Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
TODAY WE'RE HONORED TO HEAR FROM
2 COLLEAGUES AT THE NATIONAL
CENTER FOR ADVANCING
TRANSLATIONAL SCIENCES.
DR. DONALD C. LOWE AND
DR. BROOKS WHO WILL PRESENT ON
GENE THERAPY APPROACHES FOR
MULTIPLE RARE DISEASES, THE
PGGTC INITIATIVES.
DR. LOWE, THE DIRECTOR OF THE
THERAPEUTIC THERAPEUTIC BRANCH
FOR PRECLINICAL INNOVATION AT
NCATS IS OUR FIRST SPEAKER.
DR. LOWE RECEIVED Ph.D. IN
MOLECULAR AND CELLULAR
PHYSIOLOGY IN YALE UNIVERSITY.
THEN PURSUED POST DOCTORAL
STUDIES AT THE LUDWIG INSTITUTE
FOR CANCER RESEARCH AT
UNIVERSITY OF COLLEGE LONDON.
IN 1992 HE JOINED THE FACULTY OF
THE NEWLY ESTABLISHED DEPARTMENT
OF NEURAL BIOLOGY AT DUKE
UNIVERSITY AND IN THE LATE
1990S, DR. LOWE CONFOUNDED A
BIOTECH CHUSM STUDYING
NEUROSCIENCE SERVING AS CHIEF
SCIENTIFIC OFFICER UNTIL 2002,
THEN RETURNED TO DUKE UNIVERSITY
TO ESTABLISH DRUG DISCOVERY ON A
COLLABORATION MODEL THAT
PARTNERED WITH OVER A DECADE FOR
40 ACTIVE INSTITUTIONS AND MORE
THAN 20 BIOTECH AND MAJOR FORM
SUITICAL FIRMS.
DR. LOWE'S WORK HELPED TO
DEVELOP NEW DRUG AND DRUG TARGET
CANDIDATES THAT FOR DISEASINGS
THAT AFFECT THE CENTRAL NERVOUS
SYSTEM, INCLUDING HUNTING TON'S
DISEASE, ALZHEIMERS GLAUCOMA,
ESCHEMIC STROKE AND BRAIN
CANCER.
DR. LOWE HOLDS 3 PATENTS AND A
LEADERSHIP MEMBER OF TRANSLATION
TOGETHER, A COLLABORATION OF
TRANSLATIONAL RESEARCH
ORGANIZATIONS FROM AROUND THE
WORLD.
HE IS CONFOUNDER OF HD REACH, A
NONPROFIT ORGANIZATION DEDICATED
TO BRINGING QUALITY HEALTHCARE,
EDUCATION AND SOCIAL ASSISTANCE
TO ALL PATIENTS AND FAMILIES
AFFECTED BY HUNTING TON'S
DISEASE ACROSS THE STATE OF
NORTH CAROLINA.
DR. LOWE HAS RECEIVED A NUMBER
OF AWARDS TO INCLUDE THE
[INDISCERNIBLE] RESEARCH
FELLOWSHIP, [INDISCERNIBLE]
FELLOWSHIP AWARD IN
NEUROSCIENCE, AND THE BIG KNIGHT
SCHOLAR AWARD AS WELL AS
NUMEROUS NCATS DIRECTOR'S AWARDS
AND 2 NIH DIRECTOR'S AWARDS.
OUR SECOND PRESENTER IS
DR. PJ BROOKS, ACTING DIRECTOR
OF THE OFFICE OF RARE DISEASE
AND RESEARCH AT NCATS.
DR. BROOKS RECEIVED A MASTER'S
DEGREE IN PSYCHOLOGY FROM THE
UNIVERSITY OF TORONTO AND WENT
ON TO EARN A Ph.D. IN
NEUROBIOLOGY FROM UNIVERSITY OF
NORTH CAROLINA AT CHAPEL HILL.
