THE ORGAN SIMILAR

TO THE HUMAN SETTING.

AND OBVIOUSLY FOCUS ON NEED OR

NOT FOR IMMUNE SUPPRESSION.

SO PEOPLE TALKED ABOUT BENEFIT

OR STRATEGY IN USING HUMAN CELLS

IN A XENOGENEIC MODEL VERSUS

AANALOGOUS IN AN ANIMAL MODEL

AND I PUT A FEW FROZEN CONCEPTS

AN WE HAVE BEEN A PROPONENT IN

USING CELLS IN A XENOGENEIC SET

WE CAN TEST THE BANK AN

UNDERSTAND THE POTENCY OR SAFETY

REFLECTS CLINICAL PRODUCT.

IT IS EASIER TO CONNECT HUMAN

PRODUCT IN BACKGROUND OF ANIMAL

IN TERMS OF CELL PERSISTENT

STUDY.

YOU MAY NOT KNOW POTENCY WILL

CROSS OFFER AND BIODISTRIBUTION

IN ANIMAL MODEL MAY NOT BE BASED

ON ADHESION FACTORS AND

ADDRESSES WHAT YOU WOULD SEE IN

THE HUMAN SETTING.

SO THE RECIPROCAL APPLIES, YOU

AVOID DOWN SIDES OF COMPLICATION

FROM FACTORS NOT CROSSING OVER

ORsI>Q

THERE'S A BIG PLUS WHICH IS YOU

CAN TEST TRUE ALLOGENEIC CELL

USE BY USING SIN GENEIC

ALLOGENEIC COMBINATIONS OR USE

ALLOGENEIC CELLS WITH IMMUNE

SUPPRESSION AS BACKGROUND.

THE DOWN SIDE IS YOU CAN'T

ALWAYS MAKE WHAT YOU WANT,

THERE'S A -- YOU CAN'T ALWAYS

GET WHAT YOU WANT IS WHAT I'M

TRYING TO SAY N. TERMS OF BEING

ABLE TO PROVE YOU HAVE THE

ANALOGOUS CELL.

THIS IS DATA ON STROKE

PRE-CLINICAL WORK THAT SHOWS YOU

WE WENT ABOUT THIS BY SETTING UP

THE STROKE, THESE ARE BEHAVIORAL

RECOVERY READ OUTS WHERE HIGH

SCHOOL IS DETRIMENTAL AN LOW

SCORE SHOWS RECOVERY FROM

INJURY.

THIS IS ALLOGENEIC AND SOW KNOW

GENEIC CELLS WITH AND WITHOUT

CYCLOSPORINE AND ALL DIFFERENT

CELL PERSIS TEN.

WE DID A DOSE RANGINGND FOUND A

CRITICAL DOSE THRESHOLD REQUIRED

FOR A DURABLE RESPONSE AND WE

HIT A THRESHOLD THAT GAVE US NO

INCREMENTAL BENEFIT SO IT LET US

CENTER DOSE SELECTION FOR HUMAN

CLINICAL SETTING WITH GOOD

UNDERSTANDING AS GOOD AS WE WERE

GOING TO GET IN A PRE-CLINICAL

MODEL BUT WE WERE IN THE

IMPORTANT ZONE IN A COAS

RESPONSE CURVE.

IT'S IMPORTANT TO BE ABLE TO

EQUATE PRE-CLINICAL COAS TO

HUMAN SELECTED DOSE, IT'S BEEN

TRADITIONAL FOR US TO DO THAT BY

NORMALIZING DOSE TO PATIENT BODY

WEIGHT, MILLIONS OF CELLS PER

KILOGRAM.

THAT'S DRAWN FROM THE BONE

MARROW TRANSPLANT SETTING WHERE

IT'S CLEAR THAT HEMATOPOIETIC

STEM CELL DOSE COULD BE

CORRELATED WITH IMMUNE

RECONSTITUTION.

BUT THERE'S OTHER RATIONALES FOR

DOSE EQUIVALENCY ADJUSTMENTS AND

ONE IS A PUBLICATION I CAN

FORWARD YOU EVALUATING BODY

SURFACE AREA, BLOOD METABOLISM

AND BLOOD VOLUME, IT'S IMPORTANT

TO LOOK AT ORGAN GEOMETRY AN

CARDIOVASCULAR SETTING BOTH WITH

PERSPECTIVE VASCULATURE AND

OVERALL HEART SIZE.

AND BOTH IN THE NON-HUMAN

PRIMATE AND OTHER MODELS IN CNS

WHERE IT'S IMPORTANT TO LOOK AT

THE PHYSIOLOGY IN TERMS OF WHITE

MATTER GRAY MATTER DISTRIBUTION.

SO I'LL MOVE QUICKLY THROUGH

STUDIES WE HAVE DONE IN

CARDIOVASCULAR SETTING AROUND

POTENCY ASSAY DEVELOPMENT AND

SHOW YOU WHAT OUR THINKING WAS

IN GOING THERE SO WE HAVE LOOKED

AT A NUMBER OF CARDIOVASCULAR

MOADS, AMI, PERIPHERAL VASCULAR

DISEASE OR CONGESTIVE HEART

FAILURE AND WE SAW RECOVERY

BENEFIT FOLLOWING INJURY AND

THAT RECOVERY BENEFIT CORRELATED

WITH INCREASE OF VESSEL DENSITY

IN THE TISSUE.

SO OBVIOUSLY THE HYPOTHESIS THAT

THESE CELLS WERE NEOANGIOGENIC

WAS VERY CENTRAL.

SO UNDERSTANDING THAT WE WENT AN

SCREENED WHAT OUR CELLS WERE

MAKING ACROSS MULTIPLE DONORS

AND MULTIPLE DONORS WHICH WE

ALSO DERIVED MSC BASED CULTURE.

WE SAW FACTORS THAT STOOD OUT.

SO SEPARATE FROM VEGF WHICH

EVERYBODY MAKES WE SAW UNIQUELY

EXPRESSION OF CXCL-5 AN IL-8.

SO WE HAD SOME CANDIDATES AS KEY

FACTORS FOR THIS NEOANGIOGENIC

ACTIVITY AND WENT BACK TO OUR

PRE-CLINICAL MODELS AN CONFIRMED

THE FACTORS WERE DOMINANT AND

HIGHLY EXPRESSED BY USING IN

VIVO TISSUE MICROARRAYS.

SO THEN WE DID THE LOGICAL

EXPERIMENTS TO KNOCK DOWN EACH

FACTOR FOR US TO HAVE FULL

ANGIOGENIC ACTIVITY, WE NEED ALL

THREE FACTORS TO BE PRESENT.

WE UNDERSTAND BY KNOCKING DOWN

ADDING BACK WE UNDERSTAND WHAT

THAT CRITICAL THRESHOLD BUT SO

THAT LET US SET A KEY THRESHOLD

HOW MUCH OF EACH FACTOR NEEDED

TO BE EXPRESSED IN OUR CLINICAL

PRODUCTION CAMPAIGN AND GAVE US

THE ABILITY TO QUANTIFY THAT

WITH STATISTICAL CRITERIA.

THAT'S WHAT YOU'RE SEEING ON THE

BOTTOM THERE.

CLUSTERING OF FACTOR ACTIVITY IN

DIFFERENT CLINICALo� PRODUCTION

CAMPAIGNS, OPT RIGHT TENFOLD

HIGHER THAN CRITICAL THRESHOLD

REQUIREMENT.

I'M GOING TO DO THIS WITH THE

CLOCK.

THIS IS GREAT.

WE USE THE MAYTRY GEL ASSAY

WHERE WE IMPLANT CELLS OR

CONDITION MEDIA, IN THIS CASE

CELLS IN A MATRIGEL PLUG

SUBCUTANEOUSLY AND SAW NOT ONLY

WAS IT IMPORTANT TO HAVE FACTORS

FOR GREATEST ANGIOGENIC POTENCY

BUT THE COMBINATION OF FACTORS

THAT RESULTED IN PAYTANT RESELLS

WITHOUT LEAKAGE, MSC AND MES

ANGIOBLASTS WERE QUITE LEAKY SO

I'LL SWITCH TO BIODISTRIBUTION.

WE DID A PHASE # ARCMI STUDY

SHOWING YOU OUR DELIVERY ROUTE,

WE USE A CATHETER DOWN LAD AND

WHEN A BALLOON IS INFLATED AND

ADDED TO THE TISSUE LAYER, THE

CELLS ARE DISTRIBUTED AND

MIGRATE TO TISSUE TO THE

PERIINFARCT ZONE AND THE BOTTOM

IS SHOWING YOU AN OCCLUDED

VESSEL AS YOU MOVE FROM LEFT TO

RIGHT YOU SEE THE CONTRAST AGENT

AND YOU SEE WHEN WE DEFLATE THE

BALLOON WE HAVEN'T DAMAGED THE

VESSEL.

SO WE COMPARED INTERCORONARY TO

TRANSARTERIAL BY DELIVERING THE

CELLS, BREAD BONING THE HEART.

YOU CAN SEE THE CROSS SEC OF

HEART.

THESE WERE BETA GAL MARKED.

WE STAINED INDIVIDUAL RINGS FROM

THAT SEGMENT WITH SAW BLUE

SIGNAL AN WENT THROUGH AND READ

EVERY 10TH HISTOLOGY SECTION AND

COUNTED THE NUMBER OF CELLS AN

REBUILT THE HEART.

SO THIS TOOK THREE TO FOUR

MONTHS SO WE DON'T TALK TOO MUCH

ABOUT EVER GOING BACK TO IT.

WE ALSO CAME TO UNDERSTAND HOW

LONG CELLS PERSISTED BY

LUCIFERASE TAGGING CELLS AND

INTO A RODENT MODEL AND LOOKING

LONGITUDINALLY AT CELL

RETENTION.

SO YOU CAN SEE A NICE DECAY

CURVE WHERE WE'RE LOOSING CELLS

AFTER FIRST WEEK OF DELIVERY.

SO SOME EXAMPLESES OF HOW WE

APPROACH BIODISTRIBUTION.

WE HAVE ALSO DONE WHOLE BODY

IMAGING ON THE MOVIE HERE.

SO IN THIS STUDY WE SACRIFICE AN

ANIMAL CRYOPRESERVE, AND PEAL

OFF 50-MICRON SECTIONS, EACH

TIME A SEC IS PEELED OFF IT

COMES BACK OVER THE IMAGE AND

TAKE AS FLIEWR RES SENT AND

BRIEG FEELD PHOTOGRAPH SO THESE

ARE THEN TILE -- BRIGHT FEEL SO

THEY'RE TILED AND RECONSTRUCTED

TO TO REBUILD ANIMAL IN

COMPUTATIONAL WORLD SO WE'RE

REBUILDING A VIRTUAL ANIMAL.

SO ONE REASON WE HAVE BEEN

HAPPEN WHICH THIS W THIS IS IT'S

GIVEN THE ABILITY TO QUANTIFY SO

WE CAN REBUILD THE HOLE ANIMAL,

COUNT INDIVIDUAL CELLS AND THEN

CALCULATE HOW MANY ARE IN

INDIVIDUAL TISSUES.

SO LIVER, LUNG AND SPLEEN WHERE

MAJORITY OF CELLS GO, THIS IS 20

HOURS AFTER DELIVERY.

WE GET 75 TO 80% ACCOUNTING FOR

THE TOTAL NUMBER OF CELLS THAT

GO IN.

SO WE'RE STARTING TO GET A MUCH

BETTER IDEA ABOUT GLOBAL

DISTRIBUTION AND ABLE TO ACCOUNT

FOR THE MAJORITY OF CELLS THAT

GO IN SO A BIG TEN IN PKPD

PROFILING.

SO NEXT SLIDE, ACROSS THIS LIVER

AND THE LIVER WILL ROTATE,, THIS

IS VIRTUAL SO IT'S A REBUILD AND

THE PRENG MA IS GOING TO CROSS

IT, THIS IS THE LIVER THAT WILL

BEGIN TO ROTATE AND THE

PARENKEMA IS ROTATE AND YOU CAN

SEE THE VASCULARTURE ALL THROUGH

THE LIVER.

IT'S A FUN TECHNOLOGY, OUT OF

CASE WESTERN RESERVE IN A SMALL

COMPANY CALLED BIOENVISION.

SO A MINUTE AND 26 SECONDS TO DO

THIS LAST SLIDE AND I WANTED TO

MENTION THAT THERE'S ALSO

STRATEGIC VALUE IN YOUR

PRE-CLINICAL PLANNING AND

PRE-CLINICAL MODEL USE.

ONE IMPORTANT VALUE IS THAT WE

ENCOURAGE CORPORATE AND ACADEMIC

STAKEHOLDERS IN THIS SPACE TO

REALLY BE OPEN WITH THEIR

DEVELOPMENT PRINCIPLES, THE

MODEL DESIGN, STANDARDS PER READ

OUT AND SHARED DATA.

AND I SAY THAT BECAUSE IT'S

CRITICAL FOR US TO CONTINUE TO

GET CAPITAL TO SUPPORT MID PHASE

COMMERCIAL DEVELOPMENT AND

PHARMA AND HEALTHCARE NOT GOING

TO INVEST IN THIS SPACE UNLESS

WE HAVE A TIGHT UNDERSTANDING OF

MECHANISM OF AL-QAEDA.

SECOND KEY POINT WHEN YOU

UNDERSTAND SOMETHING DO IT OVER,

USE A DIFFERENT LAB, A DIFFERENT

CRO, TO A DIFFERENT SPECIES.

MAKE SURE YOU'RE NOT TRAPPED BY

SINGLE INVESTIGATOR OR SINGLE

EYE ON YOUR DISEASE MODEL.

FINALLY USEFUL FOR US TO

DISTRIBUTE OURSELVES OUT TO KEY

OPINION LEADERS TO VALIDATE

CLAIMS AN OBSERVATIONS MADE

ABOUT THE CELLS AND GET PEER

REVIEW PUBLICATION.

IT'S BEEN

TERMS OF VALIDATING THE

TECHNOLOGY WITH REGULATORY

AGENCY, BUT ALSO EXTREMELY

VALUABLE FOR US BECAUSE WE HAVE

BEEN ABLE TO SOLICIT THESE

TRANSLATIONAL CLINICIANS TO BE

PIs IN CLINICAL STUDIES AND

ABLE TO TAP INTO SOME OF THEIR

CLINICAL NETWORKS THAT HAVE BEEN

SUPPORTIVE AND HELPFUL FOR OUR

PROGRAM OVERALL.

SO WITH THAT I WOULD GIVE THANKS

TO THE GUYS INTERNALLY WHO

DIRECTED SOME OF THE DISEASE

PROGRAMS AND OUR COLLABORATORS

REPRESENTING WORK IN OUR FOUR

THERAPEUTIC AREAS.

THANKS.

[APPLAUSE]

>> YES.

WHILE HE'S WALKING TO THE

MICROPHONE.

IN TERMS OF THE FACT THESE CELLS

ARE TRAPPED IN LUNG, DO YOU HAVE

ANY IDEA WHY THEY MAIF

DIFFERENTLY IN THE LUNGS FOR ALL

THE DIFFERENT DISEASES

POTENTIALLY TREATED WITH THESE

CELLS?

>> WE SEE BIG IMPACT IN SIZE AND

ENTRAPMENT ON THE LUNG AND WITH

CELLS MORE LIKE PRODUCT WE'RE

USING WHICH ARE AROUND

15-MICRONS WE GET 50% ENTRAPMENT

IN THE LUNG.

WITH STROMAL CULTURE WE GET 75

TO 80% TRAPPING.

I SAW A PRESENTATION FROM JACK

(INDISCERNIBLE) WHO CLAIMED THAT

A FRESHLY TRIP SONNIZED PRODUCT

DID NOT SHOW ENTRAPMENT AND IT

WAS THE CRYOPRESERVED CELLS THAT

WERE RETAINED THERE SO WE DON'T

UNENOUGH ABOUT WHAT'S TRAPPING

CELLS IN LUNG WHETHER PURELY A

FUNCTION OF SIZE OR WHETHER

THERE ARE MEDIATING OR NOT.

I ALSO DON'T THINK THE CELLS OUT

OF THE CIRCULATION OR NOT WHICH

IS SOMETHING WE SHOULD HAVE A

BETTER IDEA ABOUT.

HIGH DEPOSITION OF INFLAMMATORY

CYTOKINES SO THERE MAYBE MORE

APOPTOSIS AN SIGNALING THAN

CELLS TRAPPED OUTSIDE OTHER

ORGAN SYSTEMS.

THAT'S IS SUPPOSITION.

SECOND WAVE OF CELLS IN THE

CIRCULATION, SOMEWHERE BETWEEN 4

TO 8 HOURS AFTER THE INITIAL

RESOLUTION MAYBE CELLS TRAPPED

IN LUNG AND VASCULATURE HOMING

TO THE REGION OF ENFLAMATION.

>> GARY STEINBERG FROM STANFORD.

NICE TALK.

COUPLE OF ISSUES ONE WE'RE

TRYING TO UNDERSTAND MECHANISMS

WE SHOWED SEQUESTRATION IN THE

LUNG LIVER AND SPLEEN AND SEAN

SAVITS CLB RATING WITH YOU HA

SHOWN IN A STROKE MODEL

EMPERIMENTALLY IF YOU SPLE NECK

TO M SO MAYBE YOU DON'T NEED TO

DELIVER TO THE HEART OR THE

BRAIN, YOU CAN DELIVER DIRECTLY

SYSTEMICALLY INTRAVENOUSLY AND

THE SPLEEN ACTING AS A

BIOREACTOR SO YOUR AFFECT MAYBE

SYSTEMIC ON THE SYSTEMIC IMMUNE

RESPONSE.

>> IN THE SPLEEN, IN THE CONTEXT

OF ANGIOGENESIS WITHOUT

SUFFICIENT PROOF HYPOTHESIS

NEEDS REPLACEMENT, THE ABILITY

TO STIMULATE ACT OWE GENESIS --

ANGIOGENESIS IS LESS PRACTICAL

IN THE EARLY RAT PRE-CLINICAL

STUDYS WE SAW MORE EFFECTIVE

STILL LITION OF ANGIOGENESIS BY

DIRECT -- STIMULATION OF ANG YES

GENESIS THAN DIRECT INJECTION OF

IV DELIVERY BUT THAT -- IV CELLS

HOMING TO THE SITE OF ENTRY.

YOU SCARED ME.

>> WE'RE ALL IN THIS NEW FIELD

SO WE'RE LEARNING.

SECONDLY, I WONDERED WHY YOU

CALL YOUR CELLS ADULT STEM CELLS

THESE STROMAL CELLS DERIVED SOME

DISPUTE WHETHER YOU HAVE STEM

CELLS IN THERE, WITH ERV

WISEMAN, I WOULD BE CAREFUL OR

WE'RE TRYING TO BE CAREFUL WHAT

WE CALL A STEM CELL DO THE CELLS

SELF-RENEW AND DO THEY MIGRATE,

CELLULAR THERAPY IS FINE,

DOESN'T HAVE TO BE STEM CELLS.

>> POINT WELL TAKEN.

I TRY -- I'M TRYING TO SHIFT

MYSELF TO SAY PROGENITOR INED OF

STEMS BECAUSE THESE AN ACCURATE

REPRESENTATION.

I DON'T HAVE -- I COMPLETELY

AGREE.

>> DO YOUR CELLS RECONSTITUTE AN

ORGAN OR --

>> WE CAN SEE CONVERSION TO A

DIFFERENTIATED CELL FATE, TO MY

KNOWLEDGE NOBODY IN THE

ADHERENCE STEM CELL SPACE HAS

BEEN ABLE TO DO THE SECONDARY

TRANSFER EXPERIMENT TO SEE TO

PUT THE STEM CELL LABEL ON IT. 

THERE'S MORE EVIDENCE THE CELLS

ARE THE CELLS APPEAR TO BE

COMING FROM A PERISITE

COMPARTMENT, THAT'S CURRENT

HYPOTHESIS AND MAYBE THE ACT OF

ATTACHING THEM TO PLASTIC AND

EXPANDING THEM IS ACTIVATING,

GIVING A TERMINAL COMMITMENT AND

YOU'RE LOSING THAT BASIC STEM

CELL PROPERTY.

I HAVEN'T SEEN PEOPLE HAVE TRIED

TO DO THE SECONDARY TRANSPLANT

BOUGHT EXVIVO EXPANSION.

>> YOU WOULD LIKE TO SEE THEM

FORM A TISSUE IF YOU CALL IT A

STEM CELL.

>> YEAH.

>> MALCOLM.

>> GREAT TALK AS ALWAYS.

MALCOLM (INAUDIBLE) FROM FDA.

I WAS QUITE INTERESTED IN YOUR

OBSERVATION ABOUT HOW THERE IS A

THRESHOLD DOSE.

DOES THAT DOSE VARY FROM ONE MCB

TO THE NEXT?

WHICH IS A DIFFERENT FLAVOR OF

THE QUESTION, IS IT THE SEAM

CELLS ELABORATING THREE

CYTOKINES OR DO YOU HAVE

PROPORTIONS OF DIFFERENT CELLS

COOPERATING, THOSE PROPORTIONS

MAY VARY THAT MAY ACCOUNT FOR

VARIABILITY SEEING IN

EXPERIMENTS AND IN TRIALS.

>> LET ME MAKE A COUPLE OF

COMMENTS.

FIRST WE SEE -- WE DO A LOT OF

TISSUE MICROARRAYS TO ANALYZE

HOST RESPONSE POST CELL DELIVERY

AND WE DO SEE DIFFERENT PATHWAYS

EMPHASIZE IN DIFFERENT DISEASE

SETTINGS SO THERE'S DYNAMIC READ

ABOUT THE NATURE OF THE INJURY

AND HOW THE CELLS RESPOND.

I HAD ANOTHER REALLY GOOD POINT.

>> IT WILL COME BACK TO YOU.

>> IT WILL COME BACK TO ME.

ASK YOUR QUESTION AGAIN.

>> QUICKLY.

>> DO WE -- WE HAVE TIME FOR TWO

MORE.

>> THANKS.

>> REAL QUICK QUESTION, MY NAME

IS LOU WING, WITH CARDINAL

HEALTH.

EXCELLENT TALK.

ONE QUESTION I HAVE AS FAR AS

REGULATING NOT JUST A CELL

CONTENT IN YOUR DRUG FORMULATION

THIS YOU'RE USING BUT ACTUALLY

THE STEM CELL NICHE YOU'RE

REFERRING TO, HOW WELL DESIGNED

IS THAT?

WOULD YOU CONSIDER THAT A

COMBINATION, WOULD BE SEPARATE

ENTITY?

ACTUALLY WE'RE GOING DOWN THE

REGULATORY PATHWAY,

UNDERSTANDING HOW YOU HAVE A C

OF A RELATED TO BOTH THE NICHE A

WELL AS YOURSELF.

>> WE UNDERSTAND VERY LITTLE IN

THE ADHERENT STEM CELL WORLD

ABOUT NICHE WHEN CELLS GO BACK

IN.

ONE SLIDE SHOWED OUR BETA CELLS

WERE CLUSTERING AROUND

NEUROVASCULAR CELLS IN THE

NEURAL TISSUE.

THAT'S CASE WE'RE SEEING THEM

ADOPT A PERI TYPE STATE.

OR YOU'RE SEEING CELLS INTEGRATE

REDIRECT EXAMINATION THIS A SCAR

OR WOUND RESPONSE NOT IN A

DEVELOPMENT DRIVEN REGENERATIVE

RESPONSE.

I THINK WE UNLITTLE FOR THE

NICHE FOR THE ADHERENT CELL

POPULATION.

>> UC DAVIS.

YOU WENT THROUGH QUICKLY,

OBVIOUSLY ON YOUR DATA I WAS

INTERESTED IN THE WHOLE BODY

IMAGING.

FEW QUESTIONS, DO CELLS PUT IN

PERIPHERALLY I ASSUME AND HOW

LONG AFTERWARDS ARE YOU GETTING

THIS HARD GREAT PERCENTAGE IN

THE LIVER

>> OUR CELLS HAVE BEEN LIVING

REPORTER CONSTRUCTS OR

EXPRESSING GSP OR RFP OR MORE

FREQUENTLY WE HAVE USED

NANOPARTICLE, A NEW LABELING

REAGENT CELL THAT'S BEEN QUITE

GOOD.

THE DATA I HAVE SHOWN YOU HAS

BEEN SIX HOURS OR 20 HOURS POST

DELIVERY AND IT'S BY IV INFUSION

SO WE'RE REALLY LOOKING AT A

TIME WE KNOW MOST CELLS ARE

STILL IN THE ANIMALS.

THE DOWN SIDE IS THAT TECHNOLOGY

IS VERY SLOW IN DATA ACQUISITION

AND COMPUTATIONAL RECONSTRUCTION

IN OUR GBHD SETTING WE HAVE BEEN

ABLE TO GET -- IN THE LAST TWO

MONTHS WE HAVE BEEN ABLE TO GET

TWO.

SO I CAN SAY WAIT FOR THE ENCORE

NEXT YEAR.

I DON'T KNOW.

>> OTHER QUICK QUESTIONS, YOU

THINK THESE CELLS ARE ALIVE AT

THIS POINT?

ARE THEY IN THE PRANK MA OR

ENDORELICK TAR SYSTEM?

>> THE EXPERIMENT WAS TO SET UP

A REPORTER UNDER CONTROL OF

APOPTOTIC RESPONSE GENE AND DO

EXPERIMENTS SO YOU CAN DETECT

FLUORESCENCE CELLS UNDERGOING

APOPTOSIS OR SIMILARLY

CORRESPONDING FOR NECROTIC CELL

DEATH.

I DON'T THINK WE UNDERSTAND THE

DYNAMICS OF CELL DEATH IN THIS

PLATFORM VERY WELL EITHER.

>> ARE THEY IN RELICK TAR

EPITHELIAL CELLS IN THE PAING

MALL OF THE LIVER?

-- PRANK MALL OF THE LIVER?

NOT SURE.

>> ARE THEY ENGULFED BY TICK LAR

ENDOTHELIAL CELLS.

>> WE DON'T HAVE KNOWLEDGE OF

PHAGOCYTOSIS OF -- WE WILL FIND

WHEN DOING RADIO LABELED CELLS

WE'RE GETTING A LOT BACK OUT IN

THE URINE BUT IT DOESN'T REFLECT

WHETHER IT'SLYSIS OR

PHAGOCYTOSIS.

WE DON'T SEE WITH LACK OF IMMUNE

SENSITIZATION PRESUMABLY WHICH

IS ACCOMPLISHED BY INDIRECT

PATHWAY, IT DOESN'T APPEAR WE'RE

GETTING SIGNIFICANT PHAGOCYTOSIS

AND ANTIGEN BUT I SHOULD

PROBABLY TALK MORE --

>> ONE QUICK COMMENT.

THERE IS ONE STUDY SHOWING THAT

BONE MARROW STROMAL CELLS ALSO

KNOWN AS SKELETAL STEM CELLS

ALSO KNOWN AS MESENCHYMAL STEM

CELLS SELF-RENEW BY SERIAL

TRANSPLANTATION.

>> GREAT.

>> (INAUDIBLE) CELL.

GLT THAT'S GREAT.

I NEED THAT.

>> THANK YOU VERY MUCH.

[APPLAUSE]

I WOULD LIKE TO INTRODUCE OUR

NEXT SPEAKER DALE GREINER FROM

UNIVERSITY OF MASSACHUSETTS, HE

HAS SPENT A GREAT DEAL OF TIME

WORKING ON TRANSPLANTATION,

AUTO-IMMUNITY AND DEVELOPMENT OF

HUMANIZED MICE, IN PARTICULAR TO

TRY AND DEVELOP TREATMENTS FOR

TYPE 2 DIABETES.

>> FIRST I WANT TO THANK THE

ORGANIZERS FOR INVITING ME AND

SUPPORT RECEIVED FROM NIH AND

PRIVATE FOUNDATIONS OVER THE

LAST FEW YEARS FOR THIS WORK.

I REALIZE I'M THE LAST PERSON

STANDING BETWEEN YOU AND LUNCH

SO I WILL TRY AND MAKE IT SHORT

AND TO THE POINT.

I'M GOING TO TRY TO GIVE YOU THE

CONCEPTS MAINLY IN WHAT WE'RE

TRYING TO DO WITH THIS.

SO I WANT TO FOCUS ON DIABETES

AND HOW WE LOOK AT CELLS REPLACE

TREATMENT FOR TREATMENT OF

DIABETES.

YOU READ THE PAPERS, IT'S A HUGE

PROBLEM IN THE WORLD, OVER 8% OF

THE PEOPLE IN THE U.S. CURRENTLY

HAVE A FORM OF DIABETES OR

ANOTHER.

THERE'S MORBIDITY, MORTALITY,

AND FIVE YEARS AGO COSTING OVER

200 BILLION, THE PRICE IS

PROBABLY UP NOW.

IT'S A EXPENSIVE DISEASE OUT

THERE ONE WE WOULD LIKE TO THE

TRY TO TACKLE.

DIABETES IS NOT A SINGLE DISEASE

BUT A SPECTRUM OF DISEASE,

INSULIN -- NON-INSULIN DEPENDENT

DIABETES NOW TO WHAT WE CALL

TYPE 1A DIABETES OR ABSOLUTE

INSULIN DEFICIENCY.

I WANT TO FOCUS ON CELL THERAPY

FOR TYPE 1 DIABETES.

BETA CELL REPLACEMENT MAYBE

USEFUL FOR MANY KINDS OF

DIABETES OUT THERE, JUVENILE

DIABETES, INSULIN DEPENDENT

DIABETES ARE OLD TERMS FOR IT,

IT'S CALLED TYPE #A, UP TO

3 MILLION PEOPLE IN THE U.S.

WITH TYPE 1A DIABETES, IT'S

AN@IMMUNE DISORDER WHICH MAKES

IT TYPE #A IN CONTRAST TO TYPE

#B WHICH IS ALSO INSULIN

DEFICIENCY, SEVERE INSULIN

DEFICIEN

THE GOAL IN THIS DISEASE IS FOR

THESE PEOPLE IS TO PRODUCE BETA

CELLS.

HOW DO WE DO THAT WITH CELL

THERAPY?

NIH, NEDDK, PROBABLY OVER TEN --

NEDD -- DIDDK TO BRING TOGETHER

DEVELOPMENTAL BIOLOGISTS, THESE

CELLS AS RVE KNOWS HAS

PLURIPOTENT ACTIVITIES, THEY

HAVE BEEN SHOWN TO -- WITH

DIRECTED DID YOU DIFFERENTIATION
TO MOVE

TO ADIPOSE TISSUES OR NERVES AN

NOW BECOMING VERY SUCCESSFUL IN

BC BC AN MOVING THEM INTO

INSULIN PRODUCING GLUCOSE

RESPONSIVE BETA CELLS IN THE

PETRI DISH.

WHAT I WANT TO EMPHASIZE UNDER

THOSE ISLETS BETWEEN MOUSE AND

HUMAN IS THAT MOUSE ISLETS AN

HUMAN ISLETS ARE VERY

STRUCTURALLY DIFFERENT.

THEY'RE CELL COMPOSITIONS ARE

DIFFERENT.

AND THE SIGNALING PATHWAYS AND

MOLECULES EXPRESSED BY THE CELLS

ARE DIFFERENCE AND SO IT'S

IMPORTANT IN THIS FIELD TO FOCUS

ON HUMAN BETA CELLS AND HUMAN

ISLET BIOLOGY.

WHAT ARE SOME OF THE QUESTIONS

RELATED TO USING HUMAN CELL

REPLACEMENT THERAPIES FOR

DIABETES?

FIRST ONE EVERYBODY KNOWS AND

WHAT FDA EMPHASIZES THIS MORNING

IS SAFETY.

SECOND IS EFFICACY.

IT DOESN'T DO GOOD TO PUT CELLS

IN THIS NOT GLUCOSE RESPONSIVE

INSULIN PRODUCING UNDER

PHYSIOLOGICAL CONDITIONS.

I.E., CAN CAN THEY REGULATE

GLUCOSE IN A HOMEOSTATIC

FASHION.

AND HOW MANY INSULIN SPOSTIVE

CELLS ARE REQUIRED?

WE CAN GET ESTIMATE FROM THE

ISLET TRANSPLANTS DONE IN THE

PAST AND MULTIPLY UP TO GET A

REASONABLE NUMBER OF INSULIN

PRODUCING CELLS YOU NEED IN

TRANSPLAN SETTING.

WE CAN USE -- WANT TO BE ABLE TO

EVALUATE HOW DO THESE CELLS

FUNCTION, THEIR RESPONSES, ARE

THEY FI OWE LOGICAL, FETAL LIKE,

ACULT LIKE AND HOW CAN YOU

MODULATE RESPONSE BUSINESS THE

ENVIRONMENT OR ADMINISTRATION OF

DRUGS?

CAN YOU FINAL STEP GET THEM

IMPLANTED.

HOW ARE THESE IPS OR ES DATA

SELLS FUNCTION IN AN IMMUNE

SYSTEM AND THAT'S DISCUSSEDDED

TOMORROW AFTERNOON BY DR. LYNN

SCHULTZ IN HIS MODEL.

ONE TAKE HOME MESSAGE I HAVE

TODAY IS THE CONCEPT OF USING

WHAT WE CALL HUMANIZED MICE TO

FORM THE BRIDGE, PRE-CLINICAL

BRIDGE BETWEEN HUMAN CELLS AN

TISSUES IN A PE TRE DISH TO THE

CLINIC WHERE YOU CAN USE THE SO

CALLED HUMANIZED MICE, I'LL

EXPLAIN WHAT WE ARE A CONCEPT OF

THOSE ARE, TO BE ABLE TO

ACTUALLY STUDY CELLS IN TISSUE

IN VIVO UH-UH

PRIOR TO PUTTING THEM IN

PATIENTS AND YOU CAN EXAMINE THE

SAFETY, EFFICACY AND

ENVIRONMENTAL INFLUENCES ON

HUMAN CELLS IN VIVO AND THE

EFFECT OF THE IMMUNE SYSTEM ON

IT.

WHAT ARE HUMANIZED MICE?

OUR DEFINITION, IMMUNE DEFISH

MICE ENGRAFTED WITH FUNCTIONAL

HUMAN CELLS APPROXIMATE TISSUES.

WE HAD TWO GOALS WHEN WE SET OUT

ABOUT 20 YEARS AGO NOW TO

EVALUATE HUMAN INSULIN PRODUCING

ISLETS BETA CELLS IN VIVO UNDER

VARIOUS CONDITIONS AN EVALUATE

THEM IN THE PRESENCE OF

FUNCTIONAL HUMAN IMMUNE SYSTEMS.

AUTOLOGOUS ALLOGENEIC AND

AUTOIMMUNE.

SO WE HAVE BEEN WORKING THE LAST

20 YEARS WHEN LEN SCHULTZ AND MY

LAB AT JACKS AN U MASS, OPTIMAL

MODELS FOR AN CO-ENGRAFTED WITH

FUNCTIONAL HUMAN IMMUNE SYSTEMS.

FIRST STEP HOW TO CREATE THE

IMMUNODEFICIENT MICE, THERE'S

THROUGH GENES USED IN THE FIELD

TO DO IT.

ONE IS A SKID, A SEVERE COMBINED

IMMUNODEFICIENCY GENE THAT

PREVENTS RECOMBINATION OF DNA SO

WHEN YOU BREAK APART THE T-CELL

RECEPTOR AN B CELL RECEPTOR, TO

FORM A NEW ANTIGEN SPECIFIC CELL

THEY CANNOT RECOMBINE.

THE OTHER TWO GENES HAVE BEEN

IDENTIFIED THE COMBINATION

ACTIVATING GENES THAT PREVENT

THAT BREAK SO YOU CAN START TO

RECOMBINATION EVENT.