FOLLOWING A POST DOCTORAL
FELLOWSHIP AT ROCKEFELLER
UNIVERSITY, DR. BROOKS BECAME AN
INVESTIGATOR IN THE NATIONAL
INSTITUTE ON CONTROL ABUSE AND
ALCOHOLISM, WHERE HE DEVELOPED
AN INTERNATIONALLY RECOGNIZED
RESEARCH PROGRAM FOCUSED ON RARE
[INDISCERNIBLE] DISEASES RESULT
FREE RADICALS GENERATED
DEFECTIVE DNA REPAIR INCLUDING 0
DERMA PIG MATOSEIN AND
[INDISCERNIBLE].
IN 2010 DR. BROCKS JOINED THE
OFFICE OF RARE DISEASE AND
RESEARCH WHERE HE IS NOW
DEVELOPING NOVEL APPROACHES FOR
CLINICAL TRIALS AND RARE
DISEASES BY MOVING BEYOND 1
DISEASE AT A TIME APPROACHES.
EXAMPLES INCLUDE THERAPEUTICS AT
SHARE MOLECULAR MECHANISMS
UNDERLYING MULTIPLE RARE
DISEASES AND PLATFORM
TECHNOLOGIES FOR DELIVERY OF
NUCLEIC ACID THERAPEUTICS
INCLUDING PAVE-GT AND GBTC THAT
WE WILL DISCUSS TODAY.
HE HAS CO-AUTHORED BOOKS AND A
LEADER IN RESEARCH AND
ADMINISTRATION, SERVING AS A
COORDINATOR FOR NIH COMMON--NIH
COMMON FUND, SOMATIC CELL GENOME
EDITING PROGRAM AND AS AN
INTERDISCIPLINARY SCIENTIFIC
COMMITTEE CHAIR FOR THE
INTERNATIONAL RARE DISEASES
RESEARCH CONSORTIUM.
PLEASE WELCOME OUR FIRST SPEAKER
DR. LO.
>> THANK YOU AGAIN FOR THAT VERY
GENEROUS INTRO.
MY COLLEAGUE DR. BROOKS AND I
ARE DELIGHTED AND HONORED TO BE
INVITED TO SPEAK TODAY ON THE
GENE THERAPY APPROACHES THAT
WE'VE BEEN WORKING ON.
I THINK THESE BIZARRE ACRONYMS
PAVE GT AND BGTC WILL MAKE A LOT
MORE SENSE DURING THE COURSE OF
THE NEXT HOUR.
TO TART WITH I HAVE NO FINANCIAL
DISCLOSURES AND THE LEARNING
OBJECTIVE FOR DR. BROOKS AND I
TO LET YOU KNOW ABOUT THE
STRATEGIES AND INITTIAIVE ITS
WE'RE TAKING TO IMPROVE
ACCESSIBILITY TO ALL PAIBTS,
PARTICULARLY RARE DISEASE
PATIENTS.
SO I THOUGHT I WOULD START OFF
WITH JUST A COUPLE OF WORDS
ABOUT WHO WE ARE, THAT IS WHAT
IS THE NATIONAL CENTER OF
ADVANCING TRANSLATIONAL
SCIENCES?
AND WHAT HATTER OF IT IS WORKING
ON THESE PROJECTS.
SO NCATS AS I HOPED MOST ALL OF
YOU KNOW IS THE YOUNGEST KID ON
THE BLOCK AT NIH, WE'RE THE
NEWEST OF THE 27 ICs JUST
HITTING OUR FIRST DECADE.
AND ON OUR EMBLEM, SEAL HERE,
CAN YOU SEE THAT WE REALLY WORK
ACROSS THE SPECTRUM OF
TRANSLATIONAL SCIENCES WITH THE
ACCEPTION OF BASIC RESEARCH.
SO THAT'S IN CONTRAST TO MOST
ALL OF THE OTHER INSTITUTES AT
NIH AND IT'S BECAUSE THE AMAZING
BASIC RESEARCH THAT HAS BEEN
UNDERTAKEN BY NIH AND THE
RESEARCH COMMUNITY OVER THE PAST
DECADES AND HUNDRED YEARS IF NOT
MORE, HAS GENERATED AMAZING
KNOWLEDGE ABOUT THE CAUSES OF
DISEASE.