ANY ONE OF THOSE THREE BLOCKS

ADAPTIVE IMMUNITY.

SO WHAT HAPPENED IN DEVELOPMENT

OF HUMANIZED MICE?

IT WAS DESCRIBED IN 1983

ENGRAFTED WITH HUMAN

HEMATOPOIETIC CELLS IN 1988.

AND 1995 DR. SCHULTZ DESCRIBED

THE NOD SKID MOUSE, A MAJOR

ADVANCE IN TERMS OF BEING ABLE

TO GET FUNCTIONAL ENGRAPHMENT OF

HUMAN CELLS IN TISSUES IN MICE.

WHEN YOU PUT HEMATOPOIETIC STEM

CELLS THERE NCI THERE YOU CANNOT

STIMULATE A HUMAN IMMUNE SYSTEM.

IN 2005 DR. SCHULTZ CALLED IT

NOD SKID RECEPTOR NULL MOUSE,

WHERE THEY PUT THE IL-2 RECEPTOR

NULL ON TO THE NOD SKID MOUSE.

WHY WAS THAT SO IMPORTANT?

IF ANYBODY HAS HEARD OF X LINK

SKID OR GRAY HAIR LIKE ME.

HE HAD X LINK SKID.

X LINK SKID WAS A DEFICIENCY OR

MUTATION IN IL-2 RECEPTOR COMMON

GAMMA CHAIN, RESPONSIBLE FOR

HIGH AFFINITY SIGNALING THROUGH

SIX CYTOKINES RECEPTORS

EXTREMELY IMPORTANT FOR BOTH

ADAPTIVE AND INNATE IMMUNITY.

DISABLELING THIS GENE KNOCKED

OUT WITH ADAPTIVE IMMUNITY GAVE

YOU A SEVERELY IMMUNODEFICIENT

MOUSE THAT COULD BE ENGRAFTED

WITH FUNCTIONAL HUMAN CELLS IN

TISSUES, AND IN FACT YOU CAN PUT

HUMAN HEMATOPOIETIC STEM CELLS

IN THE MICE AND GENERATE A

FUNCTIONAL HUMAN IMMUNE SYSTEM

YOU L MATTER ABOUT WEDNESDAY

AFTERNOON.

WHEN YOU WANT TO GO GO BACK AND

SAY HOW TO MOVE THE BETA CELLS

GENERATED FROM IPS CELLS IN THE

CLINIC, FIRST IS SAFETY,

EVERYBODY HERE KNOWS YOU CAN PUT

THESE CELLS INTO NUDE MICE, CD

17 SKID MICE, NOD SKID MICE,

GAMMA MICE AND TUMORIGENICITY.

THAT'S A TRIED AND TRUE TEST FOR

SECURITY OFFICERTY.

IMMUNOGENICITY, NOW THAT WE HAVE

DEVELOPED A MODEL WHERE YOU CAN

PUT A FUNCTIONAL HUMAN IMMUNE

SYSTEM THERE YOU CAN ASK

QUESTIONS OF IMMUNOGENICITY,

THAT WILL BE DISCUSSED TOMORROW

AFTERNOON.

SOILY SPEND MOST OF THE REST OF

MY TIME ON MODELS WE DEVELOPED

FOR EFFICACY.

AND WE MIMIC A CLINICAL SCENARIO

HOW WE CAN DO THAT.

SO OUR GOALS WERE MODELS TO TEST

FUNCTION OF BETA CELLS, IN

ABSENCE OR PRESENCE OF HUMAN

IMMUNE SYSTEMS IN VIVO AND THEY

MAKE BASED ON NOD SKID GAMMA I'M

ABBREVIATING MS DWRKS OR

NONREGULAR GAMMA NRG WITH SUS L

DIFFERENCES.

I'LL GIVE EXAMPLES OF NORMAL

GLYCEMIC MICE, A WELL CONTROLLED

DIABETIC.

HYPERGLYCEMIC OR POORLY

CONTROLLED DIABETES WITH GLUCOSE

ALL OVER THE PLACE AND WE HAVE

INLYNN RESISTANT MODELS WHICH

I'LL SHOW YOU BUT WON'T SHOW YOU

DATA ON THOSE DATA.

SO ONE QUESTION WE'RE ASKED IS

WHAT'S WRONG WITH THE MOADS

BEFORE YOU CAME UP WITH THE NOD

SKID GAMMA MICE.

AND THE NOD SKID WAS THE GOLD

STANDARD FOR 1995.

UP UNTIL 2005 AND HAD TWO MAJOR

DEFICIENCIES.

ONE, IT RAPIDLY DEVELOPS

LYMPHOMAS AND SLIDE OUT TO 7

MONTHS, YOU CAN'T DO LONG TERM

STUDIES IN NOD SKID MICE.

SECOND IS THEY STILL HAVE CASE

ACTIVITY, IN HEMATOPOIETIC

MESENCHYMAL AND ALL THE OTHER

AND A LOT OF CELLS SUCH AS DATA

CELLS SUSCEPTIBLE TO NK CELLS SO

YOU GET FALSE NEGATIVES BECAUSE

THE TISSUES YOU PUT IN OR

BECAUSE THE OF THE LENGTH OF

TIME YOU LOOKED AT THEM.

SO WHAT ARE MODELS, NOD SKID

GAMMA AND NSG NRG.

YOU'LL SHOW YOU A COUPLE OF

MODELS OF SPONTANEOUS INDUCED

HYPERGLYCEMIA AND WHAT YOU CAN

TEST THE FUNCTION OF THE

TRANSPLANTED BETA CELLS AND WE

HAVE A NUMBER OF MODELS LOOK AT

HUMAN BETA CELLS OR ISLETS UNDER

INSULIN RESISTANT CONDITIONS IN

MICE.

SO WHAT CAN YOU DO WITH NORMAL
FLY

GLIE SEEMIC NICE MYSELF?

HUMAN ISLETSK YOU CAN PUT IN

HUMAN BETA CELLS DERIVED FROM

IPS OR ES DERIVED CELLS AND YOU

CAN LET THEM FUNCTION AND

ENGRAFT AND YOU CAN CHALLENGE AT

VARIOUS TIMES WITH GLUCOSE

ARGININE WHICH IS NOW BECOMING A

VERY ACCEPTED PARAMETER OF

BIOMARKER OF FUNCTIONAL ISLET

MASS.

IN OTHER WORDS, THE AMOUNT OF

BETA CELLS, THE BETA CELL

ABILITY TO SECRETE INSULIN IN

RESPONSE TO STIMULATION.

SO YOU HAVE TWO ACTIVE

BIOMARKERS YOU CAN USE IN THE

BLOOD.

THAT IS HUMAN C PEPTIDE AND

HUMAN INSULIN.

BOTH WHICH ARE SPECIES SPECIFIC

ASSAYS AN EASY TO DO IN THESE

MICE.

ADVANTAGES, YOU CAN PUT THEM

INTO A NORMAL GLYCEMIC

ENVIRONMENT SO YOU DON'T HAVE

TOXICITY, VERY LOW NUMBERS

REQUIRED BECAUSE YOUR BIOASSAYS

ARE SENSITIVE OUT THERE.

THE DISADVANTAGE IS YOU CANNOT

STUDY THE TRUE HE -- ABILITY TO

REGULATE GLUCOSE HOMEOSTASIS.

SO LET'S MAKE THEM DIABETIC.

THE TRIED AND TRUE WAY OF DOING

THAT IS INJECT MICE WITH TOXINS

SUCH AS STREPTO CYTOSIS OR RA

LOCK SIN, YOU CAN INDUCE

HYPERFLY SEEMIA IN THE NOD SKID

MICE BUT YOU HAVE VARIABLE

RESULT.

INCREASE IN DOSE DOESN'T HELP,

IT KILLS THE MOUSE.

THEY ARE SENSITIVE THOUGH MORE

SEPSTIVE.

WHEN CAN YOU USE STREP INDUCED

DIABETES YOU HAVE RESIDUAL BETA

CELLS LEFT THAT CAUSE REVER

GENT, THEY LIKE TO PROLIFERATE

SO THEY CONTROL GLUCOSE

HOMEOSTASIS IRRPTIVE OF ANY

GRAPH YOU HAVE IN THERE.

SO WE USE THIS TO IDENTIFY HOW

MANY SINGLE BETA CELLS WE NEED

TO BE ABLE TO RESTORE NORMAL

GLYCEMIA, BECAUSE YOU'LL

GENERATE THE BCBC WILL BE

GENERATING ISOLATED SINGLE

CELLS, NOT ISLET STRUCTURES.

WHAT WE FOUND WHEN WE

DISSOCIATED MOUSE ISLETS AND PUT

IN SINGLE INSULIN POSITIVE CELLS

WE FOUND WE NEEDED HALF A

MILLION CELLS TO DO THAT.

MICE ARE RELATIVELY RESISTANT TO

HUMAN INSULIN AND WE'RE

ESTIMATING BETWEEN A MILLION AND

MILLION AND A HALF CELLS TO BE

ABLE TO INSULIN PRODUCING

GLUCOSE RESPONSIVE CELLS TO BE

ABLE TO RESTORE NORMAL GLYCEMIA

IN THE MICE SO WE HAVE A CELL

NUMBER, TARGET CELL NUMBER OF

WHAT YOU'RE GOING TO NEED FOR

EFFICACY IN THE MODEL SYSTEM.

SO AWAY FROM THE STREP.

THERE'S A INSULIN 2 GENE, BREAK

IN THE DISULFIDE BOND OF THE

INSULIN TUBE.

MICE IN CONTRAST HAVE TWO

INSULIN GENES, INSULIN 1 AND 2.

BY BREAKING THE DISULFIDE BOND

YOU GET MISFOLDED INSULIN

PROTEIN THAT INDUCES ER STRESS

WHICH LEADS TO BETA CELL

APOPTOSIS AN NON-AUTOIMMUNE

HYPERGLYCEMIA.

WHAT DOES THIS LOOK LIKE?

BY 3 TO 5 WEEKS OF AGE IN MALE

MSG OR IN,RG YOU GET CHRONIC

HYPERGLYCEMIA THAT CAN PERSIST

FOR THE LIFE OF THE ANIMAL.

WHAT'S INTERESTING ABOUT THE

MODEL IS BECAUSE THERE'S A BIT

OF PRO INSULIN 1 INSULIN, THESE

MICE CAN ARE MAIN IN THE STATE

OF CHRONIC HYPERGLYCEMIA, # TO

600 MGs PER DECALITER OR MONTH

IF NOT OVER A YEAR WITHOUT

ADMINISTRATION OF EXOGENOUS

INSULIN.

YOU CAN SEE BY 220 TO 224 DAYS

OUT, THERE'S A LITTLE INSULIN

LEFT, VERY DISORGANIZED ISLET

STRUCTURES OUT THERE IN THE HOST

PANCREAS.

SO CAN YOU RESTORE GLYCEMIA BY

GIVING BACK HUMAN BETA CELLS?

ANSWER IS YES.

YOU CAN PUT IN HUMAN ISLETS

WHICH WE GET FROM THE IUDP

FUNDED BY NIH WHERE THEY MAKE

HUMAN ISLETS AVAILABLE FOR

RESEARCH AND WE CAN HUMAN ISLETS

INTO THE MICE AND RESTORE NORMAL

GLYCEMIA AND THE GRAPHS SURVIVE,

WE CARE ARED -- CARRIED THEM OUT

STILL GOING UNTIL THE TIME

TERMINATE AND UNDER THE KIDNEY

CAPSULE YOU GET NICE INSULIN

CLUSTERS OF THE HUMAN ISLETS

THAT WERE TRANSPLANTED.

SO HOW CAN WE USE THIS TO STUDY

WHAT'S GOING ON IN IS IPS AN ES

DERIVED CELLS?

IF YOU FOLLOW THE LITERATURE YOU

KNOW THE ES DERIVED CELLS ARE

BROUGHT UP IN CULTURE TO A

PROGENERALTOR POINT AT WHICH

TIME THEY'RE PUT INTO

HYPERGLYCEMIC MICE, SOMETHING

MAGICAL HAPPENS OVER THE NEXT

TWO TO THREE MONTHS THAT NOBODY

KNOW ABOUT AND SUDDENLY THE

CELLS START TO REGULATE GLUCOSE

HOMEOSTASIS.

SO WE THOUGHT WE'D START TRYING

TO MODEL THIS WITH CELLS AND

TISSUES AVAILABLE TO US.

SO WE TOOK HUMAN FETAL PANCREAS

AND PUT CUBES IN A CHRONIC

HYPERGLYCEMIC MOUSE AND LET HIM

GO.

AS YOU CAN SEE WITHIN 50 TO 60

DAYS THOSE MICE STARTED TO HAVE

SOME EVIDENCE OF GLUCOSE

REGULATION.

TO THE POINT THAT 70 TO 80 DAYS

OUT WHEN STIMULATING BY THAT

ARROW WITH GLUCOSE ARGININE WE

GOT HUMAN C PEPTIDE PRODUCED BY

THOSE TRANSPLANTED CELLS.

IF YOU PULL THE KIDNEY OUT WHERE

THE TRANSPLANT WAS THE MICE

TRANSPLANT TO HYPERGLYCEMIA.

SO WE HAVE NOT ONLY THE ABILITY

TO STUDY MOUSE FETAL PANCREAS

DEVELOPMENT BUT HUMAN PAN

COLLIEIAS DEVELOPMENT THROUGH

THE BLACK BOX ERA PEOPLE WORKING

WITH IPS AND ES CELLS ARE TRY

TOIG FUR OUT -- FIGURE OUT AND

PULL THESE OUT AND LOOK AT

DEVELOPMENTAL PROCESS GOING ON.

WE CAN STUDY HOW THEY

DIFFERENTIATE NON-GLUCOSE

RESPONSIVE IP LYNN POSITIVE

CELL.

WHEN WE PUT THEM IN, A 20 WEEK

GESTATION PANCREAS HAS INLYNN

POSITIVE CELLS.

HOW THEY BECOME GLUCOSE

RESPONSIVE, I.E., HOW THEY

MATURE.

VERY EASY BIOMARKERS IN THIS

SYSTEM.

HUMAN C PEPTIDE AND BLOOD

GLUCOSE SO WE CAN FOLLOW BY

FOLLOWING THE BLOOD.

SO YOU USE THIS EVALUATE THE

ENVIRONMENTAL INFLUENCE ON

ISLETS OR BETA CELLS?

WE DID THE SIMPLEST EXPERIMENT

WE COULD THINK OF, THAT MOUSE

ISLETS AND BETA CELLS ARE

REPORTED TO PROLIFERATE IN

RESPONSE TO HYPERGLEE SEEMIA,

HUMAN BETA CELLS UNKNOWN SO WE

PUT HEIM HUMAN ISLETS FROM

VARIOUS AGE DONORS TO THESE MICE

CHRONIC EXPOSED HYPERGLYCEMIA

ONE TO THREE WEEKS, LABELED WITH

BRDU, AND LOOK FOR PROLIFERATING

BETA CELLS AND WE SAW ABOUT A

TENFOLD INCREASE IN THE HUMAN

BETA CELLS EXPOSED TO CHRONIC

HYPERGLYCEMIA.

WHAT WE'RE NOW DOING IS TAKING

THIS MODEL AND NORMAL GLYCEMIC

OR HYPERGLYCEMIC ANIMALS AND

PUTTING IN HUMAN ISLETS AND

STARTING TO EVALUATE DRUGS OUT

THERE IN THE COMMERCIAL MARKET

BEING USED FOR TYPE 2 DIABETES

REPORTED TO AFFECT THE BETA CELL

MASS OR PROLIFERATION OF HUMAN

BETA CELLS, NOT MOUSE,

DETERMINING WHETHER THEY IN FACT

DO DIRECTLY AFFECT THE HUMAN

BETA CELLS IN VIVO AND NOT HAVE

-- IN ADDITION TO THE THE

PRIMARY EFFECTS IN THE INSULIN

RESISTANCE AND TISSUES OUT

THERE.

SO YOU CAN RAL DATE THE

MECHANISM OF ACTION OF A LOT OF

DRUGS USED NOT ONLY FOR TYPE 1

BUT FOR TYPE 2 DIABETES IN VIVO

AND EFFECTS ON HUMAN ISLETS.

THAT'S A SPONTANEOUS MODEL OF

DIABETES, YOU'RE STUCK WITH IT,

IT SHOWS UP HYPERGLYCEMIC.

WE WANT TO BE ABLE TO HAVE

INDUCIBLE MOLD OF DIABETES TO

PUT CELLS INTO.

WE RELIED ON DIPHTHERIA TOXIN

RECEPTOR TRANSGENIC MOUSE BY THE

RAT INSULIN PROMOTER DEVELOPED

BY (INAUDIBLE) WHO PUT IT ON THE

NSG BACKGROUND.

THESE MICE HAVE NOW BEEN FIXED

TO HOMOZYGOSITY IF I CAN'T SPELL

IT RIGHT AND WE CAN GET

ESSENTIALLY 100% DEPLETION OF

BETA MOUSE OF DIPHTHERIA TOXIN.

WHY DID WE WANT TO DO THIS?

WE WANT TO PUT T-CELLS THIS A

NORMAL GLYCEMIC ENVIRONMENT, LET

THEM MATURE IN A NORMAL GLYCEMIC

ENVIRONMENT IN ABOUT ABSENCE OF

GLUCOSE TOXICITY ALLOWING THEM

TO BECOME REVASCULARRIZED.

YOU'RE NOT WORRIED ABOUT

METABOLIC DIABETIC HOST WHILE

WAITING FOR THE CELLS TO MATURE.

AND COME BACK IN WHENEVER WE

WANT AND ABILITY TO PRODUCE

HUMAN PEPTIDE I.E. FUNCTIONAL

AND ABLATE THE MOUSE BETA CELLS

SO SEE IF TRANSPLANTED CELLS CAN

REGULATE GLUCOSE HOMEOSTASIS.

THE ANSWER IS WE'RE ABLE AT THIS

POINT TO GET DOWN TO AS LITTLE

AS 2.5 NANOGRAMS DIPHTHERIA

TOXIN REPRODUCIBLY INDUCE DIE

BETOAS OF LATE MOUSE HOST BETA

CELLS INDUCE DIABETES IN THE DTR

MICE.

TAKES FIVE NANOGRAMS IN FEMALES

TWO AND A HALF IN MALES, WE

AREN'T QUITE SURE THE DIFFERENCE

BUT IT'S REPRODUCIBLE AND I

COULD SHOW YOU THE BETA CELLS

ARE ESSENTIALLY 100% GONE IN THE

MOUSE.

SO NEXT QUESTION DO THE DOSE

DIPHTHERIA TOXIN HARM THE HUMAN

TRANSPLANTED CELL WE PUT NSM SO

WE PUT HUMAN ISLETS TO A NORMAL

GLYCEMIC NSGTR MOUSE, LET THEM

VASCULARIZE FOR A COUPLE OF

WEEKS, LOOK AT HUMAN C PEPTIDE

INLINS, TOTAL CONTENT, LET THEM

GO FOR COUPLE MORE DAYS, HIT

THEM WITH DIPHTHERIA TOXIN, TWO

WEEKS LATER REPEATED THE TEST

AND YOU CAN SEE PEPTIDE INSULIN

AND WE TOOK DOWN THE GRAFT, LOOK

FOR TOTAL INSULIN CONTENT.

I'LL SHOW YOU THE SIMPLEST

RESULT OF THAT IS WE DID NOT

AFFECT TOTAL INSULIN CONTENT OF

THE TRANSPLANTED GRAPH, MEANING

WE WERE ABLE TO ABLATE THE MOUSE

BETA CELLS SPECIFICALLY WITHOUT

HARMING THE HUMAN CELLS WE PUT

IN.

CELL VIABILITY AN

VASCULARIZATION WE'RE DEALING

WITH CELL SUSPENSIONS INSTEAD OF

ISLETS.

THE DRAINAGE IS DIFFERENT, THE

REGULATION IS NOT NORMAL WITHOUT

GLUCOGON CELLS THERE.

THE SET POINT FOR HOMEOSTASIS IS

HIGHER IN HOUSE THAN HUMAN.

I WISH I COULD THE IT WILL U WE

HAD IT BUT YET NO AUTOIMMUNE

DIABETES MODELS IN HUMANIZED

MICE AVAILABLE.

SO I HOPEFULLY CONVINCED YOU

GAMMA CHAIN KNOCKOUT MICE O

REPUBLICAN THE OPTIMAL

RECIPIENTS.

WE HAVE NOVEL INDUCED

SPONTANEOUS MODELS IN DIE WE

TEASE.

I BELIEVE WE CAN USE THIS AS A

PRE-CLINICAL BRIDGE FOR STUDY OF

HUMAN CELLS BETWEEN THE PETRI

DISH AND THE CLINIC.

WE CAN EVALUATE DRUGS AND

OTHER

THERAPIES ON HUMAN CELLS WITHOUT

PUTTING PATIENTS AT RISK, IT'S A

STUDY OF HUMAN CELLS.

I THINK THIS IS THE OVERALL

PARADIGM THAT WE CAN GO TO THE

CLINIC.

IDENTIFY PROBLEMS, THIS

TRANSCENDS DIABETES DONE WITH

ALMOST ANY DISEASE OUT THERE,

IDE IF THE PROBLEMS PUT CELLS AN

TISSUES IN HUMANIZE MICE, USE

THEM TO DO YOUR BASIC RESEARCH,

GO BACK, IDENTIFY THE

MECHANISMS, PUT THEM BACK INTO

HUMANIZED MICE TO TEST THE

SAFETY AND EFFICACY OF ANY OF

THE DRUGS THERAPIES THAT YOU

HAVE AND MOVE BACK TO THE

PATIENT.

SO I VIEW THE HUMANIZED MICE AS

PRE-CLINICAL BRIDGE IN BOTH

DIRECTIONS IN TERMS OF WHAT

WE'RE DOING HERE.

THESE ARE PEOPLE THAT DID THE

WORK.

I PARTICULARLY WANT TO THANK THE

FUNDING AGENCIES THAT HELP

SUPPORT THIS.

THANK YOU.

[APPLAUSE]

(OFF MIC)

>> HELLO.

THANK YOU.

YOUR HUMANIZED SYSTEM IN TERMS

OF THE HEMATOPOIETIC

CONSTITUTION N YOUR HANDS WHAT

IS THE BEST LEVEL YOU CAN GET

WITH THAT?

>> WE CAN GET CIRCULATING BLOOD

CELLS THROUGH HUMAN CD 45

POSITIVE CELLS UP TO 95% IN THE

BLOOD, 90% IN THE SPLEEN.

90 TO 95% BONE MARROW.

GOOD THYMIC RECONSTITUTION IN

ALL CELLS REPRESENTED IN THE M.

VERY ROBUST, MOST OF THE TIME

WE'RE DEALING WITH ENGRAFTMENT

LEVELS DEPENDING ON MODELS

DR. SCHULTZ WILL TALK ABOUT.

ENGRAFTMENT LEVELS OF 40 TO 50%.

>> MAHENDRA.

>> TWO QUESTIONS.

THE IMMUNE SYSTEM IS IMPORTANT

--

>> I CAN'T HEAR YOU, I'M SORRY.

>> TWO QUESTIONS.

THE IMMUNE SYSTEM IS IMPORTANT

IN SEVERAL STROKE MODELS AND IN

TERMS OF DEGREE BY EXTENT OF

DAMAGE YOU SEE.

IN THESE NOD SKIN MICE FROM ARE

REPUBLICAN THE NSG MICE DO YOU

SEE A DIFFERENCE USING A

STANDARD MODEL OF LIGATION FOR

CARDIAC DAMAGE OR STROKE AND IS

THAT MUCH WORSE OR DO WE HAVE TO

RECALIBRATE THESE THING?

>> MY SIMPLE ANSWER IS I HAVE IT

IN MY IACUK PROTOCOL, I HAVE NOT

DONE IT YET AND I WOULD LOVE TO

COLLABORATE WITH SOMEBODY WHO

WOULD DO THAT TECHNICAL SURGERY

FOR ME.

NO, IT HASN'T BEEN DONE.

>> THE -- QUESTIONS ONE WOULD

ASSUME WHEN YOU PUT IN THE HUMAN

CELLS TO RECONSTITUTE THE

SYSTEM, THAT YOU GET GRAFT

VERSUS HOST DISEASE IN THIS CASE

A FOREIGN ANTIGEN AND DO YOU SEE

THAT AND DOES THAT HAVE AN

EFFECT IN TERMS OF MAKING THE

MOUSE SICK SO YOU HAVE A

DIFFERENT IMMUNE ISSUE YOU HAVE

TO WORRY ABOUT WHEN YOU USE THIS

MODEL.

>> THERE'S A SIMPLE MORE

COMPLICATED ANSWER.

PERIPHERAL BLOOD CELLS YOU GET

GBH FOUR TO SIX WEEKS OUT SO YOU

HAVE A WINDOW TO LOOK WITHOUT

THE GBH.

IF YOU PUT IN HEMATOPOIETIC STEM

CELLS CO-TRANSPLANTATION, FETAL

LIVER THYMUS, THIS CELLS ARE

EDUCATED IN THE MOUSE AND COME

OUT TOLERANT.

THEN YOU HAVE A WINDOW FROM 10

TO 12 WEEKS UP TO 26 TO 30 WEEKS

BEFORE YOU SEE ANY SIGNS OF

BREAKING THE SELF-TOLERANCE.

WHERE IMMUNE SYSTEMS ARE NAIVE,

THEY LOOK WONDERFUL, THEY

RESPOND APPROPRIATELY TO

CHALLENGES.

SO YOU HAVE A WINDOW OF 14 WEEKS

TO DO STUDIES ON COMPLETE HUMAN

IMMUNE ENGRAFTED MICE IN THE

ABSENCE OF ANY APPARENT

XENOREACTIVITY.

SO NICE WIN TOE TO WORK WITH.

>> 12 TO 14 WEEKS.

Q.OTHERWISE FOUR WEEKS SPHWHRSM

IF YOU DO THE BLOOD YOU'RE

PUTTING IN MATURE EFFECT TOR

CELLS THAT MEDIATE XENOGBH

BECAUSE THEY'RE NOT EDUCATED IN

THE MOUSE.

SO YOU HAVE 4 TO 6 WEEKS.

IF YOU DO STEM CELLS TO ALLOW

T-CELL EDUCATION TO OCCUR IN THE

MOUSE, YOU HAVE 14 TO 16 WEEKS

OF FUNCTIONAL EXPERIMENTAL TIME

YOU DONE HAVE BREAKING

SELF-TOLERANCE.

>> ONE LAST QUESTION IF I MAY.

THIS IS RELATED TO OTHER ANTIGEN

PRESENTING CELLS THAT SEEM TO BE

IMPORTANT PARTICULARLY IN THE

CENTRAL NERVOUS SYSTEM WHEN

THINKING ABOUT ANTIGEN

PRESENTATION LOOKING AT

MICROGLIA WHICH ARE PRESENT IN

THE PRAIN, IS THERE ANY DATA

AVAILABLE IN THE NSG MICE ON

WHAT HAPPENS TO THAT KIND OF

RESPONSE?

BEHAVIOR?

>> DEPENNING HOW YOU ENGRAFT THE

MOUSE YOU CAN GET HUMAN

MICROGLIA IN THE BRAIN AS MANY

AS 20 TO 30%, MAYBE HIGHER AND

IN A MEETING IN PITTSBURG LAST

OCTOBER A INVESTIGATOR REPORTED

HIV INFECTION MICROTBLEEIA IN

THE BRAIN, REPRODUCIBLE, YOU HAD

A LOT OF NEUROLOGICAL DEFECTS

YOU SEE IN HUMAN.

SO YOU CAN GET A FAIR

REPRESENTATION OF HUMAN

MICROGLIA IN THE BRAIN IN THESE

MICE.

>> THANK YOU.

>> THIS IS PRIMARILY DESIGNED TO

--

>> PLEASE IDENTIFY YOURSELF.

>> JANET DAVIS, JANSON.

THIS IS PRIMARILY DESIGNED TO

ANYMORIC ADAPTIVE ARM OF THE

IMMUNE SYSTEM IN THE MICE.

HUTCH CAN YOU REPRODUCE INNATE

INFLAMMATORY ENVIRONMENT AND THE

CROSS PLATE THAT OCCURS BETWEEN

ADAPTIVE AND THE NATIVE?

>> DEPENDS ON WHAT ASPECT OF

INNATE IMMUNE SYSTEM YOU'RE

LOOKING AT.

NK CELLS DEVELOP BUT HAVE

TROUBLE WITH CYTOTOXIC ACTIVITY,

ADDRESSED BY DEVELOPING HLA

TRANSGENIC MODELS THAT ATHROUGH

LICENSING OF THE NK CELLS TO

KILL.

THERE'S DATA WE HAVE NOT

PUBLISHED ON THAT.

IN TERMS OF DEN GRIT DRITTIC

CELLS, MACROPHAGE, ET CETERA,

THE MACROPHAGE MYELOID CELLS

DEVELOP POORLY BECAUSE THE CSF-1

IS SPECIES SPECIFIC.

WE DEVELOPED A HUMAN CSF-1 --

NSG MOUSE, WE GET 3 TO 4 FOAL

INCREASE IN CIRCULATING MYELOID

MACROPHAGE CELLS AN CURRENTLY

WE'RE TESTING THOSE MICE IN A TB

MODEL TO SEE IF WE GET BETTER

GRANULOMAS.

WE DEVELOPED MITI L 8 KNOCK OUT

MICE AND STIMULATED THEM WITH

THR-4 AND GET STRONG HUMAN

CYTOKINE RESPONSES FROM THE

TLR-4 IN THE ABSENCE OF MOUSE

CYTOKINE RESPONSE.

SO DEPENDING ON THE QUESTION OF

INNATE IMMUNITY YOU WANT TO ASK,

WE MAY HAVE MODELS THAT ARE

AVAILABLE TO STUDY THAT HAVE NOT

BEEN PUBLISHED TO DATE BUT YOU

CAN GET GOOD INNATE IMMUNE

RESPONSES IN THESE MICE.

>> DO YOU SEE CROSS PRIME?

THAT'S A HALLWAY QUESTION.

BECAUSE MIEWBIZATION, THE ONE

THING I WOULD -- IMMUNIZATION,

THE ONE THING I WOULDN'T TRY TO

SELL THE MODEL FOR IS DELIBERATE

IMMUNIZATION BY TYPICAL VACCINE.

THEY ARE NOT GOOD MODELS FOR

THAT, AT THIS POINT DR. SCHULTZ

WILL TALK ABOUT HOW HE'S OPT

MYING THE MODEL TO ALLOW THAT TO

HAPPEN.

THE ISSUE ACROSS MOWNIZATION IS

NOT A QUESTION WE CAN ADDRESS IN

THESE MODELS AT THIS POINT.

>> THANK YOU VERY MUCH.

>> THANK YOU.

[APPLAUSE]

>> I WOULD LIKE TO THANK THE

SPEAKERS FOR THIS PART OF THE

MORNING SESSION.

WE NOW HAVE A LUNCH BREAK AND WE

WILL RECONVENE AT 1:30 IN THE

CAFETERIA IS UP STAIR, KEEP

TURNING LEFT

I WOULD LIKE TO INTRODUCE

DR. RAJESH RAGANATHAN.

I'M SORRY I MISPRONOUNCED, I'M

TERRIBLE AT PRONUNCIATION, WHO

IS WITH THE OFFICE OF

TRANSLATIONAL RESEARCH.

HE JOINED NIH FROM NOVARTIS AND

DID A MAJOR TASK IN WORKING ON

THE DEVELOPMENT OF OUR NEW N

THEET CATS, THE NATIONAL CENTER

FOR ADVANCEMENT OF TRANSLATIONAL

SCIENCE.

THIS HAS BEEN A WONDERFUL THING

HE'S DONE WORKING ON THIS AND

HE'S GOING TO TALK TO US TODAY

ABOUT THE VALUE OF IDENTIFYING

MECHANISMS OF ACTION FOR PROOF

OF PRINCIPLE STUDIES.

>> OKAY.

I GUESS PEOPLE ARE STILL

FILTERING IN.

THANK YOU FOR THE INVITATION TO

TALK HERE.

I HAVE A FEW DUBIOUS HONORS.

FIRSTFÖ

OF GIVING A DATA FREE

PRESENTATION.

YOU DON'T HAVE TO WORRY ABOUT

GRAPHS OR ANYTHING ELSE,

INTERPRETATION.

THE SECOND IS BIT IS THAT THE

THING THE ORGANIZERS ASKED ME TO

DO KEEP YOU AWAKE TO PREPARE FOR

THE NEXT SPEAKER SO HOPEFULLY I

CAN ACHIEVE THAT IN THE POST

GRAND STATE YOU ARE WALKING

WITH.

AS THE INTRODUCTION SAID MY

BACKGROUND IS PHARMA,/EM A

NEWCOMER INTO THE FEDERAL SYSTEM

AND MANAGING A PORTFOLIO OF

TRANSLATIONAL RESEARCH

SPECIFICALLY NEUROLOGICAL

DISEASE AND STROKE.

THAT'S THE FOCUS OF WHAT I

OVERSEE.

AND SO MY ROLE HERE IS HAVING

LISTENED TO SO MANY

CONVERSATIONS THIS MORNING BY

THE SPEAKERS, MUCH O WHAT I PUT

UP IS EVEN SLIDES THAT I HAVE

YOU'RE GOING TO HAVE SEEN FROM

THE PREVIOUS SPEAKERS.

I DON'T KNOW WHAT PEDAGOGICAL

SYSTEM, SAYING THE THIRD OR

SECOND TIME AND SOMEBODY ELSE

WILL REPEAT AGAIN IN THE MEETING

SO IT DOES SOLIDIFY SOME OF

THESE PARTICULAR ASPECTS OF WHAT

WE'RE GOING TO TALK ABOUT.

YOU ALLUDED THE ACRONYMS UP

FRONT.

THERE ARE TWO IN THE TALK THAT

WAS ALREADY THERE, MECHANISM OF

ACTION AND PROF OF CONCEPT.

MAYBE THAT'S WORTH TAKING A

MOMENT TO TALK ABOUT WHAT WE

MEAN BY THAT.

SOMEK NISM OF ACTION IS

SOMETHING DISCUSSED QUITE A BIT.

I THINK PEOPLE MOST PEOPLE TRY

TO TEND TO UNDERSTAND WHAT WE

MEAN BY THAT IN THE CONTEXT OF

SMALL MOLECULE SPACE WHICH IS

WHAT I'M FAMILIAR WITH AND

TRANSLATING THIS THAT, IF YOU

WILL, TO STEM CELL SPACE.

BUT I ACTUALLY WANT TO FOCUS ON

WHAT WE MEAN BY THE POC OR PROF

OF CONCEPT.

I THINK PREVIOUS SPEAKERS USED

IT IN A DIFFERENT CONTEXT AND

MEANS DIFFERENT THINGS TO

DIFFERENT PEOPLE.

FOR ME THE WAY I THINK ABOUT

TRANSLATION IS THAT ALL THE

PRE-CLINICAL WORK THAT WE DO

WHICH IS WHAT THE SESSION IS

ABOUT, IN A SENSE LEADS UP TO

THE ULTIMATE END POINT OF

TRANSLATION TESTING HYPOTHESIS

IN THE HUMAN.

THAT'S THE END POINT OF

TRANSLATION AN PROOF OF CONCEPT.

THE ONES THAT GO BEFORE THAT

HELP US GET THERE BUT MY ONLY

LEXICON DON'T REFER TO THOSE

STUDIES IN THE PRE-CLINICAL

SPACE AS PROOF OF CONCEPT.

AS I HAVE SEEN THE NEXT 18

MINUTES OR SO, PROOF OF CONCEPT

I'M THINKINGN'T FIRST HUMAN

STUDY SOMETHING HOW THE

THERAPEUTIC ENTITY MIGHT WORK.

TO CLARIFY HOW I'M USING IT.

TO SET THE CONTEXT HERE YOU HAVE

SEEN FROM WALTER AND OTHER

PEOPLE FEDERAL AGENCY, FDA AND

NIH ROLE ARE DIFFERENT IN ITS

WORTH HIGHLIGHTING THAT ASPECT

OF IT AND YOU HAVE HEARD OVER

AND OVER AGAIN, THE PRIMARY

ASPECT OF IT, THERE WAS ALSO THE

EMPHASIS THE FDL HZ TO SET UP

SUBMISSIONS AND HOW THAT PLAYS

INTO IT.

WHILE THE TRAT JI I WON'T READ

FROM THE SLIDES BUT YOU SAW FROM

THIS MORNING IN THE INITIAL

PRESENTATION, WHAT PERMISSION

BUT THE NIH MUST PRIORITIZE

BECAUSE OF FUNDING DOLLARS

LIMITED, PROI YOUR ADVERTISE THE

MOST PROMISING WORK TO ADVANCE

THE MISSION.

THAT I THINK CHANGES THE KIND OF

QUESTIONS THAT GET ASKED AT

GRANTING THE WORK.

THOSE WHO MIGHT BE FROM ACADEMIA

OR FROM SMALL COMPANIES THINKING

ABOUT WORKING IN THIS

TRANSLATIONAL SPACE, IT MIGHT BE

HELPFUL TO TEASE THAT OUT A

LITTLE BIT MORE THE QUESTION

FROM THE AUDIENCE IN RESPONSE TO

MA HEN TRA'S TALK, WHICH IS

ASPECT WHETHER WHAT IS THE

ASPECT DONE FOR, WHAT IS P

PURPOSE, FURTHER CLINICAL

INVESTIGATION OR IS IT ACTUALLY

TO PUT A PRODUCT OUT THERE IN

THE MARKETPLACE.

I THINK THOSE MOTIVATIONS ARE

WORTH, I WAS THINKING THIS

MORNING, THAT'S AN IMPORTANT

DISTINCTION BECAUSE WHAT THE

QUESTIONS YOU MIGHT ASK IN THAT

TRANSLATIONAL SPACE IS

FUNDAMENTALLY DIFFERENT IF YOU

ARE -- IF YOUR FOCUS IS ONE

VERSUS THE OTHER SO BEING

PAROCHIAL IN THE CONTEXT OF WHAT

I OVERSEE IN NINDS AND THE

OFFICE OF TRANSLATIONAL

RESEARCH, MY OBJECTIVE IN

WHATEVER WE FUND WITH THE BUDGET

THAT WE HAVE IS TO GET THINGS TO

APPOINT WHERE THEY CAN BE TAKEN

UP AND MOVED TO THELY NUK AND

BEYOND SO THAW EAR HELPFUL TO A

PATIENT.

SO IT IS IMPORTANT TO THINK

ABOUT WHAT THOSE DETERMINANTS

MIESH THAT ALLOW SOMEBODY TO

PICK -- MIGHT BE THAT ALLOW

SOMEBODY TO PICK 

UNLESS YOU HAVE DEEP POCKETS YOU

NIED PARTNERSHIPS TO MOVE THEM

FORWARD.

IF YOU'RE UNDER THE ILLUSION

THAT'S NOT THE CASE I CHALLENGE

THAT NOTION IT'S GOING TO BE

DONE IN ANY OTHER WAY.

SO YOU NODE TO UNDERSTAND WHO

THOSE DOWNSTREAM PLAYERS ARE AND

WHAT THEY REALLY WANT IN TERMS

OF WANTING TO PICK THIS UP.

PUTTING ON MY OLD PHARMA HAT A

MOMENT, I WOULD SAY THE

OPERATIVE WORD IS RISK OR

DERISKING.

SO QUESTION OF CAN YOU TAKE

WHATS THAT AND THINK ABOUT RISK

BENEFIT TALKED ABOUT IN THE

CONTEXT OF REGULATORY PURVIEW

BUT FROM THE PERSPECTIVE OF

INVESTMENT AND MOVING FORWARD,

THE SAME PRINCIPLE APPLIES IN

TERMS OF THINKING ABOUT THE

RISK.

THIS IS WHERE MECHANISM OF

ACTION COMES INTO PLAY IN TERMS

OF THINKING ABOUT THE RISK PIECE

OF IT.

SO I WANT TO FOCUS ON THIS AND

TALK ABOUT WHY IT'S IMPORTANT TO

THINK ABOUT THE MECHANISM OF

ACTION.

THOUGH IT MIGHT BE LESS RELEVANT

AS WE TALK ABOUT THIS MORNING

FROM A REGULATORY PERSPECTIVE.

WHAT ARE NIH CONCERNS?

THEY MAKE NIH MAKE FUNDING

DECISIONS AND DECISIONS OF PEER

REVIEWCH THIS IS INTERESTING.

I'M NOT AS EXPOSED TO IT, THIS

IS THE COLLECTIVE WISDOM OF MANY

OTHERS PROGRAM DIRECTORS WHO PUT

THIS TOGETHER, WHICH IS THE

REVIEWERS ARE SELDOM

ENTHUSIASTIC AS APPLICANTS ARE

ABOUT PROMISE OF ACTUAL THERAPY,

AS THERAPEUTIC.

KIND OF INTERESTING IF WE PAUSE

AND THINK ABOUT THAT, WHO ARE

THESE REVIEWERS.

PEOPLE IN THE SAME IMMUNITY

VIEWING THEIR PEERS, IT'S

INTERESTING, YOU CAN BRING AN

INTERESTING INTERESTING IDEAS IN

STUDY SECTION, THEY'RE MORE SORT

OF CIRCUMSPECT ABOUT WHAT THE

POTENTIAL WHERE THIS MIGHT GO SO

THE DISCONNECT THAT MIGHT EXIST,

I'M PROPOSING THIS, I DON'T MEAN

THE CLAIM TO BE EXPERT HERE AND

I HOPE TO OPEN A DIALOGUE HERE

MORE THAN ANYTHING ELSE, ALMOST

TEEING UP FOR THE AFTERNOON

PANEL DISCUSSION IF YOU WILL,

WHAT IS DISCONNECT BETWEEN WHAT

FDA REVIEWERS ASK FOR AND WHAT

THE NIH REVIEWERS HOPE FOR.

FROM THE QUESTION OF IF IT WORKS

DOES IT MATTER HOW?

THE QUESTION ABOUT IF YOU HAVE

MECHANISM OF ACTION YOU HEARD

FROM THE FDA COLLEAGUES IT WOULD

BE HELPFUL TO KNOW BUT IT'S NOT

A REQUIREMENT OR BAR FOR

APPROVAL.

VERSUS THE NIH FOCUSING ON THE

HYPOTHESIS AND MECHANISM AND

REALLY UNDERSTANDING THAT.

AND THAT BECOMING A METRIC HOW

TO PRIORITIZE WHAT WE MIGHT FUND

IS CERTAINLY IN PLAY IN TERMS OF

HOW THE GRANTING PROCESS WORKS.

OTHER QUESTIONS, I'M NOT GOING

TO READ THROUGH THIS, YOU CAN

CERTAIN THROUGH DO THAT WHICH IS

IN TERMS OF WHETHER THE

THERAPEUTIC IS REACHING AND

HAVING ITS EFFECT AND HOW IT'S

PESK TO THE CELLS AN EFFICACY

VERSUS IN THE ANIMAL CELLS

VERSUS CLINICAL CELLS, QUESTIONS

THE NIH FOCUSES ON THAT MIGHT BE

MORE SKEWED TOWARDS THE SCIENCE

THAN NECESSARILY ABOUT THE

QUESTIONS OF SAFETY THAT THE

SISTER AGENCY FOCUSES ON FROM

THE FDA.

I'M GOING TO SPLIT THE SLIDE

BECAUSE MANY PREVIOUS TALKS HAVE

ADDRESSED THIS.

WHAT ARE THE CELLS DOING, WHERE

DO THEY GO, WHAT EFFECTS THEY

HAVE, ARE THEY PLACING -- I

DON'T THINK WE NEED TO WALK

THROUGH EVERY ONE OF THESE

ASPECTS BUT THESE ARE WHAT WE'RE

TALKING ABOUT WHEN WE TALK ABOUT

THE RUBRIC OF TALKING MECHANISM

OF ACTION AND TRYING TO

UNDERSTAND HOW WE MIGHT LEARN

MORE ABOUT WHAT THE THERAPEUTIC

IS DOING IN THIS CASE STEM CELLS

BUT THE SAME TRUE IF IT WERE

SMALL MOLECULES.

SO IN MANY CASES, FROM AN

EFFICACY PERSPECTIVE, NIH MAYBE

ASKING FOR CONFIRMATION OF

MECHANISM OF ACTION WHILE

REVIEWERS MIGHT NOT.

BUT THE CHALLENGES THAT CAPTURE

DEFINITIVE SORT OF MECHANISM

INFORMATION AT THE SAME TIME

CAPTURING SAFETY INFORMATION IN

THE SAME PRE-CLINICAL STUDIES IS

CHALLENGING.

THOUGH IT WOULD DECREASE OVERALL

COST AN TIME, IT'S NOT

NECESSARILY SOMETHING THAT MANY

OF YOU I THINK PRESENTED THIS

MORNING TALKED ABOUT MULTIPLE

STUDIES DONE SOME FOR SAFETY,

SOME FOR EFFICACY COMBINED AND

MULTI-MODAL IN TERMS OF MOVING

THROUGH THE DEVELOPMENT PATH.

SO OFTEN WHEN THE REVIEWER LOOK

THEY MIGHT NOT FIND THE SAFETY

TESTING PIECE THAT EXCITING OR

IS IN THE CONTEXT OF PEER REVIEW

TO SAY THIS IS AN IMPORTANT

ASPECT TO MOVE FORWARD.

THE CHALLENGE ALSO IS IT'S

IMPORTANT TO CONSIDER WHO IS

THERE IN THE STUDY SEB, DO THEY

HAVE RELEVANT EXPERIENCE TO LOOK

AT BOTH ASPECTS WHETHER THEY'RE

THINKING ABOUT THE SAFETY PIECE

OF MOVING THIS FORE FROM A

TRANSLATIONAL PERSPECTIVE AS

OPPOSED TO SCIENCE PIECE RO-1 OR

BASIC GRANT LOOK AT MUCH BETTER.

WANT TO FRAME THIS DISCUSSION IN

THE CONTEXT OF THE FACT THAT

MAYBE SOME TENSIONS ABOUT HOW

WHEN SCIENCE COMES IN TO THE

DIFFERENT AGENCIES HOW THEY

MIGHT BE QLIEW VIEWED AND JAITED

-- VIEWED AND -- HOW THEY MIGHT

BE VIEWED AND ADJUDICATED.

I'LL BEGIN BY PORTRAYING A BIAS

OF MY OWN, COMING FROM THE SMALL

MOLECULE SIDE, I'LL BE SPECIFIC

ABOUT CIRCUMSCRIBING COMMENTS TO

THAT EXPERIENCE.

FOR COMING TO THE SMALL MOLECULE

SIDE I FOUND IT RATHER

DISAPPOINTENING MY TIME AT

PHARMA IN WORKING WITH ANIMAL

MODELS AS WHAT IS IS THE WORD

PATRICK USED, REPRESENTATIONS OF

THE DISEASE BECAUSE THEY WERE

POOR REPRESENTATIONS IN MOST

CASES AND AT LEAST THE DISEASES

I WAS INVOLVED IN.

AND NEUROLOGICAL DISEASE IN

PARTICULAR.

QUESTION IS WHAT ARE THE ANIMAL

MODELS USEFUL FOR IN THE CONTEXT

OF TRANSLATION IF AS I DEFINED

RIGHT AT THE BEGINNING OF MY

TALK, IF PROOF OF CONCEPT IS

REALLY THAT EXPERIMENT IN THE

HUMAN THAT YOU WANT TO DO.

AND I THINK THAT'S SORT OF

SETTING THE STAGE FOR THINKING

ABOUT THE ANIMAL MODEL IN

PERHAPS A SLIGHTLY DIFFERENT WAY

THAN YOU'RE USED TO THINKING

ABOUT WHICH IS IS TRYING TO

RECAPITULATE EVERY ASPECT OF

HUMAN DISEASE AS POSSIBLE.

IS THAT WHAT WE WANT?

REASON I PUT IT AS A QUESTION TO

THE TABLE, MAYBE A LITTLE

PROVOCATIVE AND CONTROVERSIAL,

SMALL MOLECULE DRUG DISCOVERY

PLAYED OUT THE GAME AND FALLEN

ON ITS OWN SWORD AND GIVEN THIS

IS A NASCENT FIELD IN STEM

CELLS, THE CHALLENGE FOR THIS

COMMUNITY IS TO NOT REINVENT THE

WHEEL AS MAHENDRA SAID AT THE

BEGINNING BUT TO LEARN FROM

THOSE EXPERIENCES AND DO THINGS

DIFFERENTLY.

MY PERSONAL BIAS THE WAY WE

WORKED FOR WITH -- IN THE

COMPANY I WORKED IN IS FOCUSING

ON THE ANIMAL MODELS ON ASKING

THAT MECHANISM OF ACTION

QUESTION AND ASKING WHETHER WE

COULD HAVE APPROPRIATE READ OUTS

TO ALLOW IT TO BE TRANSLATED TO

THE CLINICAL SETTING AND COULD

TAKE IT THERE.

SO COULD THE MODELS BE FOCUSED

ON ADDRESSING THESE ASPECTS OF

MECHANISM WE TALKED ABOUT A

COUPLE OF SLIDES AGO IN THE

APPROXIMATE MALL SETTING, NOT

NECESSARILY WORRYING ABOUT THE

MODEL NECESSARILY RECAPITULATING

EVERY ASPECT OF HUMAN DISEASE

PER SE.

AND IN EFFECT, CURING IT.

WE DON'T WANT TO CURE THE MOUSE,

WE WANT TO CURE THE ANIMAL, IN

OTHER WORDS.

I'LL PUT IT UP IN ONE GO.

IN ABSENCE OF FULL UNDERSTANDING

OF DISEASE WHICH I WOULD CONTEND

IS OFTEN THE CASE IN MOST

DISEASES WE'RE DEALING WITH.

WHAT DO WE WANT TO DO?

WE WANT TO TEST THE ENTITY

TARGETS THE INTERFERES OR

MODULATE IT IS TARGET

EFFECTIVELY.

ALLOWING THEM TO COME BACK FROM

THE CLINIC AND EARLY

OBSERVATIONS TO INFORM THE

STUDIES DOING IN THE

PRE-CLINICAL MOLECULES IS AN

IMPORTANT ONE, WE TALK ABOUT IN

LANGUAGE TRANSLATION BEING THE

UNIDIRECTIONAL STREET, THE

PRE-CLINICAL MODELS AND YOU GO

INTO THE CLINIC.

THIS ASPECT BRINGING

TRANSLATIONAL PIECE BACK TO

INFORM THE PRE-CLINICAL WORK IN

TERMS OF WHAT YOU MEASURE, IS

ONE I THINK THIS COMMUNITY MIGHT

WISH TO CONSIDER HOW IT PLAYS

OUT IN CONTEXT OF STEM CELLS.

SO IF THERE ARE DISEASE MODELS

OBVIOUSLY I WON'T STAND IN THE

WAY OF THEM BEING USED NOR IS

ANYBODY ELSE.

WE'LL MOVE FORWARD.

BUT IF THERE AREN'T PHARMA TENDS

NOW I'M PUTTING ON MY BUSINESS

HAT IF YOU WILL IF YOUR JOB IN

TRANSLATION IS GETTING READY SO

THAT A COMPANY BIOTECH OR

WHATEVER ELSE IT MIGHT BE MIGHT

BE DOWNSTREAM PARTNER WILLING TO

TAKE THAT ON, BEFORE THEY GO TO

THE FDA OR EVEN IN THE

CONVERSATIONS WITH THE FDA, THAT

THE RISK FOR TAKING THIS ASSET

FORWARD INVESTING IN IT IS WORTH

THE BENEFIT, IF YOU WILL, THAT

IS LIKE TO PROVIDE.

OTHERS ARTICULATELY POSITIONED

THE RISK BENEFIT E QITION

EARLIER IN CONTEXT OF DISEASE,

IT IS AN INDIVIDUALIZED

DISCUSSION, IF IT'S COSMETIC

INDICATION YOU WANT SOMETHING AS

SAFE AS WATER.

AND IF IT'S SOMETHING THAT IS

TERMINAL DISEASE YOU'RE GOING TO

ACCEPT A CERTAIN LEVEL OF SIDE

EFFECT PROFILE.

THOSE ARE CONVERSATIONS THAT

NEED TO HAPPEN IN THE CONTEXT OF

WHAT YOU'RE DEVELOPING IN THE

PRE-CLINICAL MODELS AND WHAT

YOU'RE TRYING TO ADDRESS IN THE

CLINIC.

I WOULD SAY THIS PART PROBABLY

IS ONE THAT IS THE TRADITIONAL

DRUG DISCOVERY BACK TO SMALL

MOLECULE SPACE, HAS BEEN HAS NOT

PAID ENOUGH ATTENTION TO EARLY

ENOUGH.

SO THE EXTEN THIS IS A NAYSANT

FIELD AND THINK ABOUT WHERE

PREDICTIVE BIOMARKERS ARE

DEVELOPED ALONGSIDE THE RESEARCH

THERAPEUTIC, THAT WOULD I THINK

BEHOOVE US TO THINK ABOUT WHAT

MECHANISMS FROM A FUNNING

PERSPECTIVE BUT ALSO SCIENCE TO

MOVE THE FIELD FORWARD.

IN MANY CASES AT LEAST MY

EXPERIENCE WAS THAT WE OFTEN

LOOKED -- WE BROUGHT A PROJECT

FORWARD ALMOST ALL THE WAY TO

WRITING THE IND OR THINKING

ABOUT WHAT THE CLINICAL

CANDIDATE LOOKS LIKE AND THEN

SAY OKAY WHAT IS THE BIOMARK

ERGOING TO LOOK LIKE?

ALMOST TOO LATE I WOULD ARGUE,

ALMOST 2, 3, 4 YEARS TOO LATE

AND SORT OF STARTING THAT

PROCESS AND WOULD HAVE BEEN BEAR

OFF THINKING ABOUT IT ALONGSIDE

WHEN THE THERAPEUTIC WAS BEING

DEVELOPED BECAUSE IT TAKE AS

MUCH TIME AND RIG RUS SCIENCE TO

DEVELOP THE BIOMARKER AS IT DOES

TO DEVELOP THE THERAPEUTIC.

ONE ASPECT THINKING ABOUT IS

THIS ASSAY POTENCY IN THE

CONTEXT OF MANUFACTURING AND

OTHER PLACES GETS USED TO

ESSENTIALLY DO THE A WHOLE RANGE

OF ACTIVITIES BUT YOU HAVE TO BE

CAUTIOUS THE POTENCY ACTIVITY

YOU'RE MEASURING MAY NOT REFLECT

THE EFFICACY ACTIVITY SO IT'S

SOMETHING TO KEEP IN MIND AS YOU

THINK ABOUT WHAT YOU'RE

DEVELOPING FOR VARIOUS

BIOACTIVITIES FOR QA OR OR

PURPOSES AND WHAT THAT MEANS.

IF YOU KNEW THE MECHANISM OF

ACTION YOU BUILD SOMETHING THE

BIOACTIVITY IS CORRELATED WITH

THE MECHANISM OF EFFICACY YOU BE

IN A BETTER SPACE.

ANOTHER REASON GIVEN THE TITLE

OF WHAT I WAS TRYING TO PRESENT

THE VALUE OF UNDERSTANDING

MECHANISM OF ACTION IN THE

PRE-CLINICAL MODELS LEADING UP

TO THE PROOF OF CONCEPT IN THE

HUMAN SETTING.

SO I WOULD SAY NO EASY ANSWERS

TO ANY OF THESE, THE REASON

WE'RE GETTING TOGETHER IS TO

DISCUSS MANY OF THESE ASPECTS OF

IT.

FROM A PRE-CLINICAL PERSPECTIVE,

THE VALIDITY IS ONE I HAVE

QUESTIONED AND I KNOW MANY

PEOPLE IN MY INSTITUTE HAVE

HEARD ME SAY THIS OVER AND OVER

AGAIN, FOR THE DISEASES WE STUDY

P AND EFFECTIVE USE OF LARGE

ANIMALS AND THE QUESTIONS OF

WHERE THEY MIGHT BE APPLICABLE.

WE HAD A GREAT TALK THIS MORNING

ABOUT THAT.

AND ALSO I THINK THIS POINT HAS

COME UP A COUPLE OF TIMES,

ESPECIALLY NEUROLOGICAL DISEASE,

HOW WE THINK ABOUT THE

COMBINATION ASPECT AND HOW THAT

PLAYS A ROLE IN THE CONCEPT OF

STEM CELL THERAPY, ARE SOME

ADDITIVE, ARE THEY MEANT TO BE

STAND ALONE AN TO THINK ABOUT

THAT.

SO A COUPLE OF WORDS ABOUT THAT,

THE SECOND BULLET POINT HERE,

THE ASPECT OF NEEDING TO

REPLICATE THE CRITICAL

PRE-CLINICAL FINDINGS.

WHAT IS THIS ABOUT, I THINK THE

-- YOU PROBABLY READ IT IN

SCIENCE TRANSLATIONAL MEDICINE

AND OTHER REPORT IN NATURE

COMPANY'S PUBLISHING REPORTS

MANY OF THE PRE-CLINICAL STUDIES

PUBLISHED IN SINGLE NAME

JOURNALS ARE NOT REPRODUCIBLE.

AND SO WHAT IS THAT ABOUT?

WHAT DOES THAT HAPPEN?

MANY TIMES AT LEAST IN THE

COMPANY SETTING MOST TIME WE

TAKE SUCH A STUDY AND TRY TO

REPLICATE INTERNALLY.

THAT DOESN'T ALWAYS HAPPEN IN

THE ACADEMIC SETTING AND ONE

THAT WE ARE TRYING TO IN OUR

PORTFOLIO REALLY RIGOROUSLY

ENFORCE TO SAY THIS SOMETHING

THAT NEEDS TO HAPPEN BEFORE YOU

INVEST THE LARGE DOLLARS

REQUIRED TO GO THROUGH THE

TRANSLATIONAL SPACE.

WHAT WOULD THAT LOOK LIKE?

WE CAN TALK ABOUT THE NEXT

COUPLE OF SLIDES WHAT WE MEAN BY

THAT REPLICATION AN GUIDELINES

WE PUT IN PLACE IN THE CONTEXT

OF NEUROLOGICAL DISEASES.

AND IT MIGHT BE APPLICABLE IN

OTHER PLACES.

BEFORE I GO TO TO THAT ONE OTHER

ASPECT IS OFTEN SOMEBODY WHO HAS

A COOL IDEA IN ACADEMIC SETTING

WANTS TO TAKE IT FURTHER, AND

THEN ESSENTIALLY DECIDES TO JUMP

INTO THE TRANSLATIONAL, WE HAVE

FOUND AT LEAST WITH

INVESTIGATORS THAT WE FUND

THROUGH THE COOPERATIVE RESEARCH

PROGRAM, WE CAN USE MILESTONES

TO MONITOR THE PROGRESS, IS THAT

THEY'RE NOT NECESSARILY COMING

TO THE TABLE WITH THE EXPERIENCE

THEY NEED.

AND THEY ASSUME THEIR BASIC TEAM

HAS THE EXPERIENCE TO DO

TRANSLATIONAL WORK TO MOVE

TOWARDS CLINIC BUT DON'T

NECESSARILY HAVE THAT SO IT'S A

PIECE OF ENSURING YOU HAVE THE

RIGHT TOOLS FOR THE TRADE.

MIGHT SEEM A SIMPLE POINT BUT

IT'S ONE THAT PEOPLE DON'T THINK

ABOUT IN CONTEXT OF SETTING UP

THE ACTUAL PROJECT.

SO BACK TO THIS REPLICATION

PIECE.

THE CONCERNS WE HAVE IN THE

INSTITUTE AN REMAINING SPECIFIC

TO WHAT WE PUT TOGETHER IS

IMPROVING THE QUALITY OF THE

WORK THAT WE GO THROUGH

PRE-CLINICAL, CLINICAL RESEARCH

AND MORE RIGOROUS STUDY DESIGN.

WE BELIEVE THE APPLICATIONS THAT

PROPOSE RESEARCH WILL BE

STRENGTHENED IF THESE DESIGN

EXECUTION AND INTERPRETATIONS

WERE MORE ADEQUATELY DESCRIBE

THAN CURRENTLY ARE IN MOST

JOURNALS AND ALSO MOST

SUPPLEMENTARY MATERIAL PROVIDED

WITH MOST ARTICLES.

WE TRY TO ASK THE APPLICANTS TO

ADDRESS THESE THIS THE

APPLICATIONSCH YOU CAN GO TO

THIS PARTICULAR NOTICE TO GET

MORE BUT ONE SLIDE SUMMARY, THE

SUGGESTIONS ARE FOR PRE-CLINICAL

STUDIES TO SORT OF ADHERE TO

WHATEVER PROTOCOL YOU SET UP AND

ACTUALLY REPORT THE PROTOCOL IN

ITS ENTIRETY.

WITH ALL ITS DETAIL.

AND TO ALSO REPORT WHERE YOU USE

RANDOMIZATION PLIENDING AND

OTHER ASPECTS OF WORK WHICH ARE

QUITE IMPORTANT, DOESN'T MATTER

WITHER PIEWTIC YOU'RE THINKING

ABOUT BUT CERTAINLY IN THE CASE

OF STEM CELLS WHERE YOU MIGHT BE

USING -- MIGHT BE FORCED IN SOME

CASES NOT TO BE ABLE TO USE THAT

MANY ANIMALS BECAUSE OF THE

CHALLENGES INHERENT TO

THERAPEUTIC, THESE BECOME MORE

PARAMOUNT IN TERMS OF WHAT

YOU'RE PUTTING INTO THE ANIMALS.

THE POWER ANALYSIS AND QUESTION

OF WHETHER YOU CAN REPLICATE THE

STUDY, DOESN'T NECESSARILY MEAN

OUT HAS -- AT LEAST I DON'T

THINK I HAS TO BE DONE THE SAME

WAY THE FIRST STUDY WAS DONE BUT

THE KEY TENANTS ARE ESSENTIALLY

DOABLE IN A WAY THE RESULTS ARE

ROBUST ENOUGH TO WARRANT

ADDITIONAL FUNDING.

SO ONE THING WE'RE MOVING

TOWARDS IN OUR PORTFOLIO IS THAT

IF THE INVESTIGATOR IS APPLYING

HASN'T SHOWN REPLICATION AS PART

OF THEIR OWN WORK ALREADY BEFORE

APPLYING, ONE FIRST MILESTONE IN

THE PROJECT WILL BE THAT

REPLICATION, THEY HAVE TO

REPLICATE RESULTS BEFORE THEY

MOVE ON TO OPTIMIZING WHATEVER

IT IS THE THERAPEUTIC.

AND THE ASPECT OF REPORTING BOTH

POSITIVE AND NEGATIVE RESULTS.

I THINK THERE ARE MANY MOVES TO

TRY TO GET PEOPLE TO PUBLISH

RESULTS OF EXPERIMENTS THAT

DON'T WORK BUT ALSO POINT OUT

THAT THIS WORK IN ONE OF SIX

TRIAL, AND I THINK THAT'S AN

IMPORTANT PIECE OF INFORMATION

THAT'S LEFT OUT AND BIASES

PERHAPS THE STUDIES THAT WE END

UP SEEING PUBLISHED AND

SENSATIONALISM OF A PARTICULAR

FINDING GETS HIGHLIGHTED AT THE

RISK OF THOSE FINDINGS NOT

NECESSARILY BEING SUB STANT

WAITED ENOUGH -- SUBSTANTIATED

ENOUGH NOT BY MERE CHANCE OR

STOCHASTIC OCCURRENCE SO

SOMETHING TO KEEP IN MIND.

SO I'LL END WITH THE LAST SLIDE,

THIS IS REALLY THINKING ABOUT

WHAT THE FORM IS FOR IN TERMS OF

LOOKING AHEAD THERE IS A

REQUIREMENT FOR ALIGNMENT

BETWEEN TWO AGENCIES IN TERMS OF

WHAT WE LOOK FOR IN THE

TRANSLATIONAL SPACE AND ALLOWED

TO IN TERMS OF NIND FDA FORMS

AND OTHER FORMS ARE

ATESTIMONYING THAT SO IS THIS

MEETING TO GET US ON THE SAME

PAGE.

U THINK THE ONGOING DIALOGUE

OTHERS HAVE SPOKEN ABOUT IN

TERMS OF BEING TRANSPARENT ABOUT

WHAT YOU DO IN THIS SPACE, I

THINK WILL CHANGE SIGNIFICANTLY

HOW THE FIELD PROGRESSES.

I'LL TAKE AN EXAMPLE FROM MY

DISTANT PAST SCIENTIFICALLY TO

ILLUSTRATE THIS.

SO I WAS ORIGINALLY A C ELEGANS

NEUROBIOLOGIST AND WHEN I WAS A

C ELEGANS NEUROBIOLOGIST WHEN

THE FIELD WAS AN OPEN SOURCE

FIELD.

EVERYTHING THAT WE DID WE WERE

SHARING OPENLY.

OUR COLLEAGUES WORKING IN

DROSOPHILA, ANOTHER MODEL

ORGANISM HAS GROWN LARGE ENOUGH

THAT THEY STOPPED DOING THAT.

THEY BECAME INTERNALLY

COMPETITIVE IF YOU WILL.

YOU CAN SEW THE RATE -- THE KIND

OF PROGRESS WE WERE ABLE TO MAKE

IN MEETINGS IN TERMS OF US

SHARING STRENGTH, SHARING DATE

MORE OPENLY, PROTOCOLS, ET

CETERA, WE EVEN HAD AN OPEN

PROTOCOL WEB SERVER, ANYBODY WHO

DEFINES A NEW PROTOCOL PUT IT

THERE BEFORE IT WAS PUBLISHED

FOR OTHERS TO TRY, ET CETERA.

THE POINT TO MAKE, 10, 15 YEARS

LATER THE C ELEGANS FIELD

EVOLVED TO A PIBT OF BECOMING

LESS OPEN AND TO ITS DETRIMENT I

WOULD ARGUE.

WHAT'S REQUIRED IN THE COMMUNITY

THAT SPIRIT IS MAINTAINED AS WE

GO FORE BECAUSE IT WILL ENHANCE

THE SCIENCE.

AND EXPERIENCE THE IMMUNITY OF

PEOPLE DOING THE KIND OF WORK

PRESENTED HERE AND OTHERS HAVE

FROM ACADEMIC AS WELL AS COMPANY

ENVIRONMENTS, OUR WORK WILL

INFORM BOTH NIH AS WELL AS FDA

IN TERMS OF WHAT WE NEED TO DO

TO MOVE THIS FORWARD.

SO IT'S SORT OF -- THERE IS

AGAIN SORT OF -- NOT TO OVERWORK

THE PUN BUT THERE'S A PIECE OF

REVERSE TANSLATION HERE IN THE

COMMUNITY IN TERMS OF THE THE

ACTUAL ACTIVITY FEEDING INTO

WHAT SHE NEEDED TO FUND AND

SUPPORT.

SO I'LL STOP THERE AND ADDRESS

ANY QUESTIONS PEOPLE HAVE.

[APPLAUSE]

>> YOUR POINT ABOUT THE GO

BETWEEN BETWEEN TRANSLATIONAL

AND CLINICAL IS IMPORTANT, WE

HAD AN EXAMPLE IN TERMS OF

TREATING MUSCLE DISEASE WHERE

CELL THERAPIES WERE USED VERY

UNSUCCESSFULLY.

THEY HAD TO FIGURE OUT WHY.

SO THE BACK AND FORTH IS REALLY

IMPORTANT.

FIRST QUESTION.

>> PLEASE INTRODUCE YOURSELF.

>> LAUREN BLACK CHARLES RIVER

LABORATORIES.

FDA ALUM.

I'M VERY INTERESTING TO THE

HEARING YOU SAY ALL THESE THINGS

BECAUSE THEY'RE INTERWOVEN.

ONE THING THAT STRIKES ME THOUGH

IS HAVING COME FROM A SMALL

MOLECULE DRUG BACKGROUND MYSELF

WE HAD THE PLEASURE OF WORKING

WITH THINGS THAT FOR INSTANCE WE

KNEW THE TARGET, WE KNEW THE

BINDING, WE COULD MEASURE IT IN

VITRO.

WE KNEW THE MECHANISM OF ACTION,

WE MIGHT NOT BE AWARE O THE SIDE

EFFECTS THAT COULD OCCUR DUE TO

METABOLISM BUT WE WERE AWARE OF

THE STARTING POINT FOR THE

ACTION.

IN THE CELLS WE OFTEN TO THE

LARGE PART DON'T KNOW HOW

THEY'RE ACTING.

JUST TO MAKE A BIG

GENERALIZATION.

IN SOME CASES WE CAN SEE THEM

GROW OR FORM SYNAPSES, ET

CETERA.

THE PRIMARY PART OF THE CASE, WE

MOORE NOT SURE OF MECHANISMS

CAUSING THE TO CAUSE HEALING OR

TO CAUSE BENEFICIAL EFFECTS IN

DISEASE.

WITHOUT KNOWING THAT PIECE OF

THE PUZZLE, WHAT SUGGESTIONS DO

YOU MAKE TO COMMUNITIES TO DO

THIS ITERATIVE TRANSLATIONAL

RESEARCH?

WE DONE KNOW THE STARTING POINT

GOING BACK TO THE CHICKEN AND

EGG PROBLEM.

>> I DON'T KNOW, MAYBE YOURK

PEERNS WAS DIFFERENT THAN MINE.

I HAD NUMEROUS SMALL MOLECULES

IN OUR PORTFOLIO IN THE COMPANY

THAT I WORKED IN WHICH WE DIDN'T

UNDERSTAND HOW IT WORKED.

WE WERE STILL ABLE TO MOVE IT

FORWARD.

WE BELIEVED IT WORKEDDED A

CERTAIN WAY BUT IT WORKS IN TEN

DIFFERENT WAYS WE DIDN'T KNOW

EITHER.

THE OTHER PIECE IS THAT HOW MANY

DRUGS ARE ACTUALLY APPROVED

BEFORE WE KNEW HOW THEY DID AND

IT WAS ACTUALLY SUBSEQUENT WORK

THAT REVEALED HOW THEY ACTUALLY

DID WHAT THEY DID.

SO THERE'S THAT PIECE GOING BACK

TO WHAT THE FDA COLLEAGUE SAID,

YOU CAN MOVE THINGS FORE IF YOU

DON'T KNOW IT BUT MORE

SPECIFICALLY TO THE QUESTION YOU

ASKED, THE ASPECT OF DEVELOPING

SOME OF THESE THERAPEUTIC

ENTITIES IN TERMS OF CELLS WILL

HELP ANSWER THE QUESTION HOW

THEY WORK SO THERE IS A

SCIENTIFIC QUESTION THAT CAN BE

ADDRESSED IN THE QUESTION OF

CONTEXT WHICH ADDRESSES -- GOES

BACK TO ONTIVE, IT'S A MALL

MOLECULE CASE WHICH IS EASIER

BECAUSE OF FAMILIARITY TO

OUTLINE.

I ADVOCATED WHEN I WAS IN SAID

COMPANY THAT WE ACTUALLY

SHOULDN'T CARE WHETHER THE

MOLECULE WE'RE DEVELOPING IS THE

DRUG AT THE END OF THE DAY WE'RE

GOING TO SELL OR NOT.