--NO, THAT WE KNOW OF TODAY.
AND WITH IMPROVEMENTS IN GENE
SEQUENCING AND IN MORE
GERONTOLOGYSTS NME-CE
CHARACTERIZATION AND ANALYSIS,
THIS NUMBER KEEPS ON RISING.
SO THAT'S THE GOOD NEWS ON THE
BASIC RESEARCH SIDE, WE HAVE A
MUCH BETTER UNDERSTANDING OF THE
CAUSES OF DISEASE OF THOUSANDS
AND PERHAPS OVER 10,000
DIFFERENT DISEASES BUT IF YOU
LOOK AT HOW MANY DISEASES, HAVE
FDA APPROVED TREATMENTS.
THAT'S STILL LAGS BEHIND AND
AROUND 500 OR SO.
AND EACH YEAR, IF YOU FOLLOW,
WHAT THE FDA APPROVES, IT'S
REALLY ONLY A HANDFUL OF NEW
TREATMENT THIS IS YEAR, EACH
YEAR, SO AT THIS RATE WE WILL
NOT CATCH UP ANYTIME SOON.
THIS PROBLEM IS WORSENED BY THIS
ANALYSIS THAT WAS DONE A FEW
YEARS AGO, EROOM'S LAW IS FOR
ALL YOU CHP FANS OUT THERE IS
THE INVERSION OR BACKWARDS
VERSION OF MOORE'S LAW WHERE THE
COST OF MANUFACTURING MICROCHIPS
GOES DOWN EXPONENTIALLY EACH
YEAR.
EROOM'S LAW SHOWS THAT IN THIS
GRAPH, THE NUMBER OF DRUGS
APPROVED BY FDA, PER MILLION
DOLLARS IN R&D SPENDING IN IT
COUNTRY, THE X-AXIS IS TIME, CAN
YOU SEE IN THIS LOG SCALE, THE
LOG GRAPH THAT IN FACT, THE COST
OF DRUG DEVELOPMENT ARE GOING UP
EACH YEAR SO THIS CAN'T BE GOOD.
SO 1 WAY TO INCAPSULATE NCATS
MISSION IN TERMS OF TRYING TO
ADDRESS THIS PROBLEM, OF
TRANSLATING BASIC RESEARCH
STUDIES INTO NEW DRUG
CANDIDATES, 1 WAY YOU CAN THINK
OF NCATS MISSION IS THAT WE'RE
HERE TO REALLY TRY TO IDENTIFY
AND TACKLE THE COMMON
BOTTLENECKS THAT KEEP NEW DRUG
DEVELOPMENT FROM HAPPENING
BETTER AND FASTER ACROSS ALL
INDICATIONS AND REALLY FOR ALL
PATIENTS AND ESPECIALLY RARE
DISEASE PATIENTS AS THIS TALK
AND THE NEXT TALK WILL TRY TO
COMMUNICATE.
SO THE PART OF NCATS THAT I WORK
IS CALLED THE THERAPEUTIC
DEVELOPMENT BRANCH AND WE WORK
WITHIN THIS AREA BOUND BY THE
RED CIRCLE SO MANY OF HAVE YOU
SEEN THIS CHEVRON DIAGRAM MANY
TIMES.
OT LEFT YOU START WITH BASIC
SCIENCES, THAT HAVE IDENTIFIED
PERHAPS A NEW MOLECULAR TARGET
THAT COULD BE USED TO TREAT A
DISEASE INDICATION AND FROM
THERE ON, THERE ARE A NUMBER OF
STEPS BEFORE YOU CAN GET TO A
POTENTIAL DRUG CANDIDATE, THAT'S
THE B-COMPOUND THAT HAS TO BE
OPTIMIZED TO HAVE THE RIGHT
PHARMACEUTICAL PROPERTIES AND BE
DEVELOPED FULL SKPE BAKUGAN ALL
DAILY BASIS THEA SUBMITTED TO
THE FDA BEFORE THE DATA WILL
CLEAR FOR THE SAFETY AND
POTENTIAL EFFICACY OF THE THIS
DRUG CANDIDATE IN THE CLINICAL
TRIALS FOR FIRST EVALUATION OF
SAFETY AND THEN WHETHER OR NOT
THE DRUG WORKS.
SO IN THIS CIRCLE, IT'S USUALLY
CALLED PRECLINICAL DEVELOPMENT.
IT'S AIM IS TO DEVELOP NEW DRUG
CANDIDATES FOR TIME DECLEARANCE
ZONE, SO AN INVESTIGATION NEW
DRUG FILING AND CLEARANCE WITH
THE FDA AND THIS SEGMENT OF DRUG
DEVELOPMENT USUALLY TAKES
SEVERAL YEARS AND I PUT DOWN
THERE ON THE SLIDE $4 MILLION
BUT USUALLY A LOT MORE THAN THAT
AND THERE'S A BUNCH OF PROBLEMS
WITH THIS, IT'S VERY HARD
SCIENCE BUT THERE ARE ALSO VERY
FEW FUNDING MECHANISMS, IN THIS
AREA, AND COMMERCIAL INVESTMENT
IS VERY HARD TO FIND BECAUSE
HISTORICALLY, THE FAILURE RATES
DURING THIS PART OF THE DRUG
[INDISCERNIBLE] CHAIN SEQUENCE
IS EXTREMELY HIGH.
SO MANY, MANY PEOPLE CALL THIS
STAGE OF DRUG DEVELOPMENT THE
VALLEY OF DEATH AND ACTUALLY,
THAT'S WHAT WE'RE HERE TO DO.
SO OUR BRANCH LIVES AND WE HOPE
THRIVES WITH THAT.
IT'S ADDITIONALLY CALLED THE
VALLEY OF DEATH BECAUSE IF YOU
LOOK AT THIS FROM A BUSINESS
PERSPECTIVE AND IN THIS GRAPH,
THE Y-AXIS IS THE VALUE OF THE
DRUG CANDIDATE, THE MARKET VALUE
COMPUTED,--MARKET VALUE OF THE
DRUG CANDIDATE AND ON THE X-AXIS
S&P TIME OR MONEY, HOW MUCH
MONEY YOU INVEST INTO THE
DEVELOPMENT OF THIS NEW DRUG
CANDIDATE.
SO ON THE LEFT IS THE STARTING
THE BASIC SCIENCE SIDE, YOU HAVE
THE IDEA, YOU START TO GENERATE
POTENTIAL DRUG PRODUCTS AND DRUG
CANDIDATES AND AS YOU WILL SEE,
THE MORE MONEY YOU INVEST AND
MORE TIME YOU PUT INTO THIS
PROJECT, THE LESS, THE MARKET
VALUE OF THIS DRUG CANDIDATE AND
THAT'S BECAUSE THE MARKET YOU'RE
PUTTING MORE AND MORE CAPITAL AT
RISK AND REALLY AS YOU SEE FROM
THE GRAPH, UNTIL YOU GET FDA
CLEARANCE FOR FIRST IN HUMAN
TESTING, SO IND STATE AND REALLY
THROUGH PHASE 1 SAFETY TRIALS,
THE VALUE OF THE DRUG CANDIDATE
DOESN'T REALLY START TO INCREASE
AND SO THIS VALLEY OF DEATH IS
BOTH A SCIENTIFIC VALLEY OF
DEATH BECAUSE FAILURE RATES ARE
SO HIGH, IT'S ALSO AN ECONOMIC
VALLEY OF DEATH BECAUSE THE
MARKET VALUE OF THESE EARLY
STAGE DRUG CANDIDATES ARE VERY
WELL, VERY TENUOUS.
SO, OUR GROUP, THE THERAPEUTICS
DEVELOPMENT BRANCH HAS PUT
TOGETHER TO TRY TO TACKLE THE
GENERAL PROBLEMS THAT ARE
ENCOUNTERED IN THE VALLEY OF
DEATH, THIS STAGE OF THE VERY
RISKY STAGE OF PRECLINICAL DRUG
DEVELOPMENT.