IF IT'S A NEW MECHANISM OF

ACTION OR TARGET TO EXPORT WE

SHOULD THEY CAN QUICKLY AS

POSSIBLE TO HUMAN SAFETY BEING

PARAMOUNT, TO TEST THE

HYPOTHESIS TO DOING WHAT IT'S

DOING AND COME BACK TO DEVELOP

THE RIGHT THING MOVING FORWARD

SO THAT PARTICULAR CONCEPT,

MAYBE WHAT YOU TAKE FORWARD IS

TO TEST A CONCEPT TO ACHIEVE A

CERTAIN BIOLOGICAL EFFECT.

ALLUDED TO EARLIER IN THE

MORNING, A BIOLOGIC VERY THERAPY

YOU CARE ABOUT BUZZ YOU FIGURE

IT'S A PARACRINE OR ENDOCRINE

SYSTEM -- THAT DOVE TAILS

PRECISELY WITH WHAT YOU SAID

EARLIER, THE DISEASE MECHANISM

OF HUMAN IS OFTEN THE ONLY THING

WE CAN GO FOR, WE DO HAVE POOR

MODELS MECHANISTICALLY THAN WHAT

THE HUMAN DISEASE IS.

THIS SPEAKS TO CHANGING THE

MODEL OF DRUG DEVELOPMENT AWAY

FROM THE CLASSICAL MONOCLONAL

ANTIBODY OR SMALL MOLECULE DRUG

MODEL AND EMBRACING PHASE 1

STUDIES PAIZ 2A STUDIES IN

TRIALS AND LOOKING AT THAT AS

PART OF THE BASIC RESEARCH.

THAT'S DIFFERENT FROM TAKING A

PRODUCT FORWARD IN THE CLASSIC

ROLE OF DRUG DEVELOPMENT WHERE

YOU THOUGHT WHEN HE WHEN YOU

CHUCKED EVERYTHING OVER THE

PRE-CLINICAL WALL AND TO THE

CLINICAL WALL YOU'RE OFF AND

RUNNING DOWN THE TRACK AND YOU

DEVELOP THAT PRODUCT FOR THE

NDA.

THIS IS MORE A PLACE TO VIEW THE

INITIAL CLINICAL TRIALS AS PART

OF THE BASIC EXPERIMENT.

AND BE LOOING TO GO BACKWARD.

>> THAT'S WHY I DEFINED -- TOOK

A MOMENT TO DEFINE AT THE

BEGINNING WHAT I FELT PROOF OF

CONCEPT WAS IN THIS CONTEXT

WHICH IS THE HUMAN EXPERIMENT.

>> WE HAVE TIME FOR TWO QUICK

QUESTIONS.

>> A QUICK EXTENSION WHAT YOU

HEARD EARLIER, I AGREE AND ONE

ISSUE WITH THAT AN MAYBE

SOMETHING THAT YOU CAN CONSIDER

IS THE REASON THERE ARE

DISCONNECTS BETWEEN TAKING

RESEARCH FORWARD TO TRANSLATION

IS ONE, THE FUNDING TIME LINES

ARE DIFFERENT THAN WHAT A

CLINICAL TRIAL TIME LINE IS,

WHEN THINGS ARE FUNDED SO IT

BECOMES VERY DIFFICULT TO DO THE

FOLLOW-UP REQUIRED AND THERE'S

NO FUNNING AVAILABLE FOR A LOT

OF STUDIES IN TERMS OF BEING

ABLE TO DO IT.

A SECOND BIG ISSUE IS IN THE

REVIEW PROCESS ITSELF, YOU LOOK

AT IT, THERE AREN'T REVIEWERS

PRESENT DOING TRANSLATIONAL WORK

REVIEWING GRANTS IN TERMS OF

BEING ABLE TO DO IT BUT DO YOU

EXPECT PEOPLE TO EVALUATE THOSE

IN A WAY THAT WOULD BE FUNDED.

I THINK THAT'S THE REALLY

IMPORTANT ISSUE IN TERMS OF

DISCONNECT IN TERMS OF MOVING

FORWARD THAT WAY AND A THIRD

PIECE IS THERE WOULD BE A LOT OF

SYNERGY IN AN OPEN SOURCE

SYSTEM, THIS SHOULD BE A

MECHANISM BY THE NIH IN SOME

FASHION, TO SHARE THIS

INFORMATION IN AN OPEN SOURCE

WAY FACILITATED THE WAY TO MOVE

FORWARD, THAT MAYBE REALLY

IMPORTANT TO CONSIDER IN LIGHT

OF --

>> FOR THE SECOND AND THIRD

POINT YOU MENTIONED, I THINK I

WOULD LIKE TO ALLUDE O THE FACT

THAT WE HAVE THIS ISSUE WITH THE

REVIEWERS WHICH IS THAT WE DONE

NECESSARILY ALWAYS HAVE THE

EXPERTISE AND I HAVE SAT IN ON A

COUPLE OF STUDY SECTIONS SINCE

JANUARY AND HAVE SEEN THAT.

TO SAY IS THIS THE RIGHT

COMPOSITION OF THE KINDS OF

FOLKS WE WANT TO BE REVIEWING

THINGS WE HAVE NUS SPACE AND HOW

TO BRING IN THE RIGHT EXPERTISE

TO DO THAT.

THE PIECE ABOUT OPEN SOURCE, WE

ALWAYS LOOK IN THESE SITUATIONS

FOR THE GRAND CONVENER.

I DON'T KNOW IF WE CAN ALWAYS

PLAY THAT ROLE.

I'M PLAYING DEVIL'S ADVOCATE,

THINKING BACK TO THE C ELEGANS

EXPERIENCE IT TOOK A BUNCH OF

ENTERPRISING GRADUATE STUDENTS

TO SORT THAT OUT TO BE HONEST.

WE DID IT OURSELVES IN TERMS OF

OPENING THE COMMUNITY UP TO

DOING THAT AND TO EXTENT THERE

WAS ALSO THE WHAT DO YOU CALL IT

THE (INAUDIBLE) ESPOUSED BY LEET

HE WASSERS -- LEADERS IN THE

FIELD IN TERMS OF WANTING TO

SHARE THAT SET THE TONE AND

STAGE FOR WANTING TO DO THAT.

SUBSEQUENT GENERATIONS THAT HAVE

TOOK A PAGE FROM THAT BOOK.

>> WE HAVE TO -- VERY SHORT

QUESTION, VERY SHORT ANSWER.

THEN WE HAVE TO MOVE ON.

SO THIS --

>> MAHENDRA, RELATED TO

MECHANISM OF ACTION, HAVING TO

UNDERSTAND THOUGH IT HELPS,

CERTAINLY YOU HAVE TO UNDERSTAND

MECHANISM OF TOXICITY WHICH IS

DIFFERENT.

WITH RESPECT TO THE ANIMAL

MODELS AND YOU SAID THE PHARMA

MODEL, U THINK THE DISTINCTION

HERE WHILE WE EMBRACING AND SO

CONSIDER RATE ABOUT THE ANIMAL

MODELS, UNLIKE THE PHARMA MODEL

FIRST IN HUMAN IS A NORMAL

VOLUNTEER WE GO TO INDEX

POPULATION.

SO WE'RE TRYING TO TRANSLATE NOT

ONLY CROSS SPECIES BUT

PHYSIOLOGICAL STATES.

THAT IS WHY ANIMAL MODELS MAYBE

DIFFERENT IN TERMS OF THE PHARMA

MODEL TO DEAL WITH NOW BECAUSE

THAT'S THE CRITICALITY IN TERMS

OF WHAT WE FEEL IN TERMS OF

EXTRAPOLATION.

SO WOULD YOU AGREE?

>> THE ANSWER IS NOT SHORT SO

I'LL HAVE TO GIVE IT DURING THE

BREAK.

>> WE WILL HAVE MORE TIME LATER

IN THE DAY BUT WE DO HAVE TO

MOVE ON TO MAKE SURE WE GIVE ALL

SPEAKERS EQUAL TIME.

OUR NEXT SPEAKER IS IS DR. GARY

STEINBERG FROM STANFORD HE'S

WORKED IN ACUTE ISCHEMIA AND HAS

INVESTIGATED A NUMBER OF

DIFFERENT TYPES OF STRATEGIES

FOR TREATING THIS TYPE OF INJURY

AND DISEASE.

>> CAN YOU HEAR ME?

HOW IS THAT?

THANKS FOR INVITING ME.

I'M LEARNING A LOT AT THIS NIH

FDA MEETING AND WE NEED TO COME

TOGETHER WITH THIS SO MY CHARGE

TODAY IS TO TALK ABOUT

IDENTIFYING THE MECHANISM OF

ACTION FROM PRE-CLINICAL PROOF

OF CONCEPT STUDIES.

HERE MY DISCLOSURES, GRANTS FROM

NIH.

I THOUGHT HARD ABOUT THIS,

WHETHER WE NEED TO KNOW

MECHANISM OF ACTION AND

CONCLUDED THAT WE DO FOR THESE

REASONS.

I'LL GO INTO DETAILS AND SHOW

EXAMPLES HOW UNDERSTANDING

MECHANISM OF ACTION HELPS WITH

OPTIMIZING CLINICAL THERAPIES,

ASSISTING WITH CLINICAL TRIAL

DESIGN, SURROGATES, MONEYMIZING

POTENTIAL ADVERSE EFFECTS,

SUGGESTING ALTERNATIVE NOVEL

THERAPIES, DEVELOPING DARK

TICKS, ASSAYS AN POTENCY ASSAYS

AND BETTER EVALUATE CLINICAL

EFFICACY ATTRIBUTABLE TO CELL

THERAPY.

SO I'M TALK ABOUT STROKES SINCE

THAT'S THE FIELD I'M IN.

THERE ARE DIFFERENT TYPES OF

HUMAN NEURAL STEM CELLS DERIVED

NEURAL STEM CELLS MOVED INTO THE

CLU IN THIS CASE ABOUT A DECADE

AGO THERE ARE NON-NEURAL HUMAN

CELLS USED IN STROKE,

EXPERIMENTAL MODELS IN THE

CLINIC, THESE ARE THE STROMAL

CELLS, MESENCHYMAL CELLS FROM

PERIPHERAL BLD OR ADIPOSE TISSUE

AND THEY ENHANCE FUNCTIONAL

RECOVERY WHETHER DELIVERED

DIRECTLY INTO THE BRAIN OR

SYSTEMICALLY IN EXPERIMENTAL

MODELS.

MORE SO (INDISCERNIBLE) SENIOR

SCIENTISTS IN MY LAB DEVELOPED A

NEURAL STEM CELL LINE FROM THE

EMBRYONIC H-9 WISCONSIN CELL

LINE.

AND THESE CELLS PURIFIED IN

CULTURE THAT TURNED INTO THREE

TYPES OF CELLS, IN THE BRAIN AND

WHEN TRANSPLANTED INTO A STROKE

MODEL A MONTH -- A WEAK RATHER

AFTER THE STROKE THEY SURVIVE IN

HIGH NUMBERS AS OPPOSED TO

MESENCHYMAL OR MARROW STROMAL

CELLS TWO MONTHS, OTHER CELLS WE

HAVE SEEN SURVIVE UP TO FOUR

MONTHS, SIX MONTHS ASSOCIATED

BLOOD VESSELS THAT MIGRATE TO

STROKE AN DIFFERENTIATE.

WHETHER THAT'S IMPORTANT WE'RE

NOT SURE ABOUT, WHETHER THE

PARTICULAR PHENOTYPE MATTERS.

THESE TURN PRIMARILY TO NEURONS

THOUGH 30% REMAIN AS A

UNDIFFERENTIATED NEURAL STEM

CELL, FEW OLIGODN DROA SITES OR

ASTROCYTES, AND THEY DON'T

EXPRESS PLURIPOTENT MARKERS.

THEY RECOVER BEHAVIOR SO WE HAVE

SHOPE THAT IN THE SUTURE MODEL

IN RAT WITH A CYLINDER TEST AND

OTHER TESTS.

WE TRIED THESE IN A SECOND

MODEL.

THIS IS HYPOXIC ISCHEMIC

NEONATAL MODEL THAT IMPROVE

BEHAVIOR HERE TOO.

WE GAVE THEM TO A COLLEAGUE TOM

CAR MICHAEL WHO TRIED IN A MOUSE

MODEL, DIFFERENT LAB, DIFFERENT

RODENT AND THEY RECOVERED

BEHAVIOR.

WE HAD ANOTHER LAB AT STANFORD

ALSO DO IT IN A RAT MODEL SO WE

HAVE NOW SHOWN WITH THESE CELLS

IN FOUR MODELS TWO SPECIES THREE

LABS THEY RECOVER BEHAVIOR.

THAT HELPED US TO RECEIVE A

SERUM GRANT TO MOVE THESE CELLS

FROM THE LABORATORY INTO THE

CLINIC OVER AGGRESSIVE TIME

COURSE OF FOUR YEARS, WE'RE

HALFWAY THROUGH THE GRANT NOW

AND HEADING TOWARDS AS MERCEDES

KNOWS THE PREIND MEETING SOON.

THIS WAS A PROCESS I WAS NOT

FAMILIAR WITH BEFORE.

I LEARNED ABOUT THIS, THIS IS

NOT HYPOTHESIS DRIVEN SCIENCE,

THIS IS NOT ABOUT MECHANISM,

THIS IS WHY I HAVE TO APPLY FOR

NIH GRANTS TO FUND OUR MEK

ANYMORENISTIC STUDIES -- TO

SUPPLY OUR MECHANISTIC STUDIES.

SO WE THOUGHT THE CELLS ACTING

AS CELL REPLACEMENT, PUT INTO

CELLS, THEY TURN INTO NEURONS AN

RECONSTITUTE CIRCUITS.

TO SOME EXTENT YOU CAN SEE THE

CELLS MAKE SYNAPTIC PROTEIN ON

EM WE CAN SEE SYNAPSES FORM BY

THE CELLS, THEY GENERATE VOLTAGE

DEPENDENT RESPONSES IN SLICE TO

DECIDE WHERE THE TRANSPLANT

THEM, THAT'S NOT THE ONLY

EFFECT.

AS ALLUDED TO THESE CELLS

SECRETE TROPIC FACTORS THAT

ENHANCE ENDOGENOUS REPAIR,

ANGIOGENESIS, A GREAT POWERFUL

EFFECT ON IMMUNOMODULATION AND

ALSO STIMULATING ENDOGENOUS

NEUROGENESIS, SYNAPTOGENESIS,

MARROW STROMAL CELLS WORK THE

SAME WAY, THESE DO NOT SURVIVE

MORE THAN ONE, TWO MONTHS WHEN

TRANSPLANTED DIRECTLY TO THE THE

BRAIN, THEY MAYBE WORKING

SYSTEMICALLY BUT WE THINK

THEY'RE WORKING THROUGH

PARACRINE MECHANISMS TO ENHANCE

ENDOGENOUS RECOVERY.

WHAT CAN WE LEARN FROM

MECHANISMS IN THE PRE-CLINICAL

STUDIES WHAT ARE WE GOING TO

TRANSPLANT?

IF THE MAIN EFFECT IS ON

DECREASING CELL DEATH OR EDEMA

OR ACUTE INFLAMMATION WE MAY

TRANSPLANT EARLY, IF TRYING TO

TARGET ANGIOGENESIS,

SYNAPTOGENESIS AN PLASTICITY WE

MAY TRANSPLANT THEM TO SUB ACUTE

AND CHRONIC PHASE.

IF CELLS ARE TRANSPLANTED EARLY

THEY DO REDUCE CELL DEATH,

NEUROPROTECTIVE.

THEY DECREASE LESION SIZE AND

INHUBT APOPTOSIS.

WE SHOWED IN PAPER WE PUBLISHED

WHEN WE TRANSPLANT ONE WEEK

AFTER THE STROKE FOR MODERATE

SIZE STROKES NOT LARGE, WE SEE A

TE CREASE IN THE INFARCT SIZE

BOTH HISTOLOGY AND ALSO ON MR

SCANNING BETWEEN 2 AND 10 WEEKS

AFTER THE TRANSPLANT.

MECHANISM THE HELP US UNDERSTAND

PATIENT SELECTION, SO DO WE WANT

TO TRANSPLANT INTO PATIENTS WITH

LARGE STROKES VERSUS SMALL

STROKES.

WHAT ABOUT LOCATION OF THE

STROKE WHEN THE PATIENT STRIA=

VERSUS CORTICAL, ISCHEMIC VERSUS

HEMORRHAGIC AND IMPORTANT ISSUES

ARE ROOT AND SITE OF CELL

DELIVERY, CELL NUMBERS AND NEED

FOR IMMUNOSUPPRESSION,

UNANSWERED QUESTIONS.

HERE IS A CELL THAT MADE TO IT

THE CLINICCH THIS IS THE LAYTANT

CELL, SHOPE BY (INDISCERNIBLE)

AND HIS GROUP THAT IT PROTECTS

-- IMPROVES BEHAVIOR IN STRIATAL

STROKE INTO THE CLINIC.

WE DID A STUDY IN PATIENTS,

HOWEVER WE SHOWED IF YOU LOOK AT

CORTICAL STROKE IN ANIMAL, IT

DOES NOT PROTECT.

SO SOME NEED TO BE MOVED OUT AS

WE MOVE INTO THE CLINIC.

WHAT ABOUT WHERE YOU TRANSPLANT

THE CELLS.

WE TRANSPLANTED EDGE OF INFARCT

SO POOR SURVIVAL, WE MOVED A FEW

MILLIMETERS AWAY, VERY ROBUST

SURVIVAL AND DIFFERENCE IN GRAPH

BEHAVIOR, THE NUMBER OF

PERIINFARCT AREA IS BETTER THAN

TRANSPLANTING INTO THE STROKE

CAVITY ITSELF.

IN FACT WE FOUND INVERSE

RELATIONSHIP BETWEEN CELL

SURVIVING IN THE BRAIN AND

AMOUNT OF INFLAMMATION ACUTELY

IN THE BRAIN SO TIMING IS

IMPORTANT IF WE PUT CELLS INTO

THE BRAIN AS ROUTE OF DELIVERY,

IT MAYBE IMPORTANT TO WAIT AT

LEAST A WEEK TO ALLOW AQUEUE

INFLAMMATION TO DECREASE.

WHAT ABOUT ROUTE OF DELIVERY

ITSELF AND HERE IS A STUDY THAT

COMPARED INTRAPAING MALL INTO

THE BRAIN TO INTRARENTRICULAR,

WE FOUND NO EFFECT ON PHENOTYPE

OF THE CELLS THOUGH THE NUMBER

OF DONOR CELLS THAT THEY COULD

FIND IN THE BRAIN WAS GREATER

WITH THE DIRECT BRAIN VERSUS

INTRAVENTRICULAR INTRAVENOUS.

WE AND OTHERS HAVE FOUND

TRANSPLANTING THESE NEURAL STEM

CELLS HAS A PROFOUND EFFECT ON

BLUNTING DETRIMENTAL

INFROMMATION AND WE TALKED ABOUT

THIS EARLIER, WITH MULTI-STEM

HAS SHOWN PERIPHERAL RESPONSE

AND DREEN IN PARTICULAR MAYBE

VERY IMPORTANT.

SO SYSTEMIC IMMUNOMODULATION

MAYBE INTRAVENOUS ROUTE.

ANOTHER EXAMPLE ABOUT CELL TYPE

AND PHENOTYPE, JOHN CHOSE TO USE

AN EMBRYONIC DERIVED

OLIGODENDROCYTE PRECURSOR, BASED

ON HANS (INAUDIBLE) WORK AT UC

IRVINE THAT SHOWED A RODENT

MODEL OF SPINAL CORD INJURY THAT

TURNED TO OLIGODENDROCYTE

PRECURSORS REMYELENATE IN BLUNT

INJURY AND RECOVER BEHAVIOR,

TARGETED THERAPY AND YOU THINK

THAT IT'S DUE TO CELL

REPLACEMENT, HOWEVER CELLS LIKE

ALL THESE STEM CELLS PRODUCE A

NUMBER OF POWERFUL CYTOKINES

GROWTH FACTORS, ANGIOGENESIS

FACTORS AND ALSO INCREASED

AXONAL YOUTH GROWTH, THE CELLS

DO MORE THAN ONE -- HAVE MORE

THAN ONE MEK NUMBER OF ACTION

LIKELY.

WE HAVE BEEN WORKING WITH SAM

(INAUDIBLE) IN A CLINICAL STUDY,

(INDISCERNIBLE) DERIVED AN ADULT

CELL WITH TRANSCRIPTION OF KNOX

GENE IMPORTANT IN CELL

DURCHIATION AN IMPROVES RECOVERY

-- DIFFERENTIATION AND IMPROVE

RES COVERRY.

YOU CAN SEE IN THE PRE-CLINICAL

STUDIES THEY SHOWED -- THEY

LOOKED AT DOSE RESPONSE.

THIS IS IMPORTANT IN TERMS OF

HOW YOU DECIDE HOW MANY CELLS

YOU'LL PUT INTO THE BRAIN, THIS

LED TO A SCALEUP OF TWO AND A

HALF TO 10 MILLION CELLS IN

HUMANS, THE LOW DOSE DID NOT

WORK, THE HIGHER DOSE WORKED.

DO YOU NEED IMMUNOSUPPRESSION

WITH CELLS?

THESE HUMAN CELLS MAY NOT BEAR

THE IMMUNOLOGIC DETERMINANTS

THAT WILL BE -- THAT WILL

REJECTION REACTION SO HERE IS A

STUDY FROM SAM BIO PRECLINICALLY

THAT SHOWED CYCLOSPORINE HUMAN

TO RAT.

WITH NO ADDITIONAL BENEFIT IN

TERMS OF RECOVERY AND THIS

PERSUADED THE FDA TO ALLOW THE

CLINICAL STUDY WITH CELLS

INJECTED INTO THE BRAIN WITHOUT

IMMUNOSUPPRESSION.

HERE IS A CLINICAL EXAMPLE,

LAYTANT CELLS WHICH ARE NEURAL

PROGENITOR CELLS, WHICH WE

TRANSPLANTED AT UNIVERSITY OF

PITTSBURG TRANSPLANTED, NOW

ALMOST EIGHT YEARS AGO.

THE PATIENTS WERE

IMMUNOSUPPRESSED TWO MONTHS,

HERE IS A PATIENT THAT DIED 27

MONTHS MYOCARDIAL INFACTION AND

DESPITE LACK OF

IMMUNOSUPPRESSION THE CELLS CAN

BE DETECTED IN THE BRAIN AT

AUTOPSY.

WHAT ABOUT ASSISTING WITH

CLINICAL DESIGN?

VERY IMPORTANT TO DEVELOP

SURROGATES.

THIS IS WHERE IT CAN CAN PLAY A

HUGE ROLE, I'LL SHOW YOU

EXAMPLES OF THESE.

WE DID A SERIES OF STUDIES TO

SEE WHAT THE BENEFIT, MECHANISM

OF ACTION OF OUR TRANSPLANTED

CELLS WAS AND TRANSMANT AS

SHOWED YOU BEFORE WE CAN THN

LABEL WITH BDA AXONS ON THE

OTHER SIDE AND WE SEE THE CONTRA

LATERAL HEMISPHERE ACROSS THE

CORPUS COLOSOM INTO THE IPSA

LATERAL IPSA LESIONAL HEMISPHERE

INTO THE STRIATUM AND REWIRING

THE CORTICAL SPINAL TRACK.

SO VERY IMPORTANT EFFECT IS THIS

AXONAL SPROUTING THAT OCCURS

FROM TRANSPLANTATION TO THE

PERIINFARCT AREA.

WE ALSO FIND THESE NEURAL

PROGENITOR CELLS INCREASE

BRANCHING TWO WEEKS POST

TRANSPLANT, IPSA AN CONTRA

LATERAL, THE EFFECT IS ONLY

SUSTAINED IN THE IPSA LATERAL

HEMISPHERE.

SO CAN E WE USE A SURROGATE OF

FIBER TRACKS AXONAL REWIRING AND

WE CAN, WE CAN PLAN OUR STUDIES

TO LOOK AT DTI FIBER TRACKS OR

PLASTICITY AND REORGANIZATION

WITH FUNCTIONAL MR SCAN WHICH IS

A WELL ACCEPTED TECHNIQUE.

WE ALSO SHOWED, THIS IS

IMPRESSED NOW, WE FIND METABOLIC

ACTIVITY DETECTED BY FTG IN OUR

ANIMAL MODELS INCREASE AT THE

TRANSPLANT SITE.

AND THIS HAS BEEN TRANSLATED TO

CLINIC.

HERE IS A STUDY PUBLISHED WITH

OUR LAY AT THAT PARTICULAR TIME

CELLS AND YOU CAN SEE THIS IS A

PATIENT WHO HAD A STROKE IN THE

BASAL GAN TBLEEIA, SIX MONTH

AFTER TRANSPLATING CELLS,

INCREASED ACTIVITY DETECTED BY

FTG PET IMAGING.

WHAT IS IT DUE TO?

TRANSPLANTED CELLS IN THE GRAPH?

NEURITE OUTGROWTH, IMPROVED HOST

METABOLISM OR INFLAMMATORY

RESPONSE?

WE DON'T THINK INFLAMMATORY

RESPONSE BECAUSE MR DISANS LOOK

NORMAL BUT IT WOULD BE ANY OF

THESE ACTIVITIES.

INTERESTINGLY, THERE WAS A

STRONG CORRELATION BETWEEN

IMPROVED MOTOR OUTCOME IN THESE

PATIENTS AND THE INCREASED

ACTIVITY IN THE STROKE AND

SURROUNDING REGIONS ON PET SCAN.

OUR CELLS ALSO HAVE A VERY

ROBUST EFFECT ON ANGIOGENESIS

FROM NEOVASCULARIZATION, WE KNOW

CELLS SECRETE VEGF, YOU CAN SEE

A STRICT TEMPORAL AN REGIONAL

SPECIFICITY SO THE EFFECT IS

PRONOUNCED AT TWO WEEKS POST

TRANSPLANTATION HERE AND THERE'S

A PRUNING EFFECT IN THE

ANGIOGENESIS AND REGIONALLY

SPECIFIC SO MOST PROFOUND IN THE

PERIINFARCT REGION RATHER THAN

OTHER REGIONS.

WE CAN ACTUALLY IN ANIMALS IMAGE

POST STROKE ANGIOGENESIS USING

MICROPET SCANNING AND RADIO

LABELED VEGF THROUGH THE SAME IN

HUMANS SO WE CAN LOOK AT

SURROGATE MARKERS.

OUR CELLS WHEN TRANSPLANTED

MIGRATE IN TARGETED FASHION TO

THE STROKE.

THEY CAN MIGRATE ON THE OTHER

SIDE OF THE CORPUS COLOSUM, TRUE

OF MOST NEURAL STEM CELLS, AND

WHY DO THEY MIGRATE?

BECAUSE THEY EXPRESS A CHEMOKINE

RECEPTOR THAT ENTERACTS WITH A

CHEMOKINE GIVEN OFF BY STROKE

SDF-# STRONG INTERACTION AND

OTHER INTERACTIONS THAT OCCUR AS

WELL.

HOW DOES THIS HELP IN TERMS OF

CLINICAL TRANSLATION.

HERE IS A STUDY IN P PUBLISHED

FROM KOREA.

USING MARROW STROMAL CELLS,

PATIENTS CAME WITH A STROKE,

CELLS WERE CULTURED, # TO 2

MONTHS LATER 100 MILLION WERE

INJECTED INTRAVENOUSLY.

YOU CAN SEE THERE WAS A BENEFIT

IN THE REDUCING MORTALITY,

ALMOST STATISTICALLY SIGNIFICANT

A SIGNIFICANT BENEFIT IN NUMBER

OF PATIENTS WITH BETTER OUTCOME

SCORES IN THE MSC GROUP COMPARED

WITH CONTROLS.

INTERESTINGLY, THE CLINICAL

IMPROVEMENT IS ASSOCIATED WITH

HIGHER SERUM LEVELS OF THAT

CHEMOKINE RELEASED AFTER THE

STROKE THAT WE AND OTHERS

STUDIED IN PRE-CLINICAL STUDIES

AS WELL AS DEGREE INVOLVEMENT OF

THE SUBVENTRICULAR ZONE, THE

NEUROGENIC ZONE IN MAMMALS.

SO THESE BIOMARKERS, WE CAN USE

TO OPTIMIZE CLINICAL EFFECT BY

ENHANCING SURROGATE MARKERS WITH

OTHER THERAPIES AS ADJUNCTS

ADDING REHAB, CONSTRAINT

THERAPY, BRAIN STIMULATION, OR

GENE TRANSFER TO EXPRESSION OF

TROPIC FACTORS.

PRE-CLINICAL FACTORS HELP

MONEYMIZE POTENTIAL ADVERSE

EFFECTS.

HERE IS AN EXAMPLE AS A

NEUROPROTECTIVE STRATEGY FOR

ACUTE STROKE.

THE TRIAL WAS NEGATIVE AND ALSO

RAISED SERIOUS SAFETY CONCERNS

BECAUSE IT WAS A MUCH HIGHER

MORTALITY, TURNED OUT THAT 63%

OF THE PATIENTS WHO CAME IN WITH

ACUTE STROKE WERE TREATED WITH

TPA.

THAT WASN'T ANTICIPATED AND EPO

WAS TREATED WITHIN SIX HOURS

PRE-CLINICALzP„ STUDY COULD HAVE

PREDICTED THAT, EPO WAS

PROTECTED AT 2 HOURS BUT NOT SIX

AND INCREASED HEMORRHAGE RATE SO

PRE-CLINICAL STUDIES HELP INFORM

US ABOUT POTENTIAL ADVERSE

EFFECTS.

IF MODULATING PLASTICITY IS

IMPORTANT WITHIN THESE CELLS WE

NEED TO AVOID MAL ATAPTIVE THAT

COULD LEAD TO NEUROPATHIC PAIN,

IF NEUROMODULATION IS INVOLVED

WE NEED TO MON THETOR FOR

INFECTION FOR DETERMINE

IMMUNOSUPPRESSION AND MAYBE

THINK ABOUT AVOIDING DRUGS THAT

INTERFERE WITH THE BASIC

MECHANISMS OF ACTION.

SO FURTHERMORE, I THINK THESE

MECHANISTIC STUDIES SUGGEST

ALTERNATIVE NOVEL MOLECULAR

TARGETS THAT MAY NOT RELATE TO

THE STEM CELLS AS A THERAPY,

HERE IS AN EXAMPLE, WE LOOK AT

WHAT FACTORS MEDIATE AXONAL AND

DENDRITIC OUTGROWTH, NO TIME FOR

THE IMMUNODEPLETION STUDY BUT WE

CAN SHOW WITH NEUTRAL EYEING

ANTIBODIES THAT VEGF THROMBO

RESPOND DIDN'T 1 AND 2 ANOTHER

MOLECULE BUT NOT SPARK MEDIATED

IN THE AXONAL AND DENDRITIC

PLASTICITY SO ANOTHER TARGET TO

IMPROVE OUTCOME AND VEGF PLEA

OWE TROPIC EFFECTS INCLUDING

NEURITE OUTGROWTH

DIFFERENTIATION DIFFERENTIATION

AND ANGIOGENESIS WE FOCUSED ON.

AND WHAT WE DID WAS TO USE

AVASTIN TO BLOCK THE HUMAN VEGF

WITHOUT SECRETED BY THE CELLS

WITHOUT BLOCKING THE VEGF AND

WHAT WE SHOWED WASNA OUR STUDIES

THAT HUMAN VEGF WAS REQUIRED FOR

OUR NEURAL STEM CELL INDUCED

NEOVASCULARIZATION AND

IMMUNOMODULATION, NOT FOR

EVERYTHING, NOT REQUIRED FOR THE

ACCELERATED BLOOD BRAIN BARRIER

REPAIR, YOU CAN SEE WHEN WE USE

AVASTIN WE BLOCK RECOVERY IN

TERMS OF BEHAVIOR.

THIS IGG NON-SELECTIVE DID NOT

BLOCK THE RESPONSE.

VEGF IS IMPORTANT IN OUR STUDIES

FOR CELL ENHANCED RECOVERY, CAN

WE ENHANCE THIS FURTHER BY

INCREASING FURTHER VEGF BY

TRANSPLANTED CELLS, TO MOVE INTO

CLINICAL STUDIES.

WE TALKED ABOUT CHARACTERISTIC

MARKERS TO DEFINE PURITY,

PRESENCE OF SPECIFIC

DIFFERENTIATION MARKERS, AND

AGAIN, AS WAS ALLUDED TO IN THE

PRIOR TALK, MECHANISTIC STUDIES

HELP US CHOOSE WHAT

DIFFERENTIATION MARKERS WERE

GOING TO CHOOSE FOR OUR RELEASE

ASSAYS AS AN EXAMPLE.

WE FOCUSED ON THOSE SPECIFIC TO

NEURAL STEM CELLS LIKE PACK SIX

WITH HIGH LEVELS IN NEURAL STEM

CELLS AND THESE ARE CLIVE

SPENSON'S CELLS WITH A DIFFERENT

PHENOTYPE THAT BECOME MORE

ASTROSITIC, GFAP POSITIVE YOU

CAN SEE HERE.

WE CAN AVOID MARKERS IN ALL

CELLS EMBRYONIC CELLS, WITH FLOW

CYTOMETRY WE CAN LOOK AT -- GET

CLUES ABOUT WHICH

CHARACTERISTICS AND MARKERS ARE

GOING TO BE BEST NEURAL RELATED

PREFERENTIALLY EXPRESSED IN

CELLS AND FOR POTENCY ASSAYS YOU

DON'T NEED FOR PHASE 1, EARLY

PHASE 1, 2 STUDY, BUT NEED LATER

ON WHICH INGREDIENTS CONTRIBUTE

TO POTENCY WE DEVELOPED A

NEURITE YOUTH GROWTH ASSAY WITH

PRIMARY NEURAL CELLS AND SHOWED

THAT OUR STEM CELLS INCREASE

OUTGROWTH AN CORRELATE INCREASED

OUTGROWTH IN VITRO ASSAY WITH

OUR IN VIVO RECOVERY IN ANIMALS

SO THESE DIFFERENT TYPES OF

CELLS, SB-56 EMBRYONIC, THESE

ARE CLIVE SPENSON CELLS AND THEY

INCREASE NICELY IN VITRO AND IN

VIVO WHILE THE OTHERS DO NOT.

IF IMMUNOMODULATION IS IMPORTANT

WE CAN USE STUDIES DOING THIS

NOW AS THEY MOVE INTO THE -- WE

CAN USE A T-CELL PROLIFERATION

ASSAY TO ASSESS THAT ASPECT OF

THE CELLS.

FINALLY IDENTIFYING METHODS OF

ACTION CAN ALLOW US TO BETTER

EVALUATE CLINICAL EFFICACY AS

ATTRIBUTED TO CELL THERAPY AND

I'LL SHOW YOU AN EXAMPLE OF

THIS, THIS IS FROM THE SANBIO

STUDY OF PATIENT RES SENLY

TREATED, THIS IS -- RECENTLY

TREATED.

THIS IS WITH A MARROW STROMAL

CELL TRANSPLANTED CORRECTLY INTO

-- DIRECTLY INTO THE BRAIN,

CHRONIC PATIENTS SIX MONTHS TO

TWO YEARS OUT FROM STROKES AN

DOSE ESCALATION, DOING AT

STANFORD AND NOW UNIVERSITY OF

PITTSBURG COME ON BOARD.

WE TREATED 8 PATIENTS, TWO AND A

HALF BILLION CELLS AND ONE MORE

ENROLLED AN THREE MORE ON LINE.