WE HAVE A NUMBER OF TEAMS, ABOUT
60 SCIENTISTS ALTOGETHER, AND WE
USE A COLLABORATIVE MODEL TO
PARTNER WITH OTHER INVESTIGATORS
AT NIH, WITH ACADEMIC GROUPS,
AND WITH SMALL BIOTECH
COMPANIES, PERHAPS THAT HAVE
JUST BEEN SPUN OUT OF ACADEMIC
GROUPS AND THE IDEA IS TO
PARTNER TOGETHER SO THAT ALL THE
NECESSARY SKILLS CAN BE BROUGHT
TOGETHER TO REALLY AGGRESSIVELY
PUSH FORWARD AND TRY TO IDENTIFY
AND SOLVE BOTTLENECKS THAT ARE
COMMON IN THIS PRECLINICAL
DEVELOPMENT SPACE.
AND YOU CAN SEE WE'RE BROKEN UP
INTO A NUMBER OF TEAMS, THESE
ARE--THESE ARE COMMON, THE
COMMON DIVISIONS, AND THE
BIOTECH COMPANY OR FORM SUITICAL
COMPANY THAT ARE REALLY
NECESSARY TO ADDRESS ALL THE
ISSUES THAT THE FDA WILL BE
CONCERNED ABOUT.
AND THAT STARTS WITH THE BIOLOGY
AND CHEMISTRY OF A DRUG
CANDIDATE THROUGH ITS CONNECTION
WITH PHARMA CODE DMPK, SAFETY,
TOXICOLOGY AND MANUFACTURING AND
A HUGE PART OF THIS IS PROJECT
MANAGEMENT BEING ABLE TO
COORDINATE ALL THESE DIFFERENT
PIECES THAT GO INTO PRECLINICAL
DEVELOPMENT.
IS IT POTENT ENOUGH, IS IT
COLLECTIVE ENOUGH, DOES IT GET
TO THE RIGHT PLACE IN THE RIGHT
TYPES AND TISSUES AND SHOW THAT
THIS EFFICACY IN THE ANIMAL
DISEASE MODEL IF IT EXISTS AND
VERY IMPORTANTLY ESPECIALLY IN
THE INITIAL TRIALS IT'S CAN YOU
SHOW EVIDENCE THAT THAT AT THE
DRUG EXPOSURE LEVEL, YOU NEED
FOR EFFICACY, WILL THAT DRUG BE
SAFE AND NONTOXIC.
THE LAST 2 ARE ESPECIALLY
DIFFICULT AREAS TO FIND IN AN
ACADEMIC STUDY OR BASIC RESEARCH
SETTING AND THAT IS CAN YOU
ACTUALLY MANUFACTURE THIS DRUG
AND PURE ENOUGH FORM AND LARGE
ENOUGH QUANTITIES FOR TESTING IN
HUMANS BECAUSE IN THE LABORATORY
OF COURSE YOU MAY ONLY NEED A
FEW MILLIGRAMS BUT PEOPLE MAYBE
ONLY NEED GRAMS OR KILOGRAMS
MAYBE FOR SOME OF THESE STUDIES
SO MANUFACTURING IS A HUGE
QUESTION AND CAN THE DRUG BE
FORMULATED INTO THE ROOTS OF FOR
THE ROOT OF ADMINISTRATION THAT
YOU NEED.
SO MAYBE A PILL, INJECTABLE,
MAYBE A SPRAY, ALL THESE
PROBLEMS HAVE TO BE WORKED OUT
AND DATA PACKAGED VERY NICELY
FOR SUBMISSION TO THE FDA, AND
INDs AND UNTIL FDA CLEARS THE
IND, OF COURSE 1 CANNOT START
TESTING THIS DRUG CANDIDATE IN
PEOPLE.
SO THAT'S WHAT WE DO.
SO OUR GROUP OF 60 PEOPLE IN A
WAY, YOU CAN THINK OF US AS A
SWISS ARMY KNIFE OF BIOTECH
COMPANIES, SO WE PARTNER ALMOST
ALL OF OUR PROJECTS WITH OUTSIDE
PARTIES AND WE ALLEVIATE THE
OUTSIDE PARTY FROM THE NECESSITY
TO START THEIR OWN BIOTECH
COMPANY.
SO WE WORK TOGETHER WITH
PARTNERS FOR ALMOST ALL OUR
PROJECTS, I THINK WE DO A PRETTY
GOOD JOB, WE CLEARED, HOPED TO
CLEAR OVER 40 NEW DRUG
CANDIDATES, INTO THE PHASE 2
CLINICAL TRIALS OFFER THE LAST
DECADE, AND AS YOU'LL SEE FROM
THE--AS YOU WILL SEE FROM THE
TABLE, UP TOP, MANY OF THESE
DRUGS ARE PROGRESSING THROUGH
THE SEQUENCE OF CLINICAL TRIALS,
PHASE 1, PHASE 2, PHASE 3, AND
WE'RE HOPING THIS YEAR AND NEXT,
PERHAP THIS IS FIRST DRUG WILL
BE RELEASED.
SO IT'S IN THIS CONTEXT THAT WE
CAME TO WORK WITH TJ AND OTHER
COLLEAGUES ON THIS AGTG PROJECT
WHICH I WILL TELL YOU A BIT MORE
ABOUT, SO YOU SEE FROM THE
SAMPLE WE WORK IN A LOT OF
DIFFERENT AREAS, RARE DISEASES
AND WORK AS PART OF THE HEAL
INITIATIVE, WHEN COVID HIT US,
WE TRIED TO MOBILIZE AND DO OUR
BEST TO HELP ADDRESS
TRANSLATIONAL BOTTLENECKS AND
NEW COVID DRUG DEVELOPMENT, I
WON'T HAVE TIME TO TELL YOU
ABOUT ANOTHER PROGRAM WE HAVE
ONGOING, WHICH LOOKSA THE A
DIFFERENT KIND'VE GENE THERAPY,
THAT ADDRESS YOU THINK CAN BE
SENT TO THE OLIGO NUCLEOTIDE
DRUGS WHEN THERE ARE PARTICULAR
PROBLEMS WHEN THE DISEASES ARE
EXTREMELY RARE, DOWN TO PERHAPS
A DISEASE NOT ONLY A SINGLE
PATIENT HAS.
SO THEN WE STARTED THIS
INITIATIVE, THE LINK IS
UNDERNEATH AND THE CORE OF THIS
PROJECT IS LOOKING AT THIS TYPE
OF GENE THERAPY WHERE YOU
ESSENTIALLY AS YOU ALL KNOW I'M
SURE REPLACE PART OF A VIRAL
GENOME, LIKE A THERAPEUTIC
CONSTRUCT THAT YOU THINK WILL
PROVIDE PATIENT BENEFIT AND YOU
PUT THAT, SUBSTITUTE THAT INTO
THE VIRAL GENOME, WITHIN THE
VIRUS CAN BE ESSENTIALLY USEAISE
VECTOR OR AS AN AGENT TO DELIVER
THAT CHAIN TO THE DESIRED CELL
TYPES AND TISSUES.
THIS IS NOW AND INVENTED, THE
IDEA INVENTED SOME DECADES AGO,
THIS OLD JOURNAL COVER MAGAZINE
COVER FROM TIME IS OVER 20 YEARS
OLD, REALLY PROMISING GENE
THERAPY, AS FUTURE OF MEDICINE.
SO THE AV VECTORS HAVE BECOME
THE MAIN STAY.
AND IN FACT THIS FIELD IS
MATURING VERY NICELY SO THE
FIRST FEW FDA APPROVALS OF GENE
THERAPY DRUGS BASED ON AAV, CAN
YOU SEE A COUPLE FIRST 2
APPROVALSOT RIGHT AND SO WE'RE
NOT LOOKING SO MUCH THE SCIENCE
OF GENE THERAPY OR EVEN THE
FUNDAMENTAL DRUG PROCESSES FOR
GENE THERAPY, THOSE WELL ENOUGH
TO HAVE APPROVED GENE THERAPY
PRODUCTS AND MANY MORE IN LINE
FOR WHAT WE'RE LOOKING FOR IS
THE ISSUE OF ACCESSIBILITY.