THIS IS HOW WE DO IT PATIENT

AWAKE, BURR HOLE IN, SEDATED,

DEPOSIT TWO AND A HALF,

5 MILLION CELLS ESCALATING UP TO

TEN THESE WERE THE FIRST FIVE

PATIENTS, I WANT TO SHOW YOU

THIS PATIENT, TO SHOW YOU AN

EXAMPLE OF HOW THE MECHANISMS

HELP US, THIS PATIENT IS TWO

YEARS OUT AND SHE HAS A -- YOU

HAVE SOUND ON THAT?

WHAT YOU CAN DO WITH LEFT SIDE

IS REMOVE HER THUMB HASN'T

WALKED FOR TWO YEARS, BEEN

THROUGH REHAB, VERY MOTIVATED.

THAT'S WHAT SHE CAN DO WITH HER

LEFT LEG.

SO I TRANSPLANTED THE CELLS, AND

I HAVE DONE THIS NOW PROBABLY IN

15 PATIENTS AND YOU DON'T EXPECT

RECOVERY IMMEDIATELY.

BECAUSE IT'S A LONG TERM EFFECT.

AND I SAW THE PATIENT RIGHT

AFTER SURGERY, SHE'S SAYING NO

WORSE, PRIMARILY A SECURITY

OFFICERTY STUDY AND I CAME BACK

NINE HOURS LATER BEFORE GOING

HOME THAT NIGHT AND I SAID LIFT

YOUR ARM UP AND SHE MOVES HER

ARM UP TO HER HEAD.

I SAID THAT CAN'T BE RIGHT.

WE MUST HAVE GOTTEN A BASELINE

EXAM WRONG SO I CALLED NEAL

SCHWARZ WHO IS OUR NEUROLOGIST

AND THEY TEND TO BE MORE

SKEPTICAL APPROPRIATELY THAN

SURGEONS.

SO HE SAID YEAH, RIGHT.

SURE.

I SAID LET'S GO BY TOMORROW

MORNING AND SEE HER.

SO WE GO BY THE NEXT MORNING AND

HERE SHE IS A DAY AFTER WE PUT

IN THE CELLS.

I REMEMBER AN N OF 1 BUT THIS IS

AN IMPORTANT LEARNING CASE AND

NOW LOOK WHAT SHE'S DOING WITH

HER LEG.

NEAL THE SKEPTICAL NEUROLOGIST

SEND AN EMAIL AND SAYS DON'T

TELL ANYONE I SAID THIS BUT

MIRACLE.

SO HE IS NOW -- SO SHE'S NOW

FOUR MONTHS OUT AND WALKING

STILL.

HOW MANY OF YOU THINK THAT THIS

IS PLACEBO EFFECT?

NAOMI THINKS MAYBE.

PLACEBO WITHOUT ANY BIOLOGICAL

RELEVANCE, HOW MANY THINK IT'S

THE CELLS?

I DON'T THINK IT'S THE CELLS,

THOUGH I GUESS YOU CAN

HYPOTHESIZE WITHIN EIGHT HOURS

THEY ARE SECRETING SOMETHING

THAT HAS EFFECT.

CERTAINLY NOT INTEGRATING.

I THINK THIS WAS MY FIRST THAT

IT WAS A LESION EFFECT.

SOMETIMES WHEN WE PUT IN A

STIMULATER FOR SOMETHING LIKE

PARKINSON'S MOVEMENT DISORDER

BEFORE YOU START STIMULATING THE

TREMOR GOES I WAY FROM PUTTING A

LITTLE LESION THERE THAT

DISINHIBITS THE DETRIMENTAL

CIRCUITS OR INHIBITS THE

DETRIMENTAL CIRCUITS.

SO WE LOOKED AT FIBER TRACKS, NO

CHANGE.

AND THEN WE LOOKED AT THE MR

SCAN AND HERE IS THE ONE DAY OUT

NO DIFFERENT THAN THE DAY BEFORE

-- WEEK BEFORE SURGERY, ONE WEEK

LATE THRER'S A FLAIR LESION,

EDEMA, DWI NEGATIVE SOURCE, NOT

A STROKE AND RESOLVES TWO MONTHS

LATER.

IT'S RIGHT IN THE MOTOR CORTEX

AND I THINK WHAT WE DID WAS TO

THIS CHANGES THE WAY PLASTICITY

IS OCCURRING, FROM THE

PRE-CLINICAL MODELS BUT BASED ON

AND SOME OTHER GRAPH AND

ANECDOTAL INFORMATION I THINK

IT'S POSSIBLE TO RESURRECT THE

CIRCUITS THAT THEY'RE STILL

WORKING MASSIVE INHIBITION, IN

FACT FOUR MONTHS OUT NOW AND

MUCH BETTER SO IF YOU FIGURE OUT

WHY SHE IMPROVED AS OPPOSED TO

OTHER PATIENTS WE HAVE SOMETHING

AND STIRRED A PROJECT IN MY LAB

OF OPTIC REGENERATION OF MOTOR

CORTEX IN MICE.

WHAT I TOLD MY LAB ABOUT THE

PATIENT, THEY GOT EXCITED TO

AXEL L RATED THIS, YOU KNOW WHAT

OPTOGENICS IS?

USING GENETICS AND OPTICAL

METHOD METHODS, USING LIGHT TO

STIMULATE SURFACES BY STANFORD

THAT USES PROTEINS LIKE CHANNEL

RHODOPSIN THAT WHEN STIMULATED

WITH BLUE LIGHT, OPENS A CATION

CHANNEL SO CELLS ARE DEFOR

LAIZED SO WE BETTER --

DEPOLARIZED, BETTER THAN AN

ELECTRODE.

SO WE USE -- WE DID THIS IN

MICE, I DON'T HAVE TO GO INTO

THIS, NOT STEM CELLS BUT THIS IS

USING CHANNEL RHODOPSIN TRAN

GENERAL I CAN MICE AND WE

STIMULATED THE NOR CORTEX --

MOTOR CORTEX FIVE DAYS AFTER

STROKE AN THIS IS PRELUMNARY

DATA.

WE JUST SUBMITTED THIS R-21 ON

THIS AND WE CAN ACTUALLY RECOVER

BEHAVIOR WITH STIMULATION SO I

THINK HERE IS AN EXAMPLE OF

USING THE CLINICAL SITUATION TO

TAKE US BACK TO THE LAB TO LOOK

AT MECHANISMS WHICH WE THEN

HOPEFULLY BRING BACK INTO THE

CLINIC AND WE NEED TO RESURRECT

STIMULATION FROM STROKE AS

ANOTHER POTENTIAL THERAPEUTIC

STRATEGY.

I TALKED ABOUT ALL POSSIBLE

BENEFITS THAT I SEE IN TERMS OF

TURNING MECHANISM BESIDES THE

FACT WE AS SCIENTISTS LIKE TO

KNOW WHAT'S GOING ON, I WANT TO

THANK EVERYONE IN MY LAB WHO DID

THE WORK AND MY FACULTY

COLLABORATORS AT STANFORD.

THANKS VERY MUCH FOR YOUR

ATTENTION.

>> WE HAVE TIME FOR JUST ONE OR

TWO SHORT QUESTIONS.

SHORT.

IN ORDER TO STAY ON TIME I THINK

WE'LL MOVE ON TO OUR NEXT

SESSION WHICH IS ENTITLED CELL

DELIVERY AND TRACKING AND OUR

FIRST SPEAKER IS DR. JOE FRANK,

SENIOR INVESTIGATOR IN BOTH THE

CLINICAL CENTER AND IN NIBIB AND

HAS SPENT A CONSIDERABLE AM OF

TIME ON WORKING ON NEW IMAGING

METHODS THAT WE NEED TO BE ABLE

TO TRACK THESE CELLS AFTER WE

PUT THEM INTO THE BODY

INITIALLY, LONG TERM TRACKING IN

THE FEW WHUR -- IN THE FUTURE.

>> THANK YOU.

THANKS, PAM FOR INVITING E ME TO

SPEAK.

THIS IS PC.

AM I USING -- IT'S NOT HERE.

>> SO I WANT TO SWITCH GEARS,

YOU HAVE SEEN IMAGING, I WANT TO

GUF YOU PERSPECTIVE HOW WE CAN

TRANSLATE INTO THE CLINIC.

AND AT THE END OF THE TALK I'M

GOING NOT WORKING.

THERE WE GO.

SO E EAR GOING TO TALK ABOUT HOW

WE TRACK CELLS, HOW WE CAN

POSSIBLY MOVE THIS TO THE CLINIC

QUICKLY, AFTER WE LABEL CELLS

AND IF I HAVE TIME BE

PROVOCATIVE AND TELL YOU HOW WE

CAN POSSIBLY IMPROVE HOMING IN A

NON-INVASIVE TECHNIQUE.

NEXT SLIDE, SEVERAL YEARS AGO I

STARTED DOWN THIS PATH AND IT

BECAME CLEAR TO ME WE HAD FROM A

CHEMICAL POINT OF VIEW A REAL

PROBLEM HERE.

AND START THINKING ABOUT THIS

PROBLEM IT'S VERY IMPORTANT.

IF YOU GO ON LINE AND ASK JEEVES

YOU FIND 5TH AND 6TH GRADERS ASK

THE QUESTION, HOW MANY CELLS ARE

THERE IN THE BODY.

10 TO THE 15th CELLS AND

70-KILOGRAM PERSON, THERE'S 10

TO THE THE 11th CELLS IN THE

BRAIN.

AND THIS IS ALL DONE BY

APPROXIMATION, OBVIOUSLY THERE'S

ABOUT SIX TIMES 10 TO THE 9

CELLS IN THE LEFT VENTRICLE OF

THE HEART.

WHEN WE THINK ABOUT WHAT WE

TRANSPLANT INTRAVENOUSLY AND TAR

TIER YOURLY, WE'RE TALK ABOUT 10

TO THE 8 CELLS, WITH DIRECT

INJECTION INTO THE BRAIN OR

HEART WE HAVE A REAL PROBLEM.

SEVERAL ORDERS OF MAGNITUDE,

WE'RE ESSENTIALLY ONE PART PER

TEN TO THE THE 5TH, ONE PART PER

TEN TO THE 6TH TRYING THE FIND

CELLS WHEN THEY GO THERE.

WHAT WE REALLY -- NEXT SLIDE,

WE'RE ACTUALLY THINKING ABOUT

LOOKING THROUGH FOR A NEEDLE IN

A HAY STACK IN THIS PROCESS.

THE OTHER THING THAT'S BEEN

ALLUDED TO IS THE -- NEXT SLIDE

I'M NOT MOVING AT ALL.

IS THE FOLLOWING FROM CHARLES

COX ALLUDED TO THE IDEA OF

PULMONARY TRAPPING.

THERE'S CONCEPT HE TOOK A

VARIETY OF STEM CELLS AND STEM

CELL TYPES, LABEL WITH QUANTUM

DOTS INTRAVENOUSLY INJECT THEM

AND TOOK OUT THE LUNGS IN

VARIOUS ORGANS AND SHOWED NICELY

THAT IN FACT THE CELLS ARE

GETTING TRAB TRAPPED IN THE

LUNG.

SOME NOT SO MANY IN THE LIVER

BUT A SMALL ROUND CELL AT HSC

WOULD BE ABLE TO TRANSVERSE THE

LUNG AND WIND UP LIVER SPLEEN

AND KIDNEY.

NEXT SLIDE.

ONE INTERESTING ASPECT TO TAKE

INTO ACCOUNT IS WE PUT THE CELLS

INTO THE JUGULAR VEIN OT RATS

AND THEN SAMPLED WITH FAX

ANALYSIS FROM THE CAROTID ARTERY

AND INJECTED 2 MILLION CELLS,

4 MILLION CELLS, A VARIETY OF

TYPES OF STEM CELLS, ANYWHERE
œ

BETWEEN 1 TO 4% OF THE CELLS

WOUND UP IN THE CAROTID ARTERY.

THAT ABOUT .3% WOUND UP --

APPROXIMATELY 4% TRANSVERSED THE

LUNGS, .3% WOUND IN THE CAROTID

ARTERY AND FEW WHEN THE STROKE

MODEL WOUND UP IN THE BRAIN.

SO IF WE'RE TRYING TO TRACK

CELLS WE HAVE A VARIETY OF

IMAGING MODALITIES TO USE.

YOU HAVE HEARD ABOUT

BIOLUMINESCENCE AN GFP LABELING.

I WANT TO FOCUS ON SPECK PET AND

MRI, NEXT SLIDE.

I TOOK THIS FROM A PAPER BY PAM

(INDISCERNIBLE) TWO SKULL

LEAGUES HERE CONTAINING HYDROXY

APPETITE ALONE AND APPETITE N

BONE MARROW STROMAL CELLS WE CAN

SEE HEALING OF THE BONE IN THE

SCALP OF THIS DOG COMPARED TO

THE CONTRA LATERAL SIDE WHICH

DIDN'T HAVE THE STEM CELLS AT

THE SAME PERIOD OF TIME.

NEXT SLIDE.

WE THINK ABOUT WAYS TO LABEL

CELLS WE USE EXOGENOUS LABELS,

IRON OXIDE NANOPARTICLES, OR WE

CAN ALTER THE GENE POOL BY

PUTTING -- YOU HAVE SEEN THIS

WITH LUCIFERASE IMPORTANT TO

MONITOR WHAT IS HAPPENING IN THE

CELL.

IF YOU TRANSPLANT THE WILD CELL

L LIKE DOPAMINERGIC NEURON YOU

CAN USE FAIRLY COMMON COMPOUNDS

OR LOR RA DOE PA WHICH IS A PET

LIGAND AND START TRACKING YOUR

NEURAL STEM CELLS IN THE AREAS

OF PARKINSON DISEASE.

OUT THREE YEARS AND NEXT SLIDE,

WISH I COULD USE THIS, WE CAN

TRACK THE NUMBERS AND WHAT THEY

DID FINDING AT THREE YEARS LATER

ONLY ABOUT 10% DOPAMINERGIC

NEURONS SURVIVED.

THE REPORTED GENE APPROACHES

HERE WE ACTUALLY INSERT THE DNA

INTO THE CELLS, WE THEN INJECT

THEM AND ACTUALLY NOA WHERE THEY

TRACK TO AND NEXT SLIDE, WE HAVE

A VARIETY OF AGENTS YOU HEARD

ABOUT KINASE, A DOPAMINERGIC

REPORTER GENE, PORTER FOR MR,

PEOPLE ARE FOCUSING ON AND I'LL

MENTION THOSE THREE.

NEXT.

THIS IS FROM A STANFORD GROUP

WITH MACK JENSON AND THEY TOOK

CYTOTOXIC T-CELLS RECOME
RECOMBINANT

WITH IL-13 RECEPTOR AND SAM

GAMBEER IN A PATIENT WITH

RECURRENT GLIAL BLASTOMAS AND

FUSING 10 TO THE 9 CELLS EVERY

OTHER DAY AND THEY COULD SEE

WHERE THESE CELLS WOULD BE

POPULATING, IN FACT, THIS NUMBER

2 LESION WAS ONLY FIRST ON THE

PET SCAN AND THEN BIOPSIED FOUND

THIS WAS RECURRENT GLIOMA.

WITH GANG CYCLOVEER YOU CAN USE

-- BECOMES A SUICIDE GENE AND

KILLS THE CELLS.

SODIUM SIMILAR PORTER YOU CAN

PUT IN APCs, THIS IS A HUMAN

PRODUCT AND WE CAN FOLLOW BY

(INDISCERNIBLE) PET STUDIES AN

FOLLOW THEM WITH THE DIRECT

INJECTION IN THE HEART.

NEXT SLIDE.

WHAT WE CAN DO WITH -- THIS IS

FROM THE WISEMAN GROUP, THIS IS

(INDISCERNIBLE) GROUP SHOWN

NICELY YOU CAN PUT IT INTO A

TRANSGENIC MOUSE MODEL UNDER

PROMOTER AND WHEN SHE TURNS ON

THE TET AND ACTUALLY FEEDS THE

ANIMAL THE SIGNAL INTENSITY IN

THE LIVER DECREASES, THE

INTENSITY ON MR BECAUSE OF IRON

GOES DOWN BECAUSE OF

DEPHASINGING OF THE SIGNAL,

CAWING IT TO PK HUE POE INTENSE,

WE CAN MAKE SINGLE AND

TRANSGENIC MICE TIED TO THE --

SO WE CAN PUT ANYTIME PLACE AN

LOOK AT FAIR TIN EXPRESSION IN

THE TISSUE.

I COME BACK TO THIS SLIDE

CONSTANTLY FROM CINDY DUNBAR AT

NIH AND NHLBI BECAUSE OF

INSERTION OF GENES INTO STEM

CELLS, CAN BE PROBLEMATIC.

AND THERE'S ALWAYS AN ISSUE.

CINDY SAID MANYIERS AGO, RHESUS

MONKEYS, ABLATED THEM,

TRANSPLANT WHERE SHE PUT IN EGFP

GENE INTO THE CELLS,

HEMATOPOIETIC STEM CELL, BONE

MARROW TRANTS PLANT CELLS, SHE

STUDIED WHERE THE GFP GOT

INSERTED, THE ANIMALS WERE

STABLE OVER A PERIOD OF FIVE

YEARS WITH 3 TO 5% OF THE

CRELINGS EXPRESSING EGFP AND ONE

DAY 30% EGFP SHOWED UP IN ONE

ANIMAL, ONE IN SEVEN ANIMALS AND

IT TOOK 5 TO 7 YEARS TO

ACCOMPLISH.

SO FEW DAYS LATER THE ANIMAL

CAME DOWN WITH LIEUSITIC

LEUKEMIA AN DIED.

AND%

VARIETY THESE CELL WERE GFP

POSITIVE SO ONE OF THE THINGS

THAT WE HAVE TO LEARN IF WE'RE

GOING TO THINK ABOUT PUTTING

REPORTER GENES INTO CLINICAL

TRIALS, CELLS WITH CLINICAL

TRIALS WHERE THERE'S NOT

ASSOCIATED SUICIDE GENE

CONSTITUTIVELY EXPRESSED IS

WHERE TO PUT THOSE GENES AND

WHAT THEIR EFFECT WILL BE

DOWNSTREAM AND CAN WE DO

EXPERIMENT.

NEXT SLIDE.

LET'S TALK ABOUT THE LABELING

STRATEGIES.

WE CAN PUT ISOTOPE INTO A CELL,

NOT TALKING ABOUT THE OPTICAL

APPROACH.

WE HAVE A VARIETY OF AGENTS, YOU

HAVE SEEN EXAMPLES OF COPPER,

YOU HAVE SEEN SOME EXAMPLES OF

(INDISCERNIBLE).

ONE EXAMPLE OUT IN THE CLINICAL

TRIAL IN NATURE ABOUT 2005,

NEXT, WHICH THEY DO DUAL

LABELED, WITH AN IRON OXIDE

NANOPARTICLE IN DENDRITIC CELLS,

PART OF A VACCINE STUDY AND

UNDER ULTRASOUND GUIDANCE THEY

DIRECTLY INJECT IT INTO THE

LYMPH NODE IN VARIOUS PARTS,

MELANOMA OF THE PATIENT AND THEY

CAN SEE ON TO POSITION FI --

SPECK SCAN THE LYMPH NODE LIGHTS

UP, YOU CAN SEE THE M RSHI

SIGNAL THE DECREASE IN SIGNAL

INTENSITY COMPARED TO CONTRA

LATERAL SIDE.

TAKE LOOK AT BLUETOOTH BLUE

POSITIVE CELLS SO YOU CAN DUAL

LABEL AND FOLLOW WHERE YOU

INJECTED THE CELLS.

ONE OF THE MOST IMPORTANT PART

OF CELL THERAPY OR LABELING IS

THAT YOU CAN TRACK WHERE YOU

WERE INITIALLY PUT YOUR CELLS.

NEXT SLIDE, NANOPARTICLES THAT

CAN BE USED AS WELL.

THERE'S NO ENDOGENOUS FLUORINE

IN THE BODY, THIS IS ERICA

LEARN'S LAB AND THERE'S

HOPEFULLY GOING TO START

CLINICAL TRIALS SOON ONCE THEY

WORK OUT POLITICS BETWEEN

UNIVERSITY OF PITTSBURG AND

CARNEGIE MELON.

YOU CAN BLOW BUBBLES TO THE

SYSTEM, YOU CAN INJECT THESE

CELLS INTO THE ANIMAL AND YOU

CAN DETECT LOOK FOR THE FLOWING

SIGNAL AND SUPERIMPOSE ON THE

ESSENTIAL MR SIGNAL..‡A„

WHAT'S INTERESTING HERE IS MOST

RECENTLY COME OUT THAT THE

FLOORING NANOPARTICLE CAN GET

TRANSFERRED TO MACROPHAGES SO

ENDOGENOUS MACROPHAGES SO THE

FLOWING SIGNAL DOESN'T STAY

EXACTLY WITH YOUR STEM CELL.

NEXT SLIDE.

SEVERAL YEARS AGO WE WALK DOWN

THE PATH AND THE CONCEPT WAS

IRON OXIDE NANOPARTICLE YOU TEND

TO MIX THEM TOGETHER YOU

WOULDN'T UP WITH A NEW

COMBINATION DRUG BUT IF YOU

POURED DIRECTLY ON CELLS AND

INCUBATE A SHORT PERIOD OF TIME

WE WERE ABLE TO LABEL

HEMATOPOIETIC STEM CELLS, BONE

MARROW STROMAL CELLS, AND WE

WERE ABLE TO SHOW NICELY IN FACT

WE COULD TRACK THESE CELLS OVER

A PERIOD OF TIME IN VARIOUS

ANIMAL MODELS.

THIS TOOK OFF VERY QUICKLY AND

WENT INTO CLINICAL TRIALS MOSTLY

IN EUROPE, AND SOUTH AMERICA AND

CHINA.

SO IN THIS CASE AGAIN REFERRING

TO THE NATURE BIOTECH IN 2005,

COMBINATION OF MR AND SPECK

AGENT ESSENTIALLY THEY PUT THE

NANO-- IRON OXIDE NANOPARTICLE

INTO DENDRITIC CELLS ALONG WITH

THE INIAN 111 CELLS THAT

INJECTION DIRECTLY INTO THE

LYMPH NODE AND OVER A PERIOD OF

3 TO 5 DAYS FOLLOW AND TRACK

WHERE THE IRON WENT ON MRI AND

AS WELL AS WITH SPECK.

THEY COULD VISUALIZE ABOUT 500

LABEL CELLS PER VOXEL ON MRI.

THEY ALSO HAD FOUR MISS WHICH

CASE THEY COULD SHOW POSITIVE

CELLS NOT IN THE LYMPH NODE BUT

ACTUALLY FAT PAD ABOVE THE LYMPH

NODE.

THIS IS NORMAL MRI SCAN, THIS IS

NOTHING SPECIAL, THIS IS A

CLINICAL SCANNER.

OVER A PERIOD OF WEEKS, NEXT

SLIDE THE IRON OXIDE

NANOPARTICLE IN THE FAT PAD

DISAPPEARED, NEXT SLIDE AND

BECAME ISOINTENSIVE WITH THE

FACT.

THIS IS BIOAVAILABLE THEY WERE

USING AT THE TIME.

NEXT SLIDE.

THIS IS FROM CHINA.

THIS IS TRAUMATIC BRAIN INJURY,

BECAUSE WE DIDN'T GET A LOT OF

CHARACTERIZATION OF THESE

PARTICLES, THEY SCRAPED IT OFF

SUPPOSEDLY OF THINGS OUTSIDE THE

BRAIN.

THEY LABELED IT WITH ESSENTIALLY

AN IRON OXIDE AND TRANSFECTION

AGENT.

NEXT SLIDE.

THEN 50,000 CELLS AND TEN SITES

THROUGHOUT THE BRAIN ON AREA OF

TRAUMA FOR THOSE WHO KNOW MRI

THIS IS THE AREA OF TRAUMA.

THEY THEN WENT AND PUT THESE

LABELED CELLS IN VARIOUS PARTS

OF THE COMATOSE PATIENT.

THIS PATIENT GOT UNLABELED CELLS

AN OVER 2 # DAYS THEY WERE ABLE

TO FOLLOW CELLS AS THEY MIGRATED

TO DIFFERENT TRACKS WITHIN BRAIN

OF THIS PATIENT.

COMATOSE PATIENT.

THEY REPORTED ESSENTIALLY FOR

PERSONAL COMMUNICATION, DR. ZU

REPORTED TO ME APPROXIMATELY 10

WEEKS AFTER DOING THESE

IMMANATIONS IN THE PATIENTS THEY

COULD NOT SEE THE LABEL ANY MORE

SO THE LABEL GETS METABOLIZED

OVER THE PERIOD OF TIME, TEN

WEEKS OR SO.

THIS IS THE MOST RECENT STUDY IN

THE CZECK REPUBLIC WHO THEY

FOUND 16 MONTH OLD BRAIN DEAD,

TAKEN TO THE HOSPITAL AND HAD

STORED UMBILICAL CORD BLOOD AND

THE GROUP THERE DECIDED, LABEL

CELLS WITH AN IRON OXIDE

NANOPARTICLE, INTERVENTRICULAR

INJECTION OF THE CELLS, WE CAN

SEE THAT HERE.

OVER THE PERIOD OF TIME THE

SERIAL MRIs, SHOW IN FACT THE

CELLS TENDED TO LAYER ALONG THE

BACK OF THIS PATIENT WHICH IS

BRAIN DEAD BACK INTO THE

VENTRICLE AND OVER TIME

DISAPPEARED.

OVER 3 TO 4 MONTHS, ACCORDING TO

WHAT THEY SHOW.

IN OTHER MRIs DISPERSED

THROUGHOUT THE BRAIN,

PERIVENTRICULAR WHITE MATTER,

THIS IS A UNIQUE SITUATION, THIS

IS NOT STANDARD STROKE BUT GARY

TALKED ABOUT OR ANYTHING ELSE.

OR ANY OTHER TYPE OF INJURY IN

THE BRAIN.

THIS IS BASICALLY GLOBAL

ISCHEMIA AN CELL DEATH.

NEXT SLIDE.

SO LAST YEAR OR ACTUALLY THIS

YEAR WE PUBLISHED THIS COMPOUND

WHAT HAPPENED IN -- VERY EARLY

ON IN 2009, FERADEX WENT OFF THE

MARKET.

A DRUG USED FOR DEFICIENCY CAME

ON THE MARKET.

AND WE PUBLISHED ON THIS CONCEPT

COMBINING THREE AGENTS TOGETHER

TO MAGNETICALLY LABEL CELLS

USING WHAT WE NOW NANOPLEX AND

IN A CINCH TO ATTACH TO CELLS

AND GO INTO INCORPORATING CELLS.

NEXT SLXjpu

WHAT WAS NICE IS WE ACTUALLY

FARM THIS PROTOCOL OUT BEFORE

THE PUBLICATION.

SO WHAT WE DID ESSENTIALLY BE

THE FIRST SPEAKER OF THE SESSION

ACTUALLY TALKED ABOUT WE

ACTUALLY INCORPORATEDDED PEOPLE

AT -- USE PEOPLE AT DETROIT,

HENRY FORD HOSPITAL TO LABEL THE

HSCs AN T CELLS, WE GET KAREN

(INDISCERNIBLE) AT CITY OF HOPE

TO DO SOME NSC LABELING AND SHOW

NICELY THAT IN FACT WE COULD GET

THIS PROTOCOL APPLIED IN VARIOUS

FACILITIES ACROSS THE COUNTRY

AND GET CELLS TO LABEL.

NEXT SLIDE.

AND GET DIFFERENTIATION OF

BMSCs AND NEXT THEN DIRECTLY

IMPLANT THE CELLS INTO THE

BRAINS OF RATS, SHOW THAT THE

HUMAN CELLS THE MITOCHONDRIAL

ANTIBODY.

THERE'S IRON OXIDE IMAGING,

HEMORRHAGE WILL LOOK VERY MUCH

LIKE YOURSELVES.

NEXT WITH KAREN ABOUDI WE

STARTED DOWN THE PATH ON THE SIM

GRANT LOOKING AT PRE-CLINICAL

TRIAL, SHE PUT LABELED CELLS

WITH HPF BEHIND THE GLIOMA, THEY

MIGRATED TO THE AREA, AND WE

SPENT A GOOD DEAL OF SIX MONTHS

OBTAINING THE PRE-CLINICAL DATA

AND SUBMITTED THE AMENDMENT TO

THE IND WHICH IS NOW APPROVED.

SO THIS COMPLEX WILL MULTIMILTLY

GO TO CLINICAL TRIALS IN THE

U.S. IN PATIENTS WITH RECURRENT

GLIAL BLASTOMA ON RECURRENT

INJECTION.

NEXT SLIDE.

IF YOU WANT TO TALK ABOUT

MONITORING CELL THERAPY IN ROLE

OF IMAGING, OUT'S ESSENTIALLY IF

YOU THINK ABOUT CELL THERAPY.

STAGE THE PATIENT.

AS A CLINICIAN YOU NEED TO

CHARACTERIZE THE EXTENT,

LOCATION, PATHOLOGY, WHERE YOU

WANT TO PUT THE CELLS AND HOW

YOU WANT TO GET THEM TO WHERE

YOU WANT TO GO.

I TEND TO AGREE WITH GARY, NOT

SURE I AM TOTALLY CONVINCED

OTHER THAN THE OUTSIDE SORT OF

WINDOW SHORT TERM WINDOW, I NEED

TO MONITOR WHERE EVERY CELL IN

THE BODY GOES.

THERE ARE MULTI-MODALITIES

MENTIONED, DT I, FMRI, STANDARD

IMAGING, PET SPECK, A VARIETY OF

TECHNIQUES USED CLINICALLY TO

GET AT WHAT'S HAPPENING AND

RESULTS OF ESSENTIALLY OUR CELL

THERAPY.

WE CAN LOOK AT SAFETY ISSUES,

WHETHER OR NOT THE CELLS

MIGRATED EARLY ON, ESSENTIALLY

THINK AND LOOK AT BYSTANDER

EFFECTS.

AND POTENTIALLY USE IMAGING TO

OPTIMIZE CELLS.

CELL THERAPY DOSE AND WHEN TO

ADMINISTER.

THAT GETS ME TO THE NEXT POINT

AND HOPEFULLY IN THE NEXT TWO

AND A HALF MINUTES I'LL GET TO

THIS.

NEXT SLIDE.

THE CONCEPT IS I WANT TO GET

AWAY FROM THIS DIRECT

IMPLANTATION, I HAPPEN TO THINK

THAT THERE ARE WAYS TO GET AND

DELIVER CELLS DIFFERENT THAN THE

THE SORT OF STICKING THE NEEDLE

IN THE BRAIN THOUGH THAT MAYBE

HELPFUL.

THE CONCEPT IS, THIS IS STEM

CELL A FEW YEARS AGO THAT MSCs

TEND TO HOME IN LEUKOCYTES THAT

YOU HAVE AN IRAREA OF

INFLAMMATION, THIS HOLDS FOR

NSCs AND A VARIETY OF OTHER

CELLS BUT THE CELLS TETHER AND

ATTACH, ADHERE TO CELL ADHESION

MOLECULES AND EITHER AND THEN

CROSS INTO THE AREA OF THE

CYTOKINE GRADIANT.

SO ENHANCED HOMING BY DIRECT

INJECTION, YOU CAN DIRECT CELLS

AND THERE'S STUDIES DONE IN

YIEWRL WITH THAT, YOU CAN

CHEMICALLY MODIFY THE SURFACE OF

THE STEM CELL TO MAKE IT MORE

STICKY IF YOU WANT, YOU CAN

RADIATE THE AREA CAUSING THE

AREA OF INFLAMMATION, THERAPY

ULTRASOUND WHAT YOU USE FOR

PHYSICAL THERAPY IS KNOWN

ASSOCIATED WITH INCREASED VEGF

PRODUCTION IN AREA AND ALSO

ESSENTIALLY INCREASED VESICAL

FORMATION AS FO FOR THE MEET.

HEAT.

THERE'S A TECHNIQUE FOCUSED

ULTRASOUND USED FOR ABLATION BUT

CAN BE HELP TARGET AN AREA.

NEXT SLIDE.

WHAT'S NICE IS THERE ARE A

VARIETY OF THINGS THAT I CAN UP

REGULATE, I CAM AND V CAM ON THE

SURFACE OF ENDOTHELIAL CELLS, A

LOT OF OUR STEM CELLS TEND TO

HAVE INTEGRINS ASSOCIATED FOR

THOSE CELLS -- FOR THOSE CELL

ADHESION MOLECULES.

NEXT SLIDE.  WHAT'S ALSO NICE IS

WE HAVE CLINICALLY APPROVED

DEVICES THAT CAN BE USED FOR

FOCUSED ULTRASOUND.

THIS IS A PHILLIPS SCANNER BUT

USED FOR PROSTATE ABLATION.

NEXT SLIDE.

THIS IS A CT SCANNER WHICH IS

ESSENTIALLY THE BREAST OR

PATIENT BREAST OR PART OF BODY

SITTING ON TOP OF THIS AND THE

FOCUS ULTRA SOUND IS COMING FROM

UNDERNEATH.

MR SCANNERS HAVING THE FOCUSED

ULTRASOUND SYSTEM BUILT INTO THE

TABLE AND LOOKING -- BEING

APPROVED FOR UTERINE FIBROIDS.

AND THE CONCEPT FOCUSED

ULTRASOUND, IS THIS CONCEPT THAT

WE CAN FOCUS THE BEAM TO THE A

SPECIFIC AREA, BY PULSING ON OR

OFF, WE RAISE THE TEMPERATURE

ABOUT 4 OR 5-DEGREES C IN THE

TISSUE, IT RELAXES QUICKLY, WE

CAN ACTUALLY CHANGE WHAT THE

ENVIRONMENT LOOKS LIKE.

THIS IS THE CONCEPT WHAT WE DO

TRYING TO GET THE AREA WHERE

EVERYTHING ELSE WE TAKE OUR STEM

CELLS AND INJECT INTRAVENOUSLY

AND INTR AR TIER YOUR YOURLY AND

IT FLOATS ALONG -- INTERAR TIER

YOURLY.

-- INTERARTERIOL.

WE GET UP REGULATION OF

CYTOKINES, CHEMOKINES GROWTH

FACTOR, I CAM AND V CAM.

NOW BACK TO INJECTION AGAIN,

THEY SEE THE ADHESION MOLECULES

ON THE SURFACE OF ENDOTHELIAL

CELLS, THEY TEND TO STICK AND WE

GET (INDISCERNIBLE).

WE DEVELOP A TRANSIENT MOLECULAR

ZIP CODE TO FOCUS AN PINPOINT

WHERE I WANT TO GO BASED UPON

IMAGING GUIDANCE.

NEXT SLIDE.

WE DID THIS IN KIDNEY AND MOUSE

MODEL, NUDE MOUSE WE FOCUSED

ULTRASOUND, LABELED CELLS WITH

IRON OXIDE, YOU SEE THE

HYPOINTENSE AREA WHERE CELLS

WOUND UP AS COMPARED TO THE

CONTRA LATERAL SIDE, WE HAD A --

WHAT WAS TREAT AND WHAT WASN'T

TREATING WE CAN SEE OUR CELLS IN

THE INTERSTITIAL SPACES MANY THE

JUX TRA GLOMERULAR.

AND WHAT WE FOUND WHEN WE DID

PULSE FOCUS YOU WILL STRA TRA

SOUND WE UP REGULATED A VARIETY

OF FACTORS.

FOR ABOUT ONE DAY, FOR GROWTH

FACTORS VEGF, NEXT SLIDE AND

THIS TENDED TO DISAPPEAR WHEN WE

GAVE OR BMSCs.

NEXT.

WE CAN COUNT AND SHOW UP

REGULATION OF I CAM AND V CAM.

NEXT AND THAT WE CAN COUNT THE

CELLS, NEXT.