WHAT WILL IT TAKE FOR GENE
THERAPY TO BE AVAILABLE FOR MANY
MORE DISEASE, NOT A FEW AT A
TIME.
BUT TO REALLY MAKE A DENT AND
THOUSANDS OF DISEASES THAT COULD
BENEFIT FROM GENE THERAPY.
SO THE PROBLEM STATEMENT REALLY
IS WHAT CAN WE DO TO LOWER THE
BARRIERS TO ACCESSIBILITY,
ESPECIALLY TO RARE DISEASE
PATIENTS AND THE MARKET COSTS
FOR THESE GENE THERAPIES SUCH AS
READ ON THE RIGHT GIVE YOU SOME
CLUE AS THE PAIR BERNEA DEETS
THAT YOU MIGHT ENCOUNTER AND THE
FIRST 1 REALLY THE FIRST 1 IS AN
ECONOMIC 1 SO THIS IS AN
HISTOGRAPH SHOWING THE
DISTRIBUTION OF THE PREVALENCE
OF RARE DISEASES.
SO THEY'RE--THERE ARE THOUSANDS
AND THOUSANDS OF RARE DISEASES
COLLECTIVELY AND IT CONSTITUTES
SOMETHING LIKE 20 OR 30% OF ALL
DISEASE BURDEN WHICH YOU WILL
SEE IN THE HISTOGRAM WHERE THE
X-AXIS, THIS HISTOGRAM IS AN
ESTIMATED PREVALENCE OF RARE
DISEASES AND THE Y-AXIS IS THE
NUMBER OF RARE DECEASES OF THAT
PREVALENCE.
YOU CAN SEE THAT THE VAST
MAJORITY OF THE RARE DISEASES
HAVE VERY LOW PREVALENCE AND
WHAT I'VE SHOWN IN RED, IS THAT
FROM A COMMERCIAL PERSPECTIVE OF
A PHARMACEUTICAL COMPANY OR
BIOTECH COMPANY GENERALLY
SPEAKING WOULD NOTED CONSIDER
ANY ANY RARE DISEASE WITH
PREVALENCE LOWER THAN A FEW
THOUSAND PATIENTS TO BE
COMMERCIALLY VIABLE.
SO A MAIN STAY OF WHAT DRIVES
THE DEVELOPMENT AND MARKETING
DISTRIBUTION OF DRUGS IN OUR
COUNTRY THAT IS THE
PHARMACEUTICAL INDUSTRY,
BIOPHARMACEUTICAL SECTOR IS
REALLY UNABLE TO ADDRESS THE
VAST MAJORITY OF DISEASES
BECAUSE OF THIS COMMERCIAL
LIMITATION, AND SO THAT'S AND
THAT'S BECAUSE THE PREVALENCE
CONSITUTE A VIABLE BUSINESS
PROMULGATE CISION, THERE ISN'T A
TYPICAL KIND OF COLLABORATION
WITH INDUSTRY THAT WE CAN COUNT
ON.
SO THIS IN TURN DRIVES A SECOND
CLASS OF PROBLEMS SO IF THESE
DISEASES ARE NOT THAT COMMERCIAL
VIABLE AND YOU CAN SEE THAT IS
REFLECTED IN THE COST OF
TREATMENT FOR THESE DISEASES,
THERE ARE A BUNCH OF FOLLOW ON
EFFECTS AND 1 OF THESE, SO SOME
OF THESE ARE LISTED IN THE
CENTER BOX, SO 1 THING THAT
HAPPENS IS THAT INTELLECTUAL
PROPERTY, THERE IT IS ARE VERY
STRONGLY ENFORCED SO THAT IS
PROPRIETARY KNOW HOW AND THESE
ARE NOT GENERALLY SHARED BECAUSE
OF COMMERCIAL MARKET IS SO TIGHT
THAT MEANS IF YOU'RE AN
RESEARCHER, NIH RESEARCHER,
PATIENT, FOUNDATION WORK NOTHING
A RARE DISEASE, YOU WILL HAVE
VERY LITTLE ACCESS, PROBLEMATIC
ACCESS TO THE KINDS OF EXPERTISE
AND RESOURCES YOU NEED TO
DEVELOP THE GENE THERAPY.