AND WE GOT ABOUT 8 TO 10 FOLD

INCREASE IN NUMBER OF CELLS

DELIVERED TO KIDNEY THAT WE

PULSED FOCUS ULTRASOUND COMPARED

TO CONTRA LATERAL THAN LASTED 3

THE 5 DAYS.

WHICH HAVE FIVE DAY DATA WE'RE

ABOUT FIVE TIMES NORMAL NUMBER

OF CELLS.

NEXT.

WE HAVE DONE THIS ACUTE JURY,

GOING TO TRY TO WRAP UP QUICK,

PAM.

NEXT.

WE PULSE ONE KIDNEY AND DIDN'T

PULSE THE OTHER AFTER ATM MODEL

WITHSIS PLATINUM.

WE GAVE EXPERIMENT ON DAY 1 OR

DAY 4 AND IN FACT WE FOUND THAT

THE KIDNEY THAT WASN'T TREATED

WITH FOCUS YOU ULTRASOUND HAD

RETENTION OF CELLS BUT WE GOT

MORE NUMBER OF CELLS IN THE

PULSE FOCUS YOU ULTRASOUND
TREATED

KIDNEY.

HUMAN ESCs AGAIN AND SAME DAY

FOUR EXPERIMENT AND KILLED THE

ANIMAL THE NEXT.

NEXT.

AND WE DID THIS IN AN ATM MODEL.

I'M GOING TO SKIP A COUPLE OF

SLIDES TO END.

KEEP ONGOING.

WHAT WE HAVE DONE, THIS IS

SOMEWHAT PROVOCATIVE, WE DID IT

THREE TIMES IN A ROW, WE GAVE

CELLS AND FOCUSED ULTRASOUND ON

CELLS THREE DAYS IN A ROW.

WE FOUND A HIGHLY STATISTICALLY

SIGNIFICANT DIFFERENCE THAN WHEN

YOU GIVE ONCE OR YOU GIVE CELLS

AFTER ONE COURSE OF PULSE FOCUS

ULTRA SOWN, THIS IS WITH

MBSCs, SAME APPROACH, EXCEPT

THIS IS CD34, 131 POSITIVE

CELLS, THIS IS NOW IN MUSCLE, WE

CAN SEE THE EFFECT, AND IF WE

EUTHANIZE THE ANIMALS EARLY WE

CAN SEE THE CELLS INTERACTION

WITH THE CAM, NEXT.

FINALLY JUST TO COME TO THE

CONCLUSION, WE CAN USE A

NON-DESTRUCTIVE NON-INVASIVE

FORCE TO TRANSIENTLY INCREASE A

GENETIC PROFILE AND GOING -- I

DIDN'T GO INTO DETAIL ABOUT THE

DIFFERENT CHEMOATTRACTANTS THAT

GET UP REGULATED BUT WE SEE I

CAM AN V CAM UP REGULATEDDED

SPECIFICALLY IN A TARGET.

PULSE FOCUS ULTRASOUND IS USED

IN BRAIN FOR THOSE WATCHING ABC

NEWS ABOUT FOUR MONTHS AGO YOU

FOUND OUT THEY WERE ABLE TO

ABLATE AN AREA IN THE BRAIN AND

PATIENT WITH ESSENTIAL TREMORS.

THIS IS FROM UVA.

ON THEIR WEBSITE CONSTANTLY.

BUT THE CONCEPT IS THAT WE CAN

ACTUALLY ESSENTIALLY CAUSE

ENHANCED PERMIBILITY AND HOMING

PERMIBILITY AND RETENTION EFFECT

OF VARIOUS DIFFERENT CELL TYPES

AND POTENTIALLY USE FOR

DIFFERENT THINGS.

THAT WE CAN ALTER WITH

COMBINATION IC OR -- IV OR IA

INFUSION OF CELL PRODUCTS THE

MICROENVIRONMENT SO WE CREATE A

TRANSIENT MOLECULAR ZIP CODE THE

CELLS WANT TO MIGRATE TO AND

ESSENTIALLY HAVE IT DISAPPEAR

OVER ESSENTIALLY 48 HOURS.

AND THE CELLS COULD BE INJECTED

AT SPECIFIC TIME SO WE DON'T

HAVE TO TIE OURSELF TO THE ACUTE

INFLAMMATORY RESPONSE.

WE CAN TIE OURSELF A WEEK WEEK

LATER WITH POTENTIALLY INVASIVE

NEUROSURGICAL PROCEDURE AND

EXPLORE WHETHER OR NOT MORE

CELLS ARE BETTER WITH THE TIMING

OF THESE CELLS SHOULD BE.

NEXT SLIDE.

AND THIS IS JUST THE GROUP OF

PEOPLE THAT WE HAVE DONE WORK

WITH.

KAREN ABODY, THE TRIAL IS

UNDERWAY AND WE'RE RECRUITING

PATIENTS TO THE TRIAL THAT WE'LL

GET LABELED CELLS.

THANK YOU.

[APPLAUSE]

>> EVEN THOUGH YOU DID GO A

LITTLE BIT LONG -- OKAY.

NADIA.

>> THE MICROPHONE, PLEASE.

IS IT WORK SOMETHING YOU

MENTIONED ENDOGENOUS POSSIBLY

EFFECT ON ENDOGENOUS STEM CELLS

IN YOUR LAST SLIDE, DO YOU KNOW

THE EXTENT OF THIS EFFECT?

>> WE'RE STARTING THAT IN THE

BRAIN.

IF YOU LOOK AT THE GENERIC

PROFILE, I WENT THROUGH IT

QUICKLY IN THE KIDNEY BUT WE

HAVE DATA NOW TO SUGGEST THAT WE

CAN DO ESSENTIALLY WHAT WOULD BE

EQUIVALENT TO 5% DUTY CYCLE OVER

100 SECONDS.

SO YOU'RE TALKING A TOTAL OF ONE

SECOND WORTH OF PULSING, YOU GET

UP REGULATION OF CYTOKINES AN

CHEMOKINES AN GROWTH FACTORS A

BIPHASIC RESPONSE.

CYTOKINES AN GROWTH FACTORS THAT

YOU SEE UP UP REGULATED IF YOU

PUT THOSE DIRECTLY INTO A PLACE

AWAY FROM THE SBC, FOR INSTANCE,

YOU WOULD SEE MIGRATION.

WE ARE THINKING COULD WE

STIMULATE CELLS OUT OF THEIR

NICHE AND ACTUALLY GET THEM TO

MIGRATE WHERE WE WANT THEM TO

GO.

EXCITING TECHNOLOGY COMING ON

BOARD.

I'M INTERESTING IN THE HOMING

IDEA.

I PERSONALLY BELIEVE HAVING THE

CELLS AT THE SITE OF THE INJURY

OR DISEASE PROCESS IS IMPORTANT,

NOT EVERYONE AGREES WITH THAT.

WE DID A STUDY TWO YEARS AGO

SPEARHEADED BY POST DOC RAFAEL

GUZMAN WHERE WE ACTUALLY AFTER

STROKE THERE IS INCREASED

EXPRESSION OF VCAM, SO WE TOOK

ADVANTAGE OF THAT AND SORTED OUR

NEURAL STEM CELLS INTO BLA-4 IS

THE INTEGRIN THAT INTERACTS WITH

V CAM ADHESION MOLECULES SO WE

FACT SORTED THE RELS FOR DLA FOR

POSITIVE CD34 POSITIVE VERSUS

NEGATIVE AND FOUND ONLY THIS AND

INJECTED INTERARTERIOLLY AND

FOUND THE VRA-4 POSITIVE CELLS

HOMED TO THE SITE OF INJURY AND

THOSE CELLS L RECOVERED

BEHAVIOR.

I THINK IT'S A VERY INTERESTING

IDEA TO HAVE TO UP REGULATE

THOSE TO OTHER MECHANISMS.

ONE QUICK QUESTION.

WE DID SUPERPARAMAGNETTIC IRON

NANOPARTICLE LABELING AND YOU

CAN FOLLOW NICELY ON MR BUT WHEN

THE CELLS DIE AS YOU ALLUDED TO

THEY'REN BY MACROPHAGES SO HOW

DO YOU DEAL WITH THAT PROBLEM

THAT YOU SEE MACROPHAGES LABELED

WITH IRON?

>> I THINK -- I HAVE GOTTEN THIS

QUESTION A LOT.

SINCE I WENT THROUGH THIS

PROCESS YEARS AGO.

I THINK THIS IS -- WE HAVE

REALLY FEW ALTERNATIVES.

WHEN THE CELL DIE YOU WIND ONE A

NUMBER OF VARIOUS DIFFERENT

PLACES, WHAT'S MOST SHOCKING IS

ALMOST ANYTHING YOU PUT IN THE

CELL, WE HAVE BEEN ABLE TO SHOW

GFP YOU PUT IN CELL AN BRAIN YOU

FIND IT IN BASICALLY -- YOU FIND

IT IN MICROGLIA, YOU CAN FIND IT

IN MACROPHAGES SO I THINK THAT'S

CONCEPT JUST NOT TO THE

NANOPARTICLE, IT'S NOT CLEAR.

THERE'S THE OTHER THING THAT WE

HAVE -- AND IF YOU THINK IT'S

ABOUT PREPARATION, OVER TIME

BRAIN IS A LITTLE SLOWER THAN

EVERYTHING ELSE, I THINK ED

(INAUDIBLE) HAS SHOWN CLEARANCE

IN THE BRAIN MAYBE 3 OR 4 MONTHS

BEFORE THE MACROPHAGES CLEAR OUT

THE IRON.

I THINK IT'S SOMETHING WE HAVE

TO LIVE WITH.

IT'S THERE, IT'S GOING -- THE

ISSUE IS I'M NOT SURE HOW TO

DEAL WITH IT OTHER THAN I DON'T

HAVE ANOTHER ALTERNATIVE.

ANY NANOPARTICLE YOU PLAN TO PUT

INTO A CELL IS GOING TO FOLLOW

ALONG THE SAME PATH.

IF IT'S A QUEUE DOT, SOMETHING

ELSE, I DON'T THINK THERE'S

REALLY ANY ALTERNATIVE.

RIGHT NOW QUESTION IS DID YOU

PUT ANYTIME THE RIGHT PLACE, DID

IT MIGRATE, IF YOU THINK IT WILL

CROSS THE CORPUS COLOSSUM YOU

WOULD LIKE THE SEE IT

CLINICALLY.

DOES IT NEED TO GO THERE?

I THINK THERE'S STILL A LOT OF

QUESTION ABOUT THAT I LIKE THE

IDEA OF HOMING IN THE PENUMBRA

AREA, I LIKE PARACRINE EFFECTS,

BASICALLY CHANGING TO A

MORPHOLOGY THAT WILL RECONNECT

THINGS.

>> OKAY UNFORTUNATELY WE HAVE TO

MOVE ON.

OUR NEXT SPEAKER IS EMERSON

PERIN FROM TEXAS HEART

INSTITUTE.

HE'S PERFORM AD NUMBER OF

CLINICAL TRIALS THROUGH THE

TREATMENT OF CARDIOVASCULAR

DISEASE WITH BONE MARROW CELLS

AND IS GOING TO TALK ABOUT SOME

OF IN THIS EXPERIENCES.

-- SOME OF HIS EXPERIENCES.

>> I WANT TO THANK MY COLLEAGUES

FROM CBER AND NHLBI FOR THE

PLEASURE TO SPEAK TO YOU.

MY CHARGE IS DELIVERY IN THE

STEM CELL WORLD AND I'M GOING TO

USE CARDIAC AS BACKGROUND

BECAUSE THAT'S WHAT I KNOW A

LITTLE BIT ABOUT.

AFTER DR. FRANK GIVING STAR WARS

OF FUTURE DELIVERY I'LL BRING

YOU BACK DOWN TO EARTH A LITTLE

BIT AND TRY TO BUILD A FRAMEWORK

THE IMPORTANT THING IT IS THINK

ABOUT WHEN CONSIDERING DELIVERY

STRATEGIES ARE AND HOPEFULLY GET

TO THE STAR WARS PART OF THIS.

IN GENERAL THE ROLE OF

PRE-CLINICAL STUDIES YOU KNOW

VERY WELL, REALLY TO GET TO THE

CLINIC TO ESTABLISH SAFETY, AND

TO LOOK AT SOME OTHER IMPORTANT

THINGS WE NEED TO MOVE FORWARD

TO HUMANS.

AND ONE OF THOSE THINGS IS

REALLY LOOKING AT

ADMINISTRATION, HOW WE'RE GOING

TO GIVE THE CELLS, WHAT'S THE

METHOD WE'RE GOING TO USE.

SO REALLY IN THE CLINIC WHEN

TALKING CLINICAL TRIALS STEM

CELL THERAPY, DELIVERY PLAYS A

VERY IMPORTANT ROLE.

THIS IS A SIMPLER TALK AND I

DON'T HAVE TO GU YOU A LOT OF

DATA, HOW YOU GET THE CELLS TO

THE PATIENTS AND THERE ARE A LOT

OF INTRICATE ASPECTS HOW THIS

CAN BE DONE SO IT PLAYS A VERY

IMPORTANT ROLE.

SO HERE IS THE FRAMEWORK I

ESTABLISHED, FIRST JUST AS A

GENERAL PRE-CLINICAL TRIALS,

SAFETY IS PARAMOUNT SO WE HAVE

TO PROVIDE EVIDENCE FOR SAFETY.

PROCEDURAL SAFETY AND SAFETY

REGARDING THE OTHER PRODUCT AND

WE NEED TO LOOK AT OTHER THINGS

SUCH AS CELL CATHETER SYSTEM BY

COMPATIBILITY, FEASIBILITY OF

THE FORMS OF THE PROCEDURE,

RETENTION, DISTRIBUTION OF THE

CELL PRODUCT, PARAMETERS OF

ADMINISTERING THE DOSE AND

EFFICACY OF THE DELIVERED

PRODUCT.

SO THAT GETS US TO LARGE ANIMAL

SMALL ANIMAL THING WHICH WE'RE

FAMILIAR WITH AND ACTUALLY LARGE

ANIMALS THOUGH GIVE US THE

ABILITY TO USE NUMBERSES AND

KNOCK OUTS AN TRANSGENIC AND

MORE SOPHISTICATED MODELS, THE

LARGE ANIMALS PROVIDE WAS A

COMPARATIVE PHYSIOLOGY, THE

ABILITY TO REALLY REPRODUCE

ANATOMY AND ADMINISTRATION JUST

AS A DRESS REHEARSAL AS WE DO IN

HUMAN.

AND WORK IN ORGANS AN TISSUES

VERY SIMILAR TO THOSE WE FIND IN

HUMAN.

SO I WOULD SAY REALLY IN THE

LARGE ANIMAL WERE ABLE TO

OPERATIONALIZE WHAT WE'RE GOING

TO DO WHEN WE GO TO CLINIC WITH

STEM CELL THERAPY.

IT'S A MATTER OF SCALE.

WHEN YOU THINK ABOUT THE MOUSE

AND HUMAN HEART, A SCALE IS

IMPORTANT.

THINKING ABOUT A BRAIN,

PRACTICAL LEVEL.

SO AS BIT OF A BACKGROUND

THERE'S A DIFFERENT BETWEEN

ANIMALS LIFE SPAN, AMAT MY AND

PHYSIOLOGY AND CO-MORBID FACTORS

ANIMALS DON'T HAVE, EXPERIMENTS

ON YOUNG ANIMALS, VERY, VERY

DIFFERENT IN OUR 80-YEAR-OLD

SMOKER DIABETIC SEDENTARY

PATIENT.

SO WE START ANATOMY IN THE

HEART.

BIG AD VOA VOA KATES HERE, IF

YOU THINK RETRO GRADE DELIVERY

IN A CORONARY SINUS IN HUMAN

HEART THAT'S GREAT BECAUSE YOU

GO INTO THE HEART AROUND THE

BACK, UP THE SIDE AND TO THE

FRONT.

YOU CAN NAVIGATE AND DO HIGH

PRESSURE LOW PRESSURE INFUSION

OF CELLS, THE P YOU GO TO ANIMAL

MODEL THIS GOES INTO THE

SYSTEMIC CIRCULATION, YOU JUST

TOTALLY GOT YOUR SYSTEM MESSED

UP IN A BIG WAY AND YOU CAN'T

USE IT SO THESE ARE THE PITFALLS

YOU HAVE TO WATCH OUT FOR.

SO ONE THING WE DEAL WITH A LOT,

FOR EXAMPLE ISCHEMIC HEART

DISEASE MODELS, IF YOU TAKE A

MOUSE, THIS IS INFARCT AND

MOUSE, THIS IS ABSOLUTELY

NOTHING TO DO WITH HOW INFARCT

IS IN HUMAN.

WE HAVE PATCHY INVOLVEMENT, YOU

DON'T GET A BIG SEGMENT OF SCAR

OR SOMETHING LIKE THIS,

SOMETHING TO TREAT AND LOOK AT

THIS AND THINK ABOUT HOW WE'RE

GOING TO TREAT A PATIENT.

YOU'RE DEALING WITH A SUBSTRATE

THOUGH THIS IS FANTASTIC TO

ANSWER MOLECULAR MECHANISTIC

TYPE QUESTIONS.

IT IS NOT VERY GOOD FOR

OPERATIONALIZING PROCEDURE.

WE DO A BALLOON INCLUSION, HERE

WE CREATE INFARCT.

THIS IS A YOUNG PIG, WITH

PAYTANT ARTERY OF SCAR.

THIS IS A DECENT SURROGATE

FAIRLY SIMILAR TO WHAT WE DEAL

WITH.

OR YOU CAN PUT COILS DOWN, YOU

STOP UP THE MICROVASCULATURE

THAT DOESN'T ALWAYS HAPPEN BUT

IT CAN HAPPEN AND IT'S VERY

IMPORTANT POINT THE THINK ABOUT

WHEN TREATING A PATIENT WITH

ACIEWD CARDIOVASCULAR DISEASE.

SO THESE ARE THINGS THAT GET

PICKED UP, SOMETIMES THEY GET

LOST IN MODELS.

HERE IS A MODEL OF CHRONONIC

ISCHEMIC AND VERY SLOW FLOW DOWN

THE CIRCUMFLEX SO THESE

BASICALLY SWELL UP AND CAUSE

CONSTRICTION OF CORONARY ARTERY

AND YOU CREATE A MIX OF INFARCT

WITH -- YOU CAN SEE IN THE

CIRCUMFLEX TERRITORY INFARCT AND

ISCHEMIA, AND IT IS A A DECENT

MODEL OF CHRONIC ISCHEMIA,

BIGGEST PROBLEM IN THE WORLD IN

TERMS OF TYING OF DISEASE.

WHEN YOU CREATE THAT, YOU CAN BE

HELPFUL IN SOME ASPECTS.

HERE IS A STRESS ECHO AND IF YOU

LOOK AT THE KAPPA, NORMAL

WITHOUT AN AMYLOID CONSTRICTOR

AND YOU SEE ALTERATION

CONSISTENT WITH ISCHEMIA, WHEN

YOU USE THIS.

SO SOME THINGS ARE HELPFUL.

IF YOU LOOK AT CORONARY ANATOMY

USING DOG MODELS, BACK IN THE

DAYS TRYING TO REDUCE INFARCT

SIZE, COLLATERALIZATION IS

DIFFERENCE AND GOT LED THE WRONG

WAY BECAUSE OF ANATOMIC

VARIABLES.

DIASTOLIC FUNCTION, THIS IS A

DOPPLER PROFILE OF NATURAL

INFLOW OF HUMAN AND A WAVE IS

DUE TO CON TRAT SHUN, SO THIS IS

NORMAL PATTERN.

THIS HIGHER IS CONSISTENT WITH

FUNCTION OR STIFFER HEART THAT

FILLS AT HIGHER PRESSURE SO THIS

IS SOMETHING USEFUL, VERY USED

IN CLINIC.

HERE IS PROFILE OF A PIG AND

THEY START WITH ALTERED E TO E

RAISH SO YOU DON'T DO MUCH IN

TERMS OF DIE STOLG, YOU HAVE TO

BE AWARE OF PITFALLS THAT HAPPEN

WHEN YOU USE ANIMALS.

ENDOTHELIALIZATION, IF YOU LOOK

AT ARTERIES AFTER PUTTING A

STINT IN, A PIG IT (INAUDIBLE)

REALLY QUICK IN TWO WEEKS,

REALLY IMPRESSIVE.

A RAN PIT TAKE THERE'S WEEKS.

WE PROBABLY TAKE SOMEWHERE,

MAYBE LONGER THAN THAT.

BUT IT DOESN'T MEAN YOU CAN'T

USE THAT MODEL AND MAKE

SIGNIFICANT INTERPRETATIONS AND

BE ABLE TO PLACE A HUMAN STINT

IN A PIG AND OBSERVE IMPORTANT

THINGS SO BUT YOU HAVE TO BE

MINDFUL OF THE SCENARIO THAT

YOU'RE USING AND TAKE TECHNOLOGY

LIKE THIS, LIKE OCT WHICH IS

SOMETHING WE USE CLINICALLY

EVERY DAY, GO IN AN EVALUATE

HERE IS ACUTE IMPLANTATION, YOU

SEE THE SIDE BRANCH, HERE IS --

YOU SEE THE STRESS, TISSUE OVER

THE SIDE BRANCH SO WE CAN USE

THIS IN THIS EXAMPLE AND

ANALOGOUSLY PERFECTLY WELL,

SOMETIMEIOUS DONE KNOW IF YOU'RE

IN THE HUMAN CATH LAB OR ANIMAL

LAB BUT THINGS ARE SIMILAR.

SO SOMETIMES THESE THINGS ARE

VERY HELPFUL.

SO BACK TO MY FRAMEWORK, SAFETY

OF THE PROCEDURE CELLULAR

PRODUCT, CATHETER

BIOCOMPATIBILITY, FEASIBILITY OF

PERFORMANCE, RETENTION,

ADMINISTRATION, AND EFFICACY OF

THE PRODUCT.

I USE THE HEART AS BACKGROUND

BUT I THINK THERE YOU CAN DRAW

PARALLELS IN THE OTHER FIELDS.

SO WE CAN DO THIS LOOK AT THE

BIG PICTURE IN A FEW DIFFERENCE

WAYS, WE CAN GO BACK AND GIVE

IV, WHICH IF YOU'RE TRYING TO

TARGET AN ORGAN SNOT THE BEST

WAY.

JOSH IS HERE, HIS STUDY WHERE

THEY FIRST GAVE MSCs THEY GOT

THAT IMPROVED PFTs GIVING TO

PATIENTS WITH INFARCT, BECAUSE A

LOT OF THE CELLS OBVIOUSLY GO TO

THE LUNGS.

IF YOU WANT TO FOCUS A LITTLE

BIT MORE ON THE ORGAN YOU CAN

GIVE RETRO GRADE ADMINISTRATION

LIKE I MENTIONED IN THE SINUS OR

MAJORITY OF ACUTE MI CLINICAL

WORK IN STEM CELL THERAPY AND

ESPECIALLY OVER IN EUROPE BUT

NOW IN THE U.S. IS GIVING

INTERCORONARY INFUSIONS.

VERY ELEGANT TO GIVE CELLS IN

THE DISTRIBUTION OF THE INJURY

WHICH IS EXACTLY WHAT YOU'RE

DOING.

YOU RUN INTO THE PROBLEM OF

HOMING AND RETENTION OF THE CELL

WHICH IS A DIFFERENT PROBLEM.

OR INSTEAD OF A VASCULAR ACCESS

YOU CAN DO DIRECT INJECTION SO

IF YOU HAVE AN OPEN HEART YOU

CAN INJECT DIRECTLY OR AS WE

PREFER TO DO USE A CATHETER TYPE

SYSTEM WE CAN DO IT IN A

NON-INVASIVE FASHION.

IN THESE CATHETERS YOU HAVE SEEN

TODAY THIS IS THE TECHNOLOGY NO

LONGER IN USE BUT SOMETHING YOU

CAN NAVIGATE THE H VENUS SYSTEM

OF THE HEART, ULTRASOUND AND

GUIDE NEEDLE TO THE MYOCARDIUM.

THIS IS A BALLOON WITH A NEEDLE

AND YOU HAVE SEEN THIS BEFORE

HERE PRESENTED WHERE YOU CAN PUT

CELLS INTO THE ARTERY, IT WORKS

AN AN INTERESTING WAY THE TO GET

CELLS THERE.

YOU CAN DO REGULAR TWO

DIMENSIONAL FLUOROSCOPY GUIDED

CATHETERS OR HELIX CATHETERS.

SOME ARE NO LONGER PRESENT OR

YOU CAN GET MORE SOPHISTICATED

SYSTEM YOU CAN MAP A HEART,

CREATE A THREE DIMENSIONAL

SHELL, NAVIGATE AND IDENTIFY THE

AREA, THAT YOU'RE GETTING INTO

AND INJECT THE CELLS L IN A

TARGETED FASHION.

IN THE CARDIAC WORLD THERE'S A

FAIR AM OF LITERATURE COMPARING

THE EFFICACIES, ADMINISTRATION

THOUGH ONE IS SPECIFIC TO THE

COMPARISONS MADE, THERE IS A

FAIR AM OF LITERATURE SO IF

YOU'RE STARTING TO THINK ABOUT

HOW YOU DELIVER THERE ARE A LOT

OF RESOURCES TO LOOK AT.

FOR EXAMPLE, HERE YOU HAVE A

CATHETER, THIS IS A MYOSTAR

CATHETER, A NEEDLE THAT TRANSITS

THROUGH THIS WHOLE THING SO THIS

IS RETRO GRADE AND THE AORTIC

VALVE AND INTO THE MYOCARDIUM.

YOU HAVE TO THINK IN TERMS OF

DELIVERY ALL THE WAY FROM HOW

YOU FILL THE SYRINGE.

IF YOU THINK ABOUT STORAGE WHERE

THE CELLS ARE, FOR EXAMPLE IN A

PRE-CLINICAL STUDY WE HAD, WE

GET FROZEN CELLS AT EXACTLY THE

RIGHT DOSE AND VOLUME DOSE, BUT

WE CAN NEVER GET THE TOTAL

VOLUME OUT OF THE BAG.

HOW WOULD YOU LIKE TO GO O THE

CLINIC AND GET THE DOSES IN 3

CCs BUT YOU CAN'T GET IT OUT

OF THE BAG SO SIMPLE BUT

IMPORTANT THINGS YOU NODE TO GO

THROUGH TO UNDERSTAND HOW YOU'RE

GOING TO BE ABLE TO DO THINGS

MORE PERFECTLY WHEN YOU GET INTO

THE CLINIC.

SO YOU GOT TO THINK ABOUT

NEEDLES, COMPATIBILITY, IS THERE

CLUMPING OF THE CELLS, WHAT

ABOUT THE VIABLE, CAN YOU

TRANSIT CELLS THROUGH NEEDLE

THROUGH A CATHETER, ARE THEY

VIABLE ON OTHER SIDE, YOU GET

THE SAME NUMBERS, DO YOU GET THE

SAME KIND OF PRODUCT YOU GET

FROM ONE SLIDE TO THE OTHERS.

SO THESE ARE STUDIES YOU DO

BEFORE YOU EVEN REALLY GET

STARTED, SO HERE YOU HAVE AN

EXAMPLE OF A DIFFERENT CATHETER,

HELIX CATHETER HAS A COURSE

SCREW WITH IT, INTUITIVELY MAKES

A LOT OF SENSE THAT'S USED TO

DELIVER CELLS AS WELL.

THE SAFETY AND PERFORMANCE OF

THE PROCEDURE.

IN HEART ONE OF THE MAIN PROBLEM

IS PERFORATION, IF YOU USE A

CATHETER FROM INSIDE OUT YOU CAN

GO RIGHT THROUGH THE HEART.

YOU CAN SEE BLOOD ON THE

TRANSLIEU SENLY ON THE OTHER

SIDE OF THE PERICARDIUM SO THIS

IS WHAT WE'RE NOT TRYING TO GET.

IF YOU DO THIS ENOUGH AND USING

A LARGE ANIMAL MODEL YOU MIGHT

FIND OUT WITH THE HELIX CATHETER

IF YOU GET ENTHUSED AN TWIST

THAT TOO MANY TIMES YOU WILL

TWIST THROUGH THE MYOCARDIUM SO

THESE ARE LESSONED YOU CAN

LEARN.

HERE YOU CAN SEE A SUB HEMATOMA

WITH A MYOSTAR CATHETER AND WE

KNOW FOR EXAMPLE, YOU CAN HAVE

SMALL HEMORRHAGES AND THAT IS

RELATED TO VOLUME.

SO THAT'S ONE REASON WE HAVE

LEARNED TO RESTRICT THE VOLUME

THAT WE GIVE WITH EACH INJECTION

TO TRY TO MINIMIZE THIS KIND OF

THING.

BUT IN ESSENCE THIS IS A FAIRLY

COMMON FINDING NOT NECESSARILY A

BAD THING.

HOW ABOUT GIVING SAY MSCs TO

THE CORONARY.

SO THIS STUDY THAT WAS PUBLISHED

A WHILE BACK, SHOWED THERE'S A

SPEED LIMIT FOR PUTTING MSCs,

THEY'RE BIG STICKY CELLS, YOU

CAN PUT BONE MARROW CELLS DOWN

THE CORONARY, NO PROBLEM, BUT IF

YOU PUT THEM DOWN TOO FAST YOU

CAN GET NO REFLOW AND BASICALLY

THAT'S WHAT THIS IS, THE ARTERY

STOPS FLOWING AND MANY ANIMALS

IN THIS GROUP DIED AND YOU CAN

SEE THE MSCs -- ACTUALLY THE

GREATEST RETENTION IN THIS CASE

IS WITH INTRACORONARY BUT FOR

THIS REGION, NOT FOR THE REGION

OF EFFICACY OF DELIVERY.

SO A LOT OF THINGS CAN BE

LEARNED.

WE CAN LEARN RISK THIS CATHETER

IS GOING INTO A LEFT MAIN

CORONARY ARTERY.

WHEN YOU'RE TREATING A

7-YEAR-OLD WITH A LEFT STENOSIS

AND CORONARY DISEASE YOU DON'T

WANT TO PUT YOUR CELL DELIVERY

CATHETER DOWN THE CORONARY

SYSTEM AND CREATING A NEW

PROBLEM WHICH YOU DIDN'T HAVE.

YOU CAN DO THINGS, HAVE A FELLOW

THAT TIED UP A CORD WITH A

MYOSTAR CATHETER AND RIPPED SOME

PART OUT OF THE MUSCLE SO YOU

LEARN TECHNIQUE, HOW YOU

MANIPULATE A CATHETER, WHAT ARE

THINGIOUS DO TO STAY OUT OF

TROUBLE.

SO THESE PROCEDURAL THINGS, THIS

IS A LONG LIST BUT SOME OF THE

THINGS WE HAVE COME UP WITH

WORKING TOGETHER WITH CEBR TO

ACTUALLY TAKEN OUT OF PROTOCOL,

SOME OF THE STOPPING RULE THINGS

WE HAVE LEARNED.

HOW WE MANAGE A PROCEDURE, HOW

TO DECIDE WHEN TO STOP, HOW WE

KNOW IF ARRHYTHMIA IS OKAY OR WE

CAN GO FURTHER.

THESE ARE THINGS WE WORK OUT

WITH EXPERIENCE AS YOU GAIN

HUMAN EXPERIENCE.

WHAT ABOUT SECURITY OFFICERTY OF

THE CELLULAR PRODUCT?

THERE'S ALL KINDS OF PROBLEMS

THAT CAN HAPPEN IN TERMS OF

GENETIC MODIFICATION, EXPANSION

OF THE CELL IMMUNE RESPONSE,

INTERESTING EXAMPLES OF THAT IN

APPROPRIATE DIFFERENTIATION,

MIGRATION AND TRAFFICKING,

DR. FRANK JUST TALKED ABOUT

THAT.

UNCONTROLLED PRIF RATION OF

TUMORS.

THIS IS VERY IMPORTANT ASPECT

AND A GREAT EXAMPLE VIE BLAST,

ONE THING THAT WAS MAINSTREAM A

WHILE BACK IS SKELETAL MYOBLAST

IN HEARTS SO ALL THE

PRE-CLINICAL WORK WAS DONE BUT

WHEN THE CLINICAL WORK CAME OUT

PEOPLE WERE DROPPING LIKE FLIES

BECAUSE THEY HAD VENTRICULAR

ARRHYTHMIAS AND DROPPED DEAD.

THEY WENT BACK TO THE DRAWING

BOARD AND YOU CAN SEE

CONTROVERSY CONFLICTING CLINICAL

DATA.

THAW TRIED TO INDUCE IT AGAIN,

NOT THAT THEY MISSED THE VT OR

THE F IN THE ARIT ARRHYTHMIAS IN
THE

ANIMALS, IT'S THE ANIMALS DON'T

HAVE THE ARRHYTHMIAS IN THE

SKELETAL MYBLAST AND THE HEART.

SO YOU CAN ONLY GO SO FAR IN AN

ANIMAL MODEL AND SOMETIMES NO

MATTER HOW GOOD A JOB YOU DO

YOU'RE NOT GOING TO BE ABLE TO

REPRODUCE THINGS.

HERE IS AN EXAMPLE OF CORED

BLOOD CELLS, HERE IS THE HEART,

HERE ARE THE DOTS OF INFARCT.

AND IN THIS CASE YOU CAN SEE --

THIS IS TALKED ABOUT, YOU USE A

XENOGRAPH MODEL, THIS IS

PUBLISHED, VERY SIMILAR TYPE

SITUATION WHERE YOU CAN SEE

ALONG THE INFARK BORDER ZONE

HERE SIGNIFICANT REACTION AND

THIS IS DESPITE CYCLE SPOARN

THERAPY.

AND SO IT'S VERY IMPORTANT

NUMBER ONE TO USE HISTOLOGY

CAREFULLY AND IT'S LIKE KIND OF

LIKE A NEEDLE IN A HAY STACK YOU

HAVE TO FIND WHERE THE

INJECTIONS ARE, IF YOU DON'T

SLICE IN IN THE RIGHT PLACE YOU

GO RIGHT PAST IT AND MISIT, AND

NOT EVEN KNOW IT'S THERE.

LOOK AT THE AMOUNT OF REACTION

YOU'RE GETTING FROM THESE CORED

BLOOD CELLS THAT ARE SUPPOSED TO

BE OKAY.

THIS IS AN INTERESTING PART.

TBES WHAT, THE -- GUESS WHAT,

THE CONTROL DID WORSE, THE

TREATMENT ANIMALS IN THIS IN A

FUNCTIONAL STANDPOINT DID

BETTER.

IF YOU MISTHE HISTOLOGY, AND SAY

THIS IS GREAT, THE CELLS ARE

WONDERFUL, EJECTION FRACTION

DETERIORATES LESS AND THIS IS A

GOOD PRODUCT.

SO YOU HAVE TO REALLY BE

CAREFUL, I HATE TO USE THE WORDS

FROM THE PHILOSOPHER FROM YOGI

BERRA BUT YOU CAN OBSERVE A LOT

BY WATCHING AND YOU DO THESE TO

LEARN WHAT YOU'RE GOING DO, THIS

IS AN IPS CONFERENCE SO TUMOR

FROM IPS MOUSE EMBRYONIC

FIBROBLASTS.

SO THIS IS INTERESTING, IN THE

LARGE ANIMAL YOU CAN USE

IMMUNOSUPPRESSION, AS OPPOSED TO

KNOCK OUT OR IMMUNOCOMPROMISED

MODEL IN A RODENT.

SO WE'RE LOOKING AT DOING A MSC

EXPERIMENT AND WE KNOW IN THE

HUMAN, THIS IS WELL KNOWN, ALLO

GENIC REJECTION ISN'T PRESENT

AND WE ACCEPT THIS, AND CLINICAL

TRIALS HAVE BEEN DONE, MSCs

ARE HYPERIMMUNOGENIC, THEY DON'T

EXPRESS MHC CLASS 2.

AND CREATE AN ENVIRONMENT WHERE

THEY SECRETE CYTOKINES THAT ARE

ANTI-INFLAMMATORY, EXPRESSED I

CAM AND V CAM AND MECHANISMS

WHICH THEY ARE FLY UNDER THE

RADAR OF IMMUNOLOGY.

IN THE PIG WORLD IN THE KIDNEY

INJURY MODEL THERE WAS LIMITED

IMMUNE MODULATING ACTIVITY.

IN ANOTHER STUDY THEY WERE

IMMUNOGENIC IN VITRO BUT NOT IN

VIVO SO CONTRADICTORY DATA IN

TERM IF YOU USE MSC ALLO

GENICALLY FROM PIGS, INTO PIGS

THERE SEEMS TO BE A PROBLEM.

SO OUR GROUP DID WORK, WE WANTED

TO LOOK AT THE DIFFERENT BETWEEN

THE SPECIES.

SO TGF BETA RELEASE IS KNOWN TO

HAPPEN AND IS IMMUNOPROTECTIVE

IT HAPPENS IN HUMANS BUT YOU CAN

SEE IN YOU CAN TAN PIGS YOU

DON'T ARE THAT RELEASE.

ON THE OTHER SIDE OF THINGS YOU

CAN SEE THAT THERE'S MHC-2

UP-REGULATION THAT IS VERY

SIGNIFICANTLY HIGHER IN THE

YORKSHIRE VERSUS THE YUCATAN

PIG.

THIS IS EQUAL TO WHAT WE SEE IN

HUMANS.

SO NOT A GOOD THING IN TERMS OF

RED FLAG FOR LYMPHOCYTES.

SO THIS IS SOMETHING IF YOU'RE

PREPARING AN EXPERIMENT THAT YOU

NEED TO GET ANSWER TO, THIS WILL

HELP YOU UNDERSTAND THIS IS NOT

THE ONE TO WORK WITH.

HERE YOU SEE THE REACTION GIANT

CELLS INCREDIBLE REACTION IN

ALLO GENIC MSC IN PIG PRODUCT.

WE HAVE RAC OF UP REGULATION IN

YORKSHIRE AND YUCATAN PIG AS

OPPOSED TO HUMAN CELLS SO THESE

ARE IMPORTANT ASPECTS.

IF WE LOOK AT EMBRYONIC

CARDIOMYOCYTES IN A PIG MODEL

WHICH IS EXTENSIVE, YOU HAVE TO

DO IMMUNOSUPPRESSION, EXTENSIVE

IMMUNOSUPPRESSION, INCREDIBLE

HEMORRHAGES YOU CAN COMBAT THE

PROBLEM NO MATTER HOW BAD AS A

FLIGHT SIMULATOR, THAT'S SORT OF

THAT TRANSLATIONAL ASPECT OF

BASICALLY HOW TO GET THE JOB

DONE.

FOR EXAMPLE WE CREATE A

MAGNETICALLY GUIDED CATHETER TO

MAP ON AN ALGORITHM, INJECT --

YOU CAN BE IN CONTROL LIKE A

CASE IN EUROPE AND BE IN THE US.

IT IS A VERY SOPHISTICATED

SYSTEM WE HAVE DONE TWO CASES IN

EUROPE PCR BUT IT'S NOT TAKEN

FORWARD GIVING LACK OF FUNDING,

BUT WHAT DR. FRANK WAS TALKING

ABOUT WE CAN USE MAGNETISM TO

GREAT ADVANTAGE AN IN THE JUST

IN THIS CATHETER SYSTEM I SHOWED

YOU BUT MANIPULATE VECTORS IN

SPACE AND PATIENT IN THE MIDDLE

OF THAT SPACE.

I CAN FOR SEE A DAY TO

MAGNETICALLY NAVIGATE CELLS

WITHOUT CATHETERS AND THINGS OF

THAT NATURE.

WHAT ABOUT RETENTION AND

DISTRIBUTION IN GOLD STANDARD

WHERE YOU CAN USE IN THIS

NANOPARTICLES AND PUT IN LINEAR

ACCELERATORND KNOW HOW MANY

CELLS YOU DELIVER.

HERE IS CATHETER STUDY AT ONE

SPECIFIC CATHETER WITH ONE CELL,

WHAT ACUTE RETNGS YOU GET, YOU

SEE WITH MYOSTAR CATHETER, WITH

ADRC YOU GET 20% RETENTION IN AN

HOUR, IN AN ACUTE MODEL.

AND HERE IS ONE REASON REASON

THEY GO I WAY.

YOU CAN SEE A VEIN HERE, SO

YOU'RE PLAYING RUSSIAN RAO LET,

THAT'S 1 RUN YOU DONE GET 100%

RETENTION, IF YOU HAPPEN TO HIT

WITH YOUR 27 GAUGE NEEDLE YOU

HAPPEN TO HIT WITH A VEIN THAT'S

OFF INTO THE VENUS SYSTEM.

SO WHAT HAPPENS IS A REPORTER

GENE WORK THAT WE HAVE DONE AND

YOU CAN SIGH THE CELLS THERE YOU

CAN IMAGE WHERE YOU HAVE DONE

AND WE FOLLOW THIS AND SEE THE

CELLS ARE THERE FOR SIX MONTHS

BUT IN A DIFFERENT PATTERN.

SO A BIMODAL ENGRAPHMENT THING

THAT HAPPENS AT 30 DAYS STILL

THERE AT SIX MONTHS AND WE FIND

THEM IN THE LYMPHATIC.

SO IT'S IMPORTANT TO KNOW LONG

TERM WHAT'S HAPPENING.

MABT EFFICACY?

IT'S GOOD TO SEE AND HELPFUL TO

SEE IN THE LARGE AN MA'AM

DESPITE OTHER THINGS YOU'RE

LOOKING AT EFFICACY.

SO HERE YOU SEE INFARCTION,

INJECTED IN CANINE MODEL YOU CAN

SEE HOW THE CELLS, LOOK AT THE

NUCLEI DISTRIBUTING BEAUTIFULLY

IN THE BORDER ZONE OF INFARCT

LIKE YOU SPREAD THEM OUT

UNIFORMLY AND YOU SEE A

FUNCTIONAL EFFECT OF THE

DIFFERENT KINDS RELATING TO THE

DIFFERENCE KIND OF DELIVERY IN

THIS CASE TRANSENDOCARDIAL

DELIVERY BETTER IN TERMS OF

FUNCTION AND VOLUME.

THEN YOU SEE HISTOLOGICAL CORE

LIT OF THAT EFFICACY.

THIS ALL COMES TOGETHER.

SO HOPEFULLY YOU CAN -- DID I

LOSE MY SLIDES HERE?

PUTTING THINGS TOGETHER.

HOPEFULLY THIS ALL DOES COME

TOGETHER AND HERE IS A LARGE

ANIMAL MODEL.

SO WE CAN LOOK ALL THE DIFFERENT

THINGS, IN THE LARGE ANIMAL,

UNDERSTAND THE QUESTION,

UNDERSTAND THE ABLE OF THE

MODEL, THE PITFALLS OF THE MODEL

AND REALLY AT THE END OF THE DAY

SET OURSELVES UP FOR SUCCESS AND

THE MODEL THAT REALLY MATTERS

WHICH IS THE HUMAN.

SO THAT'S THE END OF MY TALK BUT

I HAVE ONE LITTLE ANECDOTE THAT

I THINK YOU'LL FIND INTERESTING

WHICH IS -- RELATED TO ANIMAL

MODELS.

SOMETIMES IT'S NOT ROCKET

SCIENCE.

SCIENCE -- SCIENTISTS AT NASA

BUILT A GUN SPECIFIC HI TO LUNCH

AT DEAD CHICKENS, MILITARY JET

SPACE SHUTTLE AT MAXIMUM

VELOCITY TO SIMULATE INCIDENTS

OF COLLISION WITH AIRBORNE FOUL

TO TEST THE STRENGTH OF

WINDSHIELDS.

BRITISH ENGINEERS HEARD THE GUN

AND WERE EAGER TO TEST ON

WINDSHIELDS OF NEW HIGH SPEED

TRAINS.

WHEN IT WAS FIRED EVERYONE WAS

SHOPPED WAS CHICKEN HURDLE CRASH

SHATTER PROOF SHIELDED AT THE

SMITH REENS, SNAPPED THE

ENGINEERS BACK INTO AND IMBEDDED

ITSELF INTO THE BACK OF THE WALL

CABIN LIKE ARROW SHOT FROM A

BOW.

THE HORRIFIED BIER SENT NASA THE

DISASTROUS RESULTS OF EXPERIMENT

ALONG WITH DESIGNS OF THE

WINDSHIELD AND BEGGED THE

SCIENTISTS FOR SUGGESTIONS.

NASA RESPONDED WITH A ONE LINE

MEMO.

ANY TAKERS?

THAW THE CHICKEN.

THANK YOU VERY MUCH.

[APPLAUSE]

>> THANK YOU.

ANY QUESTIONS?

THAW THE CHICKEN.

SO I THINK ONE OF THE POINTS YOU

BROUGHT UP ABOUT THE VARIABILITY

IN RESULTS REALLY STEMS FROM --

NO PUN INTENDED, STEMS FROM THE

FACT THAT PEOPLE GROW CELLS IN

DIFFERENT WAYS.

UNTIL WE AGREE NUMBER ONE WHAT

AN MSC IS AND TWO, WHERE IT

COMES FROM, THREE, HOW TO GROW

IT, THIS IS GOING TO BE A

RECURRING PROBLEM IN THIS

PARTICULAR FIELD IN TERMS OF

EFFICACY.

I DON'T KNOW IF ANYBODY WANTS TO

COMMENT ON THAT.

>> IT'S VERY DIFFICULT YOU

ALMOST HAVE TO SPECIFICALLY

DESIGN YOUR PRE-CLINICAL STUDY

TO ANTICIPATE AND ANSWER THE

QUESTIONS THAT YOU NEED FOR THAT

PARTICULAR EMPERIMENT OR THE

PARTICULAR THING YOU WANT TO DO.

THERE'S TOO MANY VARIABLES IN

THE FIELD SO WE DON'T UNDERSTAND

THE VARIABLES.

HEWE CAN SEE IF WE CAN USE THEM

TOGETHER.

Q.HI (INAUDIBLE) ACCESS BIO.

THE EXPERIMENT YOU HAD THE PIG

WHERE YOU SAW THE EFFICACY AND

YOU ALSO SAW PATHOLOGY, WAS THAT

STUDY DESIGNED TO LOOK AT

EFFICACY SO HISTOLOGY EFFICACY

OR SAFETY AS PART OF THAT

EXPERIMENT?

>> THE STUDY WAS DONE A WHILE

BACK.

IT WAS A CANINE MODEL OF ACUTE

INFARCTION WITH (INDISCERNIBLE)

AT THE TIME.

IT WAS SORT OF A FIRST AND LARGE

ANIMAL TYPE EXPERIMENT AND IT'S

KIND OF A HYBRID OF TOXICOLOGY

PHARMACOLOGY PROOF OF CONCEPT,

IT'S NICE WHEN IT COMES

TOGETHER, SOMETIMES IT DOESN'T

AND THEN YOU HAVE TO UNDERSTAND

WHAT'S GOING WRONG.

>> JOSH (INAUDIBLE) UNIVERSITY

OF MIAMI.

GREAT TALK, EMERSON, AS ALWAYS.

I WANT TO ASK YOU ABOUT YOUR

CELL RETENTION STUDIES, IT'S

MENTIONED SEVERAL TIMES TODAY

THAT CELLS DON'T STICK AROUND

VERY LONG.

IN OUR STUDIES WHICH I'LL

PRESENT TOMORROW WE SEE LONG

TERM ATTENTION AND YOU PRESENTED

DATA QUICKLY THAT YOU SAW,

RETENTION UP TO SIX MONTHS AFTER

INJECTION AND SOME MODELS.

HOW DO YOU RECONCILE THESE TWO

SOMEWHAT DIVERGENT CLASSES OF

FINDINGS?

>> THAT'S A GREAT SO YOU HAVE TO

UNDERSTAND WHAT YOU'RE DOINGCH

THIS WAS A PIG MODEL, AND TALK

ABOUT SPECIFICS AUTOLOGOUS MSC

FROM A PIG WITH HS VTC REPORT

--K REPORTER GENE.

THOSE QUESTIONS ARE THERE, THERE

ARE A LOT THERE AT THE

BEGINNING.

IT TOOK SIX YEARS WITH THE FOLKS

ACROSS THE STREET AT MD

ANDERSON.

SO CELLS ARE INITIALLY THERE,

THEY DROP OFF, YOU SEE A SIGNAL

IN 30 DAYS AND THEY DROP OFF

AGAIN BUT THEY'RE STILL THERE AT

SIX MONTHS.

AND WE DID OTHER -- I DIDN'T

SHOW A T LO HERE BUT WE DI

STUDIES TO LOOK AT WE SAW CELL

INCORPORATED INTO LYMPHATIC

ENDOTHELIUM, WE SAW CELL IN THE

LYMPH NODES SO IT'S VERY

REASONABLE, AGAIN, THIS WAS A

SPECIFIC SETTING BUT AUTOLOGOUS

MSCs THESE CELLS DID TICK

AROUND AND AS YOU SEE WHEN YOU

DO A CONTRAST INJECTION IF YOU

SEE CONTRAST INJECTION INTO A

HEART IT LOOKS LIKE A FLAME AND

IF YOU DON'T HIT A VEIN AND IT'S

NOT GOING AWAY, IT STAYS THERE

AND SLOWLY GOES AWAY AND I THINK

ONE OF THE GREAT FORGOTTEN

ORGANS OR VASCULAR SYSTEMS IS

THE LYMPHATIC SYSTEM.

WE'RE DRAINING A LOT OF CELL

PRODUCT INTO THE LYMPHATICS AND

YOU CAN EVEN THINK THAT'S AN

INTERESTING PLATFORM FROM WHERE

CELLS CAN ACTUALLY HAVE AN

EFFECT IN A PARACRINE WAY

LOCALLY ON AN ORGAN.

SO THAT'S INTERESTING, THEY WERE

THERE FOR SIX MONTHS AND THIS

NEEDS TO BE EXPLORED MORE.

>> THANK YOU.

[APPLAUSE]

SO NOW WE HAVE A HALF AN HOUR

BREAK AND THEN WE'RE GOING TO

COME BACK AND MAHENDRA RAO IS

GOING TO LEAD A PANEL DISCUSSION

WITH ALL OF THE SPEAKERS THAT

YOU HAVE HEARD TODAY TO ASK THE

QUESTION WHAT ARE THE CHALLENGES

AND HOW CAN WE ADDRESS THEM.

SO WE'LL BE BACK HERE AT

4 O'CLOCK.

OKAY, WHILE THE SPEAKERS ARE

ASSEMBLING A NUMBER OF YOU ASKED

ABOUT THE AVAILABILITY OF SLIDES

FROM THE SPEAKERS, THE SLIDES

FROM THE FDA WILL BE DEFINITELY

POSTED IN TERMS OF NON-FDA

SPEAKERS, SOME MAYBE VIDEOCAST,

WE'RE STILL GOING TO BE WORKING

ON THAT, YOU CAN CHECK THE

WEBSITE FOR THE MEETING AND NIH

EVENTS IN THE FUTURE BUT NOT

SURE AT THIS POINT IF THOSE

VIDEOCAST LBS AVAILABLE.

-- WILL BE AVAILABLE.

HAVING SAID THAT I'LL TURN IT

OVER TO MAHENDRA.

>> WELCOME BACK AND GOOD

AFTERNOON, EVERYONE.

WHILE EVERYBODY IS GETTING TO

THEIR SEATS, --

>> MORK PHONE.

CAN YOU HEAR ME NOW?

WHAT EVERYBODY IS GET -- WHILE

EVERYBODY IS GETTING TO THEIR

SEATS WHAT I WANTED TO DO IS

ENCOURAGE EVERYBODY TO ASK

QUESTIONS AND I WANT TO SERVE AS

MODERATOR RATHER THAN MY ASKING

MOST OF THE QUESTIONS.

BUT WAPPED TO HOPE TO TRY TO

KEEP A THEME IN THE INTEREST OF

TIME SO WHAT I WANT YOU TO THINK

ABOUT IS SENSE OF QUESTIONS --

SETS OF QUESTIONS RELATED TO

ANIMAL STUDIES YOU HEARD FROM

THE SPEAKERS AND STAR OFF BY

TELLING YOU WHAT I THINK WE

HEARD FROM A LOT OF THE

DIFFERENT SPEAKERS, THE FDA DOES

NOT SAY THAT YOU HAVE TO HAVE A

SPECIFIC ANIMAL MODEL OR NUMBER

OF ANIMAL MODELS SO YOU HAVE TO

DO EVERYTHING IN A STANDARDIZED

WAY BUT IT'S CONTEXT SPECIFIC

AND THEN YOU HEARD FROM EACH OF

THE SPEAKERS HOW THEY HAVE TAKEN

THAT AND LOOKED AT THE SPECIFIC

EXAMPLES IN TERMS OF WHAT THEY

NEEDED TO DO IN DELIVERY OF

CELLS, WHETHER TRACKING OR

TRACING THEIR -- OR IT WAS ON

THE KIND OF CLINICAL TRIALS

STUDIES OW MIGHT NEED TO DO IN

TERMS OF ROCKING AT THE SAFETY

STUDIES OF THE MECHANISM OF

ACTION STUDIES.

SO KEEPING THAT IN MIND, RATHER

THAN ASKING SPECIFIC DETAIL

QUESTIONS, ASK QUESTIONS RELATED

TO THE TOPICS TO ANY OF THE

SPEAKERS BECAUSE THE PEOPLE IN

THE FIELD WITH HANDS ON

EXPERIENCE AND PROBABLY CAN TELL

YOU THINGS NOT ALL SUMMARIZED IN

THE SLIDES THEY HAVE SO KEEP IT

OPEN AND ANYBODY WANTS TO ASK

THE FIRST QUESTION.

COLLIDE (INAUDIBLE) FROM CEDARS

SINAI.

I WANT TO GET BACK TO IMAGING

AND TRACKING OF THE CELLS

BECAUSE THAT SEEMS TO BE A HUGE

ROADBLOCK, EVEN A PATIENT TRIAL,

THE EMORY TRIAL AND NEURAL STEM

CRIEL WITH STEM CELLS AND SPINAL

CORD OF ALS PATIENTS HAVE

PATIENT WHOSE DIED AND CAN'T

FIND THE CELLS THEN THEY HAVE NO

WAY OF KNOWING HUMAN TO HUMAN

WHERE CELLS ARE BECAUSE THERE'S

NO MARKER.

ONE OF THE HOPES IS MALE TO

FEMALE MAY WORK BECAUSE YOU CAN

DO Y CHROMOSOME PROBE, ONE WAY

TO DEFINITELY FIND THE CELL.

(INAUDIBLE) WAS DEAD FOR LONG

TERM TRACING MAY IT WILL YOU

WHERE THE CELLS LIVE IN.

WHAT ABOUT A LIVING TRACE SPHR

IF YOU LOOK A TRACER WITH A

SHORT HALF LIFE ONLY EXPRESSED

BY LIVING CELLS, AT LEAST THAT

WOULD GIVE AN IDEA WHETHER

YOU'RE LOOKING AT A CELL THAT'S

MIGRATING.

ONE IS PAIR TIN THAT PEOPLE ARE

PLAYING WITH BUT THE RESOLUTION

AND SENSITIVITY MAY NOT BE HIGH

ENOUGH.

ANY OTHER LIVING TRACES THAT YOU

WANT TO TALK ABOUT THAT COULD

TELL YOU NOT A MACROPHAGE THAT'S

TAKEN IT OUT BECAUSE IT'S A GENE

EXPRESSED IN THE LIVING CELL

ONCE THE CELL DIE, THE GENE

DISAPPEARS, INTEGRATES TO THE

DNA SO THAT MIGHT -- IF WE HAD

THAT WE ALL NEED THE USE THE

SAME TECHNIQUE AND THIS COMES

BACK TO CORE RESOURCES TO

DEVELOP TRACES, ALL TRYING TO DO

IT IN DIFFERENT LAB.

NIH CORE RESOURCE FOR DEVELOPING

TRACES --

>> CAN I ASK YOU TO EXPAND ON

THE QUESTION A BIT?

LIVING TRACER WHICH IS SHORT

TERM OR LONG TERM DIVIDING CELLS

OR NOT DIVIDING CELLS?

>> IDEALLY THE TRACER ITSELF

SHOULD HAVE A SHORE HALF LIFE IT

DISAPPEARS QUICKLY.

OTHERWISE TAKEN OUT BY

MACROPHAGES AND THE TRACER HAS

TO BE INTEGRATED TO THE GENOME

SO IF THE CELL DIVIDES THE

TRAYERS FOLLOW WITH IT.

PRESUMABLY A LENTIVIRAL

CONSTRUCT TO INTEGRATE AND BRING

UP THE PROBLEM WITH THE FDA BUZZ

NOW YOU HAVE ANOTHER

MODIFICATION TO DEAL WITH.

IF THERE WAS A STANDARDIZED WAY

LIBLLING HUMAN CELLS WHETHER

MESENCHYMAL CELLS, IPS CELLS, I

THINK THE REALLY HELP THE FEEL

MOVE FORWARD BUT FOR EVERYBODY

ON THE PANEL, WITHOUT THAT

TRACER AND MARKER, IN THE EYE OR

BRAIN OR BLOOD OR HEART, WE

REALLY DONE KNOW WHERE CELLS

ARE.

>> YOU WANT TO LOOK AT IF YOU

HAD TO DESIGN SOMETHING, COULD

BE MADE AVAILABLE OR WHAT SHOULD

THE NIH DO IN TERMS OF

ENCOURAGING THIS?

>> IT'S A TOUGH QUESTION BECAUSE

OF THE GENETIC MARKER, ADDING

INTO THE CELL.

YOU HAVE TO GO TO THE COMMITTEE

JUST FOR THE REPORTER AND YOU

HAVE TO KNOW WHETHER OR NOT IT

WILL BE CONTINUALLY BE EXPRESSED

BY THE CELLS OR ULTIMATELY BE

SILENCED AS WELL AS ULTIMATELY

SILENCED YOU DON'T REALLY KNOW

USING IMAGING WHETHER OR NOT

IT'S GOING TO -- WHETHER OR NOT

THE CELLS ARE THERE OR NOT.

AND I THINK EVEN WHEN YOU LOOK

AT SOME OF THE GROUPS FROM

STANFORD OR A VARY OF OTHER

PLACES THAT HAVE DONE -- OR JUST

EVEN A INGLE REPORTER LIKE A TK

GENE, YOU RUN INTO THE ISSUE OF

WHETHER OR NOT THE CELL WILL

ULTIMATELY DIVIDE OR SILENCE IT.

SO THEN YOU'RE LEFT WITH CAN YOU

PUT SOMETHING MORE NATURAL THAT

OCCURS NORMALLY IN HUMAN SO LIKE

A SOUTHERN BORDER OF A VARIETY

OF OTHER THINGS WHICH COULD BE

EXPRESSED TURNED ON WHEN YOU

WANTED TO.

AND THOSE ARE POSSIBILITIES.

THE REASON I ASKED TO PUT THE

PARKINSON SLIDE IN IS BECAUSE

YOU USE A PET REPORTER COME BACK

ANYWHERE DURING THAT PERIOD OF

TIME AND DOPAMINERGIC CELLS

WOULD BE ABLE TO BE DETECTED.

AND IT WAS VERY NICE, VERY NICE

STUDY THOUGH (INDISCERNIBLE) SO

THAT'S WHERE WE HAVE TO GO,

TRYING TO DEVELOP THIS IN A WAY

WHERE THE CELL -- FAIR TIN HAS

ITS OWN PROBLEMS SO JUST TO

ADDRESS YOUR FAIR TIN QUESTION,

MODIFYING THE GENE POOL AND IT'S

STILL NOT CLEAR THOUGH THE MICE

DONE DEVELOP CANCER, WHAT'S

GOING TO HAPPEN LONG TERM WITH

THIS.

SO IF YOU COULD DO THE IPS LEVEL

AND GENERATE A BANK THAT HAS IT

INTEGRATED, THAT MAYBE THE WAY

-- BUT YOU HAVE TO FIGURE OUT

THE THARGT'S GOING TO BE

EXPRESSED HIGH ENOUGH TO BE ABLE

TO GET YOUR BASIC PET AGENT

BECAUSE IT WILL BE A PET PROBE.

>> SO THAT'S REALLY LONG TERM.

ONE OF THE SLIDES PUBLISHED IN

RADIOLOGY A COUPLE OF YEARS AGO

SHOWED WITH THE TRIPLE REPORTER,

THE TK GENE, GFP WHEN HE

IMPLANTED THOSE CELLS INTO A

(INAUDIBLE) USING STANDARD

CLINICAL IMAGING, STANDARD PET

CT, THAT HE HAS ON THE ORDER OF

.8 TO ONE WHEN HE WAS LOOKING

FOR THE MSC WITH BASICALLY

LOOKING FOR A PROBE.

SO THAT'S WHAT 100 MILLION CELLS

IN A MATRIGEL AND WHEN INJECTED

TO SALINE HE COULDN'T FIND CELLS

AT ALL SO THERE'S PROBLEMS LIKE

THAT.

I WOULDN'T RULE OUT THE IRON

BECAUSE THE IRON WILL STAY WITH

CELLS AND GIVES YOU A SORT OF

BACK IN 1999 HN WE FIRST STARTED

WORKING PUBLISHING ON THIS, Y

CELLS MIGRATE, DEAD CELLS DONE.

IT'S A TITRATION SYSTEM TO WORK

ON AND YOU WILL TEND TO SEE

CELLS LATER ON THAT ARE

RETAINING THAT DON'T DIVIDE, BUT

AT LEAST GIVE YOU A STARTING

POINT WHERE TO LOOK FOR AN

AUTOPSY.

I THINK THAT WAS THE WHOLE

INTENT, THE WHOLE INTENT OF WHEN

WE DEVELOP THIS CONCEPT WAS WE

WOULD NEVER REALLY WANT TO TRACK

CELLS SIX MONTHS, 8 MONTHS, TEN

MONTHS, GOING TO COME BACK AND

SAY I STARTED OUT IN THE MS

FIELD, WE'RE GOING TO COME BACK

AND SAY LET'S USE OTHER

TECHNIQUES WHICH WE'LL TALK

ABOUT REMYELINATION AND TALK

ABOUT HEALING OR SOMETHING LIKE

THAT, THAT WOULD ESSENTIALLY

TELL US THAT WITH SPECTROSCOPY,

ADHESION, WITH A VARIETY OF

OTHER PROBES THERE WAS NEW

FUNCTION GOING ON WHICH DIDN'T

EXIST ANY MORE.

>> CAN I ASK TO SORT OF

ADDITIONAL RELATED QUESTION TO

THAT BEFORE WE MOVE ON FROM THIS

TOPIC.

THE TWO RELATED QUESTION ALSO

FOR MOST CASES WE USE TRACERS

WHICH ARE ALREADY APPROVED SO IF

YOU HAVE TO HAVE GET A NEW

TRACER THROUGH THE FDA CLINICAL

TRIAL FOR APPROVAL HOW LONG

WOULD IT TAKE?

IN TERMS OF DOING THAT.

SO THAT'S ONE QUESTION.

THE SECOND IMPORTANT QUESTION IN

TERMS OF BEING ABLE TO TO THIS

VELLED TO REGULATORY AUTHORITIES

AS WELL, WE CAN MAKE A REPORTER

AND DO IT BY HOMOLOGOUS

RECOMBINATION OR PARTICULAR CELL

LINE AN PARTICULAR SITE, WHAT

THE FDA -- WOULD THE FDA ACCEPT

THAT AS REPORTER SYSTEM WHEN

YOU'RE USING A COMPLETELY

DIFFERENT ES LINE OR REPORTER

LINE TO BE ABLE TO DO YOUR

CLINICAL THERAPEUTIC STUDY OR

MAKE THE REPORTER IN EVERY LINE?

BECAUSE THAT MAKES THE PROBLEM

MUCH LARGER.

OR MAYBE DO A QUICK ANSWER.

>> SPEAKING ABOUT IMAGING, MY

UNDERSTANDING IS IMAGING

COMPOUND WOULD REQUIRE FDA

REVIEW BY COLLEAGUE FROM CENTER

FOR DRUG, AT LEAST THAT'S MY

UNDERSTANDING.

>> IT ISN'T AS LONG A PROCESS.

SO A NEW PET AGENT IN PHASE 0

TRIAL, EXPLORATORY IND COULD GET

INTO CLINIC FIRST IN MAN FIRST

IN HUMAN STUDY.

A SHORT PERIOD OF TIME BECAUSE

OF THE DOSING, YOU DON'T NEED TO

HAVE GLP MEANING GET TO THAT

TRIAL QUICKLY.

SO THIS CAN HAPPEN VERY QUICKLY

IF YOU HAVE THE RIGHT ORDER AND

RIGHT CELL BUT REAL EYE THIS IS

PROBABLY A NORMAL VOLUNTEER, YOU

WANT PROBABLY MORE FOR PATIENTS

THAT ARE BASICALLY NEAR END OF

LIFE SO IT'S LIMITED TO WHAT

KIND OF POPULATION.

YOU CERTAINLY CAN GET A NEW

AGENT TO THE AT LEAST PROOF OF

PRINCIPLE CLINICAL TRIAL VERY

QUICKLY AS LONG AS YOU DEAL WITH

PET.

IF YOU DEAL WITH MR, IT'S A LOT

LONGER TIME COURSE.

>> I WOULD COMMENT, WE CONSIDER

IT LABELING OURSELVES WITH IRON

WHICH IS EASY TO DO AND THERE'S

CLINICAL EXAMPLES OF IT BUT WE

FIGURE OUT QUICKLY THE

REGULATORY HURDLES OF ADDING IN

IRON LABELING TO EVERYTHING ELSE

SO EXTREME THAT IT WASN'T WORTH

IT.

>> LET ME COMMENT.

ESSENTIALLY WHAT WE DID WITH

KAREN AND CITY OF HOPE WE LET

THE IND GO THROUGH DISCUSSION

WITH THE FDA AND CAME BACK WITH

(INAUDIBLE).

-- AMENDMENT.

AMENDMENT UP FRONT IS AFTER

SPENDING --

>> YOU GOT THE IND THEN HAD

AMENDMENT WITH LABEL.

>> COME BACK (OVERLAPPING

SPEAKERS)

>> IT WAS TO GET ESSENTIALLY

WHAT WAS IN THE NATURE MEDICINE

ARTICLE.

>> SO YOU CAN SEE THERE'S

CLEARLY PROBLEMS WITH BEING ABLE

TO LABEL AND TRACK CELLS AND

WHILE WE HAVE MANY TECHNOLOGIES

THERE'S ISSUES WITH USING THOSE

TECHNOLOGIES AND TISSUES -- YOU

SHALL SHOES HOW EXACTLY WE'LL DO

IT AND WHATTISH -- ONE ISSUE NOT

DISCUSSED BECAUSE WE DON'T HAVE

TIME IS EVEN FOR PULLING IN

REPORTER GENES IN HUMAN CELLS

THE BIG ISSUE IS SILENCING THAT

WE HAVE TO SOLVE WHICH IS NOT AN

EASY ISSUE TO SOLVE.

ONE YOU SHALL SHOE BROUGHT UP

WITH THIS TOPIC IN TERMS OF

IMMUNE RESPONSE, ET CETERA, TO

DO TRANSPLANT REHOMOLOGOUS

SPECIES.

YOU HEARD FROM DR. PERIN ISSUES

WITH THAT BECAUSE YOU DONE HAVE

A HOMOLOGOUS CELL AND PEOPLE

THAT KNEW THAT IN SOME FASHION

WITH MSC FOR EXAMPLE, MOUSE MSC

ARE DIFFERENT FROM LOOKING AT

MSC IN HUMAN AND WE HAVE KNOWN

THAT FOR A LONG TIME AND YOU HER

ABOUT AS WELL AS WHAT HAPPENS

WITH MSC CLASS ANTIGENS AND WE

HAVE A MORE MAJOR PROBLEM WITH

IF YOU DONE DEFINE YOUR PRODUCT

YOU CAN'T COMPARE OUT IN ANY

CASE BECAUSE YOU DON'T KNOW WHAT

WILL BE THE EQUIVALENT PRODUCT

WHEN YOU'RE MAKING IT FROM THAT

PARTICULAR SPECIES.

SO THIS IS A QUESTION FOR

EVERYBODY HERE, IS THERE DATA

OUT THERE WHICH SAYS I CAN LOOK

UP AND SAY OH, MY GOD I

SHOULDN'T USE A PIG MSC FOR THIS

EXPERIMENT BECAUSE U CAN'T DO

THIS HOE MOLL GOWS EXPERIMENT OR

VICE VERSA IN NEURAL STEM CELL

AND FOR US IT WAS VERY DIFFICULT

WE COULD NEVER FIND THAT DATA,

WHEN IT DOES EXIST BUT IN VIVO

PEOPLE LOOKING AT CELLS IN

CULTURE TURNS OUT THE MOUSE

CELLS HAVE TENFOLD HIGHER

RESPONSE TO HUMAN INHIBITORY

FACTOR THAN HUMAN CELLS DO.

IT'S CROSS SPECIES.

THEY RESPOND BETTER TO HUMANS

THAN MOUSE.

SO NOW YOU HAVE A BIG PROBLEM IN

BEING ABLE TO INTEGRATE THAT

DATA OR DO ANY KIND OF DOSING

EXPERIMENT.

AND I'M SURE THERE ARE ANY ONE

OF YOU CAN TELL US.

IS THERE SOME SOLUTION OR SHOULD

WE WRITE IT OFF AND SAY YOU CAN

DO HOMOLOGOUS CELL EXPERIMENTS

THAT IS A BYPASS FOR THE SOW

KNOW ISSUE AND WE HAVE TO SOLVE

THE XENO ISSUE IN TEMS OF DOING

ANIMAL MODEL -- IN TERMS OF

DOING ANIMAL MODEL EXPERIMENTS.

ANYONE?

>> I'LL TAKE A STAB AT IT.

CASEY, CORRECT ME IF I'M WRONG.

BUT SANBIO HAD AN ISSUE USING

HUMAN CELLS AND THAT'S STROMAL

CELLS IN RAT.

THE PROBLEM WAS CELLS DON'T

SURVIVE IN RAT SO THE FDA COMES

BACK WITH IF THEY SURVIVE HUMAN,

BECAUSE HUMAN TO HUMAN WHAT'S

GOING TO HAPPEN?

ARE THEY GOING TO SURVIVE IN

TEAR TOME AND SO FORTH SO THEY

REQUIRED A RAT TO RAT STUDY.

WHICH WAS DONE BUT NOT MUCH MORE

IN LENGTH BECAUSE THEY DIDN'T

STICK AROUND LONG IN RAT TO RAT

EITHER.

THERE'S SO MANY ISSUES.

YOU DON'T KNOW, I DON'T THINK

THERE'S GOOD DATA WHAT THE

ANGIOGENIC DETERMINANTS ARE OF

THE CELLS.

MANY CELLS AS I ALLUDED TO MAY

NOT HAVE THE HLA DETERMINANT.

YOU CAN SORT FOR THAT SO IN THE

BIOSTUDIES, THERE'S NO

IMMUNOSUPPRESSION AND THE THE

CELLS PROVIDE IMMUNOSUPPRESSION

BUT BY THEMSELVES EXCLUSION

CRITERIA ARE PATIENTS WHO HAVE

ANTIBODIES TO THE HLA ANTIGENS

EXPRESSED ON THE CELLS THAT

EXCLUSION CRITERIA, SO YOU CAN

GET AT IT THAT WAY BUT IT'S VERY

DIFFICULT USING HUMAN CELLS AN

ANIMAL MODELS, I DON'T SEE A WAY

AROUND IT.

MAYBE IF YOU HAVE A HUMANIZED

IMMUNE SYSTEM, THAT'S WHY I

THINK THESE HUMANIZED MOUSE

MODELS ARE VERY, VERY USEFUL.

WE'RE MOVING TOWARDS THAT WITH A

GROUP IN GERMANY USING A

HUMANIZED MOUSE.

>> THE EXTENSION WHICH CAME UP

IN THE LAST MEETING, WE ALWAYS

TALK IMMUNE SUPPRESSION WITH

ALLO GENIC MODELS, AND THERE'S

NO QUICK WAY TO TEST IT IN A

XENO MODEL ALREADY

IMMUNOSUPPRESSING.

IF YOU GO BACK AND LOOK AT THE

LITERATURE WITH THE CLINICAL

TRIALS THAT HAVE BEEN DONE IN

HUMANS, EVERYTHING IS USING

IMMUNE SUPPRESSION PROTOCOL AND

WE DON'T REALLY KNOW WHAT THAT

IS.

AND SHOULD WE BE DOING SOMETHING

ABOUT THAT OR IN TERMS OF DOING

-- THE ANSWER WE DONE KNOW WHAT

WE NEED TO?

>> THANK YOU FOR PRESENTING MY

TALK FOR TOMORROW.

NO --

>> IT WASN'T PLANNED.

>> FROM SANB ISHO AGAIN, TO

EXPAND EVER SO SLIGHTLY.

YES, WE WERE ASKED TO DO

HOMOLOGOUS STUDY USING RAT

DERIVED MSC IN OUR

TUMORIGENICITY STUDY.

WE FOUND DURING THE COURSE OF

THAT STUDY, PAM KNOWS THIS QUITE

WELL, MSCs IMPLANTED IN THE

BRAIN REGARDLESS OF SIN GENEIC

MOUSE MSCs IN THE BRAIN ARE BY

INNATE IMMUNITY.

THAT'S WHAT WE SAW.

AND FARCE DIFFERENCES BETWEEN

HUMAN AND RAT MSCs AND BUY

LODGE DAL PROPERTY WE WERE

CONCERNED ABOUT THAT GOING INTO

THE STUDY.

TUMORIGENICITY STUDY.

I WILL PROVIDE MORE BACK GROUND

ON THAT TOMORROW.

IT WAS A BEAUTIFUL INTRODUCTION.

THANK YOU.

>> YOU HAD A QUESTION?

>> I THINK DR. RAGANATHAN THIS

MORNING SUMMARIZED THINGS

ESPECIALLY AT THE STAGE FOR IN

ACADEMIC REVIEW MOSTLY REVIEWER

AND GRANT WRITER MYSELF RECENTLY

ENCOUNTERED A SITUATION WHERE I

HAD ROI I NEEDED HOMOLOGOUS

MODEL.

I DID IT AND THEN PUBLISHED IT

WITH PAPER REVIEWER TOLD ME IT

WASN'T RELEVANT TO HUMANS.

KIND OF NEED TO GET THE SCIENCE

ON BOAR THERE AS TO WHERE WE'RE

GOING TO GO IMAGINE THIS IS

ACROSS THE SPECTRUM OF PEOPLE

PLANNING EMPERIMENTS TO MOVE

THESE FORWARD INTO LATE

PRE-CLINICAL AND EARLY

TRANSLATIONAL STAGES.

ANY SUGGESTIONS?

>> I THINK YOU'RE RIGHT ON

TARGET.

THE ISSUE IS IT'S LANGUAGE OF

DISCIPLINE IN THE FIELD.

-- IT'S LACK OF DISCIPLINE IN

THE FIELD.

I'M ONOLOGIST BY TRAINING AND I

DON'T GO OUT AND DECIDE TO MIX

DRUGS IN ANY SORT OF HAPPEN

HAZARD WAY DEPENDING UPON THE LD

50 IN A MOUSE.

BUT WHAT WE FIND IF YOU LOOK

ACROSS THE SPECTRUM OF THE FIELD

OF STEM CELL THERAPY, YOU FIND

ANYBODY IN ANY LAB USES A

DIFFERENT DOSE ROOT OF

ADMINISTRATION TIMING AFTER

INJURY AND A VARIETY OF OTHER

THINGS AND WE HAVEN'T COME TO,

WE'RE STILL IN THE INFANCY OF

THIS PROCESS.

THAT WE HAVEN'T COME TO A SET OF

RULES SO TO ANSWER YOUR QUESTION

DO YOU WANT TO GIVE CYCLOSPORIN

TO ALL YOUR ANIMALS OR COME TO

AN IMMUNOSUPPRESSIVE REGIME THAT

WORKS ACROSS DIFFERENCE ISSUES.

AND UNTIL WE DEVELOP A WHITE

PAPER WHICH SAYS WITH NEED TO

LOOK AT TWO SPECIES MODELS SO

YOU HAVE TO GIVE CELLS IN RAT

AND MOUSE IN ORDER TO PROVE THAT

THE CELLS ARE BENEFICIAL OR YOU

NEED TO GIVE THIS

IMMUNOSUPPRESSION, IT WILL BE

DIFFICULT TO CAUSE WHEN YOU GO

INTO THE LITERATURE YOU HAVE THE

EXACT SAME PROBLEM, I GAVE MOUSE

CELLS TO A MOUSE AND I GOT THE

HEALING AND BY THE WAY, WHO

CARES BECAUSE WITH WE'RE IN THE

TREATING -- NOT PLANNING TO G

INTO THE CLINIC WITH MOUSE

CELLS, WE GIVE HUMAN CELLS TO A

MOUSE AND NO EFFECT.

DOES THAT MEAN ANYTHING AS FAR

AS CLINICAL TRIALS ARE

CONCERNED?

SO THAT DISCIPLINE IS SORELY

MISSING FROM THIS FIELD AND

NEEDS TO BE SORT OF INCORPORATED

AND DEVELOPED BECAUSE WE'RE IN

THE WILD WEST.

I TRAIN HERE AT THE NIH BACK IN

THE LATE -- EARLY '80s AND IT

WAS -- I KNOW FROM THE HISTORY

OF THE NCI IT WAS THE WILD WILD

WEST WHERE WE GAVE DRUGS,

ANTIBODY, WHATEVER YOU WANT TO,

TO TRY TO GET THE CLINICAL

TRIALS INTO PLAY.

WE STILL NEED TO DO THAT WITH

THE STEM CELLS.

>> YOU'RE NOT DOING CELLULAR

CONTROL WHAT I HEAR.

A LOT OF MECHANISTIC QUESTIONS

AND NON-SPECIFIC MECHANISTIC

QUESTIONS RAISED TODAY BEG THE

QUESTION IF THERE ARE TWO CELLS

SIDE BY SIDE WOULD WE LEARN MORE

ABOUT SPECIFIC MECHANISM OR

GENERALIZABLE THING THAT MIGHT

NOT NEED TO BE CAREFULLY

SPECIFIED BEFORE WE MOVE

FORWARD.

>> MAYBE THE GENERAL QUESTION TO

ASK ANYBODY WHO WANTS THE

ANSWER, IMPORTANCE FOR CONTROLS.

>> AND ALSO THE IDEAD THERE'S NO

STANDARDIZATION WITHIN THE FIELD

AND SO PEOPLE GET THROWN BACK

AND FORTH ON JUST THE IDEA OF

HAVE HAVE YOU DONE THE

APPROPRIATE CONTROLS.

>> SO TO THAT POINT CONTROLS AN

STANDARDS IF YOU YOU HAVE A WISH

LIST WOULD YOU SAY YOU LIKE TO

HAVE A CONTROL AND IF SO WHAT

WOULD BE THE CONTROL U USE FOR

THIS SET OF TRANSPLANT TYPE OF

EXPERIMENT?

WOULD IT BE SOMETHING THAT THE

NIH COULD DO IN TERMS OF

PROVIDING THAT KIND OF CONTROL

STANDARD.

MAYBE CAN GO QUICKLY FROM LEFT

TO RIGHT, YES, NO, MAYBE.

>> MAYBE.

>> WE STRUGGLE WITH THIS WHEN

DESIGNING THE EXPERIMENT BETWEEN

BUFFER WE THINK IS A GOOD

CONTROL AND WE THOUGHT USE OF

RADIATED CELLS OR DEATH CELLS T

PSALM CELL TYPE THAT DOESN'T

WORK OUT BECAUSE DEAD CELLS

RADIATED ONES INSIGHT

INFLAMMATORY REACTION THAT

WORSENS THE INJURY SO NO GOOD.

FIBROBLASTS, WE TRIED,

FIBROBLASTS HAVE THERAPEUTIC

PROPERTIES IN THEMSELVES, RIGHT?

THEY SHOULD BE USING

FIBROBLASTS.

SO THAT MAY NOT BE --

>> CHEAPER THAN --

>> CELLS ARE DEVELOPING

FIBROBLASTS.

SO I DON'T HAVE A GOOD ANSWER, I

THINK A CELL CONTROL IS VERY

IMPORTANT THOUGH.

SO WE'RE PROBABLY GOING TO USE

FIBROBLAST IN OUR STUDY IN SOME

OF OUR PRE-CLINICAL STUDIES AS A

CONTROL.

>> ANYBODY ELSE THINK

DIFFERENTLY, SIZE SPACE CONTROL?

>> IT'S CELL TYPE SPECIFIC

BECAUSE IN DIABETES FIELD YOU

NEED NEED CONTROL, ANYTHING BUT

BETA CELL ISN'T GOING TO DO THAT

FOR US SO DEPENDS ON WHAT YOU'RE

LOOKING AT, IT'S EAT ERGOING TO

WORK OR NOT WORK.

>> MSC MAYBE YOU NODE A CONTROL.

>> THAT'S WHERE YOU -- WHERE YOU

MODULATE THE IMMUNE SYSTEM,

FUNCTIONAL ACTIVITY OF THE CELL

YOU TRIED TO DIFFERENTIATE WHICH

IS A TOTALLY DIFFERENT QUESTION.

>> ANYTHING DIFFERENT OR

EVERYBODY AGREE?

CONTROLS ARE IMPORTANT?

>> NOT SHOWER MY RAT MSC IS

BEHAVE ONE THING I NEED TO

CONTROL IS MARKERS TO LOOK AT

WHEN WE LOOK AT -- THAT'S THE

REAL IMPORTANT THING.

MACROPHAGE WHETHER OR NOT IT'S

SOMETHING ELSE.

MULTIPLE STAINING, WHEN

PROTOCOLS ARE STAINING TO PROVE

THE CELL IS THERE IS VERY

IMPORTANT AND SHOWING THE

CONTROLS AS WELL.

SO YOU CAN USE THE NONSENSE

CELL, WE COULD DEVELOP A

NONSENSE CELL THAT WOULDN'T MAKE

SENSE AT ALL BEING IN THAT AREA

BUT YOU NEED TO MAKE SURE THAT

IF YOU USE A REPORTER GENE YOU

WOULDN'T USE IRON OXIDE, FRIN

YOU NEED TO MAKE SURE WHAT YOU

THINK IS A CELL AND H IS THE

CELL CONTAINING THE ENDOGENOUS

IS THE CELL THAT YOU ACTUALLY

PUT INTO THE TISSUE.

>> CONTROLS ARE IMPORTANT BUT

NOT NECESSARY WHAT EXACTLY WE

HAVE CONSENSUS ON.

>> I WAS GOING TO SAY THIS IS

ANOTHER CASE OF ONE SIZE FITS --

DOES NOT FIT ALL AND IT'S A

MATTER OF THE CONTEXT WE'RE

PUTTING THE CELLS IN.

IN TERMS OF CONTROL CELL, THE

SKIN PIEBORO BLAST --

FIBROBLAST, I WOULD LIKE TO

REFRESH A PAPER WRITTEN BY FRAN

WHICH HE

FRANCESCO (INDISCERNIBLE), THIS

IS A CASE WHERE WE'RE DEALING

WITH POPULATIONS OF CELLS THAT

ARE FIBROBLAST IN NATURE AND

MAKE GROWTH FACTORS AN CYTOKINES

BECAUSE THAT'S PART OF THEIR

NORMAL JOB AND WHETHER A

FIBROBLAST FROM A STROMA, FROM

ADIPOSE, BONE MARROW, FAT HAS

THE SAME PROPERTIES I DON'T

THINK THAT WE KNOW.

BUT WE CAN'T DISCOUNT, WHAT

WE'RE DOINGNB TO THEM IN
CULTURE.

IF THEY'RE SO MAGICAL, WHY DONE

THEY ACT THAT WAY IN THE BODY?

WE ARE MAYBE GIVING THEM

PROPERTIES THEY WOULDN'T

NORMALLY HAVE.

SO THAT'S THE COMMENT ABOUT NEED

FOR CONTROL CELL.

>> I THINK YOU NODE TO BE

CAREFUL A WELL IF TERMS OF

(INAUDIBLE) PRODUCING.

A NUMBER OF DIFFERENT APPROACHES

PEOPLE ARE USING AND WHICH

AREN'T NECESSARILY PUTTING BACK

THAT I CELL SO NOT PUTTING BACK

OUT RPA, THEY'RE ACCOMPANIED

THROUGH NEURAL PROGENITOR.

I WOULD SAY NEURAL PROGENITOR A

CONTROLLED CELL BUT ITS MODE OF

ACTION ISN'T THE SAME AS RPE

CELL.

SO PE DEN PENT ON WHAT THE

THERAPEUTICS ARE, WHAT THEY'RE

BEING PRODUCED, DISCUSSED THIS

MORNING, WHETHER YOU BELIEVE

MECHANISM OF ACTION THAT

PARTICULAR CELL IS.

NEURAL PROGENITOR TAKING THE

PLACE OF RPA ISN'T GOING TO

HAPPEN IN TERMS OF FUNCTION OF

THE I CELL WHERE IT'S CLEARLY

DUE TO SOMETHING IN THESE ANIMAL

MODELS.

SPECIFICALLY PRESUMABLY

PRODUCING A TROPIC FACTOR.

IT'S GOING TO DEPEND ON WHAT

THESE THERAPEUTIC ARE, VARIOUS

GROUPS ARE PRODUCING AND WHERE

THEY BELIEVE THAT MODE OF ACTION

IS.

SO IN TERMS OF CONTROLS WE DO

NEED SOME CONTROL TO DECIDE

AGAINST THE COMPARISON, ARE YOU

REPLACING THE CELL OR IMPROVE

THE MILE EWE OF THAT PARTICULAR

ENVIRONMENT -- MILIEU OF THAT

PARTICULAR ENVIRONMENT IN

>> CONTROL SHOULD BE FOR THE

MODE OF ACTION YOU'RE PROPOSING

FOR YOUR PRODUCT.

>> IT SHOULD BE SOMETHING TO

GIVE AN INVITATION, IF YOU

BELIEVE MODE OF ACTION IS BASED

AROUND A PARTICULAR FUNCTION,

YES, YOU SHALL HAVE A CONTROL.

ONE OF THE THINGS WE -- HOMOLOGY

IS COMPARING AGAINST (INAUDIBLE)

DO A COMPARISON AGAINST DISEASE

BUT THEY TEND TO FORGET HOW GOOD

IS THE ACTUAL IMPROVEMENT

AGAINST THE NORMAL BASELINE.

>> THAT'S THE OTHER IMPORTANT

CONTROL, YES.

WHAT IS STATE OF ART IN SOME

FASHION, WHAT'S NOVEL IN SOME

FASHION AS CONTROL.

>> ROBERT (INAUDIBLE).

I HAVE A CONCEPTUAL QUESTION,

BACK TO THE A COMMENT MADE ON

THE EARLIER SESSIONS ABOUT E --

BECAUSE OF UNCERTAINTIES THAT

CAME WITH ANIMAL MODELS AN CELLS

TO INCORPORATE THE FIRST HUMAN

STUDY TO THE QUOTE, PRE-CLINICAL

PART OF THIS.

AND I GUESS ONE WORD OF CAUTION

IN CLINICAL TRIALS IS THAT YOU

DONE KNOW WHAT WHEN WRONG UNTIL

YOU HAVE A SUCCESS.

SO I THINK THE THE IDEA OF

MOVING INTO PEOPLE IS A GREAT

IDEA BUT WE NEED THE MARKERS,

THE BIOMARKERS OF EFFICACY AND

OFF TARGET EFFECTS WHICH REALLY

DON'T APPEAR TO BE PRESENT IN

MOST OF THE STUDIES THAT I

HEARD, MAYBE DIABETES FIELD IS

THE ONE EXCEPTION.

BUT I THINK YOU HAVE TO KNOW

WHAT'S HAPPENING, IF YOU DON'T

KNOW WHERE THE CELLS ARE, WHERE

THEY WENT, THIS IS VERY

DIFFICULT.

>> SO RAJESH, YOU BROUGHT UP THE

POINT ABOUT COMPANION.

>> I WOULD WHOLEHEARTEDLY AGREE

IF YOU'RE GOING TO GO INTO THAT

HUMAN EXPERIMENT AND YOU WANT TO

BE ABLE TO INTERPRET THE RESULT

EITHER WAY.

SO THEREFORE YOU SHOULD HAVE THE

WAYS TO MEASURE WHATEVER IT IS

THAT IS IMPORTANT TO ARRIVE AT

THAT CONCLUSION.

IT'S -- WE HAVE HAD TOO MANY

TRIALS THAT HAVE BEEN DONE AND

CLOSED WHERE YOU SAY DIDN'T WORK

BUT YOU DONE KNOW WHY IT DIDN'T

WORK, THAT'S NOT VERY SATISFYING

AND SMALL MOLECULE FIELD AN

CERTAINLY DON'T -- I WOULD NOT

-- I WOULD HOPE THAT DEFENSE

FEEL DOESN'T CHOOSE TO DO THAT

OVER AN OVER AGAIN BECAUSE

THAT'S NOT GOING TO ADVANCE THE

SCIENCE.

>> JUST ADD TO THAT, SURELY --

PROTOCOL CLINICAL PACKAGE, ONE

THING WE'RE FACENING THE CELL

THERAPY AREA ESPECIALLY IN THE

EYE, IN TERMS OF CLINICAL END

POINTS IT'S LIMBING WHAT THE FDA

CONSIDER AS AN END POINT.

THOUGH THEY USE VISUAL ACUITY Z

THEIR END POINT.

THAT'S CRITICAL IN MANY WAYS

WHERE YOU'RE RESTRICTING VISUAL

OUTCOMES IN TERMS OF TYPE OF

THERAPIES THAT WE'RE GOING TO BE

INTRODUCING.

SO I THINK THERE HAS TO BE SOME

GIFT FROM THE FDA IN TERMS OF

ACCEPTING SECONDARY END POINTS,

WHICH NEED–

THE PRIMARY END POINTS IN

FURTHER ONGOING TRIALS SO THAT

WE CAN ACTUALLY ADDRESS THESE

ISSUES AND SOMETHING HAPPENING

THERE IN TERMS OF CELLS AN

FUNCTION TOWARDS THE PATIENT.

WE WENT INTO THAT IN THE STROKE

FIELD ARGUING STRONGLY, FOR

INSTANCE, MR SCANNING IN

NEUROPROTECTION MR SCAN SHOWING

THE LESION SHOULD BE THE PRIMARY

END POINT.

YOU CAN REDUCE THE MR BURDEN,

NEW STROKES ON MR, THERE'S NO

CLINICAL BENEFIT THAT SHOULD

HELP US AND SHOULD BE VALID AS

PRIMARY ENPOINT BUT THAT'S A

HARD CELL WHO CARES ABOUT WHAT

THE MR LOOKS LIKE, WHO CARES

ABOUT CLINICAL OUTCOME?

>> YOU'RE RIGHT.

SO I MEAN THE LOGIC IS ALWAYS

BEEN SUBJECTIVE END POINTS,

OBJECTIVE END POINTS AND HOW

THEY CORRELATE WITH THE PROPOSED

ACTION THAT YOU HAVE AND IT'S

COMPLICATED IN TERMS OF

CHOOSING.

BUT YOU'RE RIGHT, THERE SHOULD

BE SOME WAY TO BE ABLE TO

DISCUSS THIS OR COME TO SOME

MEETING OF MINDS IN SOME FASHION

IN TERMS OF BEING ABLE TO DO

THAT, CARDIAC ISSUE IN TERMS OF

HAVING A CONSENSUS BUT IN THE

FDA DEFENSE IT'S -- THEY DON'T

HAVE A CONSENSUS SO WE HAVE AN

ISSUE THERE.

>> I WANT TO PUSH A LITTLE BIT

BECAUSE THIS ISN'T A EGGLATORY

ISSUE.

I WANT TO BE FAIR TO THE FDA

COLLEAGUES IN THE ROOM.

THIS IS ABOUT WHAT HAPPENED,

WHAT WORK DIDN'T WORK FROM A

SCIENTIFIC POINT OF VIEW TO

FIGURE HOW TO PROPEL THE FIELD

FORWARD, NOT THE REGULATORY PATH

WHICH FOR A PARTICULAR CELL IN

CONTEXT OF PARTICULAR

INDICATION.

A VERY DIFFERENT QUESTION.

>> I COMPLETELY AGREE, I WANT TO

SAY EXACTLY THAT BECAUSE SEEMS

TO ME AT LEAST IN MY PAST WITH

IN A COMPANY SETTING WE

CERTAINLY TOOK TRIALS FORWARD TO

ASK A SPECIFIC SCIENTIFIC

QUESTION THAT CERTAINLY WASN'T

GOING TO BE THE END POINT THE

FDA WAS GOING TO ACCEPT FROM A

EFFICACY OR APPROVAL PERSPECTIVE

BUT TO ANSWER A QUESTION, IT

FORMS A STUDY WE THEN DID AGAIN

TO MOVE SOMETHING ELSE FORWARD.

HUMAN HYPOTHESIS TESTING WE NEED

TO DO TO MOVE THINGS FORWARD.

OBVIOUSLY FROM THE PERSPECTIVE

OF FDA YOU SHOW FROM THAT STUDY

USING LIGANDS AND MICRODOSING AN

PHASE 0 STUDIES AND ET CETERA

THE BAR COMES DOWN FURTHER IN

TERMS OF SAFETY CHALLENGE.

>> I'LL ADD ONE THING THAT'S

IMPORTANT TO THE POINT, THE FDA

MANDATE THE SCIENTIFIC STUDIES,

THAT'S AN IMPORTANT THING TO

REMEMBER AND THERE IS A CATCH 22

TO THE THE POINT YOU MAKE

BECAUSE THE NIH DOES NOT DEBT

THOSE OR FUN THOSE STUDIES TO

GET THAT MECHANISM OF ACTION OF

PROCESS THAT'S HAPPENING IN A

CLINICAL TRIAL.

SO THAT'S SORT OF GETS LOST IN

LIMBO AND IS A REALLY IMPORTANT

PIECE THAT NEEDS TO BE DONE.

BUT THAT'S GOING TO BE IMPORTANT

IN TERMS OF KEEPK IT IN MIND AND

IT'S AN IMPORTANT REMINDER IF

THAT'S THE CASE.

>> JUST MAKE SURE THAT WE DON'T

-- WHY DO YOU SAY WE DON'T FUND?

IT NOT SURE I UNDERSTAND.

>> LET'S NOT GO INTO THAT.

>> PUTTING ON MY DIVISION

DIRECTOR HAT, IT'S ACTUALLY OUR

ROLE HERE OCCASIONALLY TO TAKE

AREAS WE IMMEDIATE TO FUND THOSE

KINDS OF STUDIES NOT FOR

REGULATORY APPROVAL BUT SHOW

PROOF OF CONCEPT THIS STUDY IS

POSSIBLE AND HERE IS THE BEST

DESIGN, TO WORK UP DESIGN ISSUES

TO HELP (INAUDIBLE).

AND WE ADDED DPI FIBER TRACK

REORGANIZATION AND STUDY PRIMARY

OUTCOME AND BIO AND OTHER

STUDIES WE HAVE DONE IS CLINICAL

BUT I WANTED TO ADD FMR BECAUSE

THAT WILL BE VERY USEFUL TO HELP

US BUT WHO IS GOING TO FUND IT?

FUNDED THROUGH MY OWN GIFTS.

>> SO WE WERE TALKING EARLIER

ABOUT WE TOUCHED ON THE NOTION

OF STANDARDS AND MAYBE

EMBOLDENED TO ASK A QUESTION

ABOUT STANDARDIZED IF POSSIBLE

OR CLOSER TO STANDARD SET OF

QUESTIONS AROUND CONCEPT OF

TUMORIGENICITY, PEOPLE I TALKED

TO SAID I WOULD NEVER BE THE

RECIPIENT OF A CELL BASED

THERAPY AND THE REASON THEY GIVE

IS BECAUSE THEY'RE WORRIED ABOUT

THAT AND THEY DON'T KNOW IF WE

HAVE THOUGHT THROUGH THE SYSTEM

WELL ENOUGH BECAUSE OF COURSE IF

YOU'RE GOING TO USE THE YOGE

BERRA APPROACH AND WATCH, IT

COULD TAKE A LONG TIME UNTIL YOU

GE THE DATA THAT'S MEANINGFUL

FOR THE QUESTION YOU WANT

ANSWERED, ESPECIALLY FOR A SLOW

GROWING CELL.

SO THE QUESTION I IS, ARE THERE

WAYS WE MIGHT BE ABLE TO TAKE

ONCE WE LOOK AT THE ENGRAFTMENT

OF WHAT THE CELLS ARE, ARE THERE

WAYS WE CAN PUT STRETCHERS ON

THE SYSTEM THAT WE MIGHT BE ABLE

TO IN A STANDARD -- MORE

STANDARDIZED APPROACH LOCK FOR

TUMORIGENICITY YOU SHALL SHOE IN

WAYS WE CAN BE MORE CONFIDENT

ABOUT THE POTENTIAL THERE.

>> ANYBODY HAVE ANY IDEAS TO THE

TUMOR GENICITY ASSAY?

>> ONE THING THAT

(INDISCERNIBLE) DID WAS TO SPIKE

THEIR FINAL PRODUCT, CLINICAL

PRODUCT WITH THE PURE EMBRYONIC

CELLS AND FIGURE OUT HOW MANY

PURE EMBRYONIC THEY NEEDED TO

PRODUCE TUMORS IN

IMMUNOSUPPRESSED ANIMALS.

TITRATED AND SHOW THERE WERE SO

MANY LEVELS BELOW THIS IN TERMS

OF HOW MANY -- IN TERMS OF

EMBRYONIC CELL, PLURIPOTENT CELL

IN THEIR CLINICAL MIX THAT WAS

NOT -- THAT IT WAS VERY, VERY

SAFE AND THAT WAS SOMETHING THAT

THEY NEGOTIATED WITH THE FDA,

ONE WAY OF DOING IT.

>> THIS MEANS SOME CONSENSUS,

YOU SHOULD DO IT WITH YOUR FINAL

PRODUCT AND QLIEWS SPIKEING IF

YOU CAN'T DETECT.

DO IT AT THE SAME SITE WHICH YOU

PUT YOUR PRODUCT RATHER THAN

STANDARDIZED SITE AND YOU SHOULD

LOOK AT CERTAIN NUMBERS WHEN

DOING THIS AND IT SHOULD BE A

BETTER IMMUNE SUPPRESSED MODEL

THAT YOU HAVE BECAUSE OTHERWISE

THE XENO ISSUE THE IMMUNE SYSTEM

MIGHT PREVENT TUMORIGENICITY IN

THIS DATA TO SUGGEST THAT BUT I

DON'T THINK ANYBODY ELSE HAS M

COUP WITH SOMETHING COMPLETELY

NEW AND UNIQUE IN FASHION.

SO IT'S GOING TO BE DISCUSSED AS

WELL TOMORROW IN TERMS OF BEING

ABLE TO DO THAT.

SO YOU WERE GOING TO SAY

SOMETHING ABOUT THIS ISSUE OF

DOING THE CLINICAL TRIALS AND

BEING ABLE TO HAVE THIS FUNDING

FOR SOMETHING THAT GARY TALKED

ABOUT THAT THERE IS NOT REALLY

SOME SORT OF FUNDING.

DO YOU WANT TO ADD TO THAT?

>> OBVIOUSLY IN ANY CLINICAL

TRIAL REGARDLESS OF THE END

STAGE RESULTS, THE PRIMARY END

STAGE, THE CELL THERAPY FIELD

DOES NEED TO ACTUALLY TAKE ON

BOARD, IT NEEDS TO EXAMINE

PRECISELY WHETHER THOSE CELLS

REALLY ARE SURVIVING, WHETHER

THEY ACTUALLY FUNCTION, WHETHER

THERE IS A BENEFIT TO THE

PERSON.

BUT AGAIN IN DECIDING THE

PROTOCOL ITSELF AS YOU PRESENT

IT, THE CLINICAL TRIAL WILL

DETERMINE WHAT YOU'RE ALLOWED TO

DO TO A PATIENT THERE.  IS THE

PATIENT THERE AS WELL.

SO THERE'S ONLY SO MANY THINGS

YOU WILL BE ALLOWED TO DO TO A

PATIENT THAT WAS TRYING TO

ALLUDE TO THIS MORNING, WE

STARTING TO DEVELOP IN VIVO

IMAGING IN THE EYE WHICH WILL

ACTUALLY DETERMINE WHETHER

FLUORESCENCE BEING STANDARD

CLINICAL PROCEDURE TO LOOK AT

SURVIVAL OF RPE, ALSO OTHER

IMAGING METHODS AS WELL LIKE

ADAPTIVE OPTICS FOR THE EYE.

AGAIN, I THINK THE EYE LENS

(INAUDIBLE) CELLULAR THERAPY

APPROACH, BECAUSE THERE IS SUCH

A GOOD SYSTEM TO ACTUALLY USE

FOR A CELL THERAPY TYPE

APPROACH.

I THINK THIS IS THE WAY I LRN

PEOPLE WHY YOU NEED TO DO

PRE-CLINICAL TESTS.

PHYSICIAN WHEN HE'S TREATING A

PATIENT NEEDS TO KNOW WHAT TO

GIVE, WHAT INDICATIONS TO GIVE,

HOW MUCH TO GIVE AND WHAT TO DO

WHEN THINGS GO WRONG.

IN TERMS OF BEING ABLE TO DO IT.

AND YOUR PRE-CLINICAL ANIMAL

TESTING IS SUPPOSED TO PROVIDE

THE DATA IN A CONVINCING ENOUGH

FASHION THAT YOU GO FORWARD IN

TERMS OF TREATING A PATIENT.

SO I THINK IT'S ALWAYS USEFUL

THAT YOU POINT OUT TO REMEMBER

THAT.

SO THAT YOU DESIGN YOUR

PRE-CLINICAL STUDIES WITH THAT

GOAL IN MIND.

IT'S NOT I SHOULD DO TWO ANIMAL

EXPERIMENTS BECAUSE THE FDA SAYS

SO, IS IT THE ELEMENT TO MY

TREATMENT OF A PATIENT AND WHY

WOULD IT HELP IN TERMS OF BEING

ABLE TO DO IT.

I THINK THE FDA ITSELF ALSO

TAKES INTO ACCOUNT THAT AND

THAT'S WHY THEY KEEP SAYING WE

DO THIS IN A CONTEXT-SPECIFIC

FASHION.

WE WANT TO MATCH THE RISK AND

BENEFIT.

I THINK ALL OF US YOU HEARD FROM

OTHER PEOPLE HERE THAT'S WHAT

YOU THEY KEPT TRYING TO

EMPHASIZE IN DIFFERENCE WAYS.

WE NEED TRACKING, BUT WE NEED

TRACKING FOR A SHORE TIME PERIOD

BECAUSE THAT'S THE DISTRIBUTION

WE ARE MOST INTERESTED IN OR

LOOK AT THE RIGHT ANIMAL SPECIES

BECAUSE WHEN WE HAVE TO DO THE

INJECTION IN THE HEART WE NEED

TO WORRY WHETHER THE SIZE AND

MODEL IS APPROPRIATE TO WHAT WE

ARE DOING.

WE DON'T NEED TO DO SOMETHING

BECAUSE HECK, WE CAN ALREADY

DIRECTLY VISUALIZE SO WE DON'T

NEED TO LABEL AND ADD ANOTHER

LEVEL OF COMPLICATION THAT WE

NEED TO DO.

I HOPE YOU GOT THE SENSE FROM

THAT ON THE TOP THAT TWR THERE

IN TERMS OF WHETHER NEEDS TO BE

DONE.

I'M GOING TO LET ANYONE WHO

WANTS TO MAKE A COMMENT AS TO

THE COSTS, BE CONVINCED THE

GOALS THAT YOU HAD IN MINE WHEN

YOU PRESENTED, IF YOU NEEDED TO

MAKE ADDITIONAL COMMENTS BEFORE

WE WRAP UP.

>> ONE THING TO MENTION IS RISK

SAFETY, ONE THING WHICH IS

PROBABLY THE NEXT FDA IND

SECTION, WHAT WE'RE GOING TO DO

WHEN IT GOES WRONG, BECAUSE IT

WILL GO WRONG IN SOME PATIENTS.

WHAT IS IT WE WE DO TO LIMIT

THAT PROBLEM AND THAT IS CRUCIAL

IN TERMS OF THERAPIES AS OPPOSED

TO ANY OTHER THERAPY INTRODUCED.

>> WE LEARNED LESSONS FROM GENE

THERAPY.

>> ABSOLUTELY.

IN FACT, WITH THE EYE WE'RE

FORTUNATE AGAIN BECAUSE WE HAVE

A VERY EFFECTIVE METHOD WHICH IS

A LASER WHICH ACTUALLY IS ONE OF

THE BEST TOOLS USED IN TERMS OF

PROLIFERATING CELLS OR CELLS

ABERRANT IN THE OCULAR SYSTEM,

WHAT IS IT IN TERMS OF SYSTEM,

IN TERMS OF PATIENT, IN TERMS OF

RISK WHEN THIS GOES WRONG WHAT

WE'RE GOING TO DO, BECAUSE IT

WILL GO WRONG T NUMBER OF

PATIENTSTS.

>> LAST COMMENT.

>> IT'S NOT LIKE WE HAVE NOT

THOUGHT ABOUT THAT.

AND AGAIN, THAT'S A CLINICAL

TRIAL DESIGN ISSUE OBVIOUSLY THE

TRIAL IS CONSERVATIVERY

CAREFULLY DESIGNED.

I SEE PRE-CLINICAL IN THE

MIDDLE.

YOU HAVE GOT PRODUCT ISSUE

MANUFACTURING ISSUE, METHODS OF

ACTION, PROOF OF CONCEPT AND THE

CLINICAL TRIAL DESIGN.

AND THE PRE-CLINICAL IS IN THE

MIDDLE.

WE ASK THE SPONSORS WHAT YOU

THINK YOU WANT TO DO CLUNICALLY

BASED ON WHAT YOU THINK YOU

NOTICE POINT AND THAT

PRE-CLINICAL HOPEFULLY,

HOPEFULLY IT'S NOT IN A VACUUM

WE'RE EVALUATING.

THERE'S AN END POINT WE'RE

LOOKING FOR.

>> THAT'S A VERY IMPORTANT

POINT.

THERE ARE NO MORE QUESTIONS, I

THINK WE HAVE GONE OVER TIME.

>> RIGHT.

SO TOMORROW I WOULD LIKE TO

POINT OUT THAT WE'RE STARTING AT

8:15.

SO PLEASE REMEMBER TO SHOW UP A

LITTLE BIT EARLIER, WE HAVE

THREE VERY INTERESTING SESSIONS

PLANNED FOR YOU.

SO HAVE A GOOD EVENING.