CONSEQUENTLY BECAUSE OF THESE OF
WHAT IT COSTS TO MANUFACTURE
THIS, GENES CAN BE EXTREMELY
HIGH TO GENERATE ENOUGH AV GENE
VECTOR EVEN TO CONDUCT PHASE 1
CLINICAL TRIAL CURRENT MARKET
COSTS ARE 5 MILLION OR MORE.
AND EVEN IF YOU HAVE 5 MILLION
OR MORE, IT'S TIGHTLY HELD AND
IT'S DIFFICULT TO GET A
MANUFACTURING SLOT THAT
IS--MANUFACTURING FACILITIES ARE
SO TIED UP IN COMMERCIAL
PRODUCT, VERY HARD TO GET A
NONCOMMERCIAL PRODUCT MADE EVEN
IF YOU HAVE TO FUND IT.
AND THEN THE THIRD PROBLEM IS
BECAUSE OF THESE ISSUES IN
ACCESSIBILITY IN THE GENERAL
COMMUNITY THERE'S A LACK OF
THESE IN MAKING GENE VECTORS AND
CERTAINLY A LACK OF EXPERIENCE
INTO THE PRECLINICAL DEMANDS IN
TERMS OF GOING FROM THE AAV GENE
CONSTRUCT THAT WORKS IN THE LAB
THROUGH THE DEVELOPMENT PROCESS
TO A POINT WHERE MAYBE GENE
CANDIDATE, GENE THERAPY
CANDIDATE CAN BE EVALUATED BY
THE CLEARANCE AND THE TESTING SO
IT'S A FOLLOW ON, SET OF
PROBLEMS AND SO, WHAT WE'RE
SEEKING TO ADDRESS IN THE AGT
PROGRAM IS TO MAKE THAT AN OPEN
BOOK, PROCESS INSTEAD SO INSTEAD
OF HAVING THE ENTIRE METHODOLOGY
AND ROADMAP THROUGH AAV GENE
THERAPY IS A HELD TIGHT CLOSE
SECRET, PUT IT TOGETHER AND MAKE
A PUBLIC VERSION, OPEN BOOK,
PUBLIC VERSION OF HOW TO
CONSTRUCT AN AAV GENE THERAPY
AND HOW TO THAT I CAN THAT GENE
THERAPY CANDIDATE ALL THE WAY
THROUGH PRECLINICAL DEVELOPMENT
AND SUBMITTING THAT DATA PACKAGE
TO FDA FOR THAT IND PACKAGE FOR
CLEARANCE INTO PHASE 1 TRIALS.
MORE OVER WE WILL TRY TO SHOW
SOME ECONOMY OF SCALE.
THE WHOLE PROMISE OF GENE
THERAPY IS THAT IT'S A PLATFORM
THAT IS THE VERY SAME OUTSIDE
VECTOR, THE CAPSID, THE AAV
VECTOR CAN BE THE SAME BUT CAN
BE USED TO TREAT DIFFERENT
DISEASES BY SWAPPING IN
DIFFERENT GENE THERAPY PAY
LOADS, DIFFERENT GENE CONSTRUCTS
INTO THE PAY LEAD SIDE UP IN AAV
GENE VECTOR SO WE CAN SHOW THAT
BY DEVELOPING 4 THERAPIES AT
ONCE.
WE WILL USE THE SAME OUTSIDE
GENE THERAPY VECTORS SO AAV 9,
WHICH IS A CAP SID TYPE OF AAV
THAT HAS VERY BROAD TROAPIC--SO
THAT IS AAV 9 OR CAN BE USED TO
TRANSDUCE SO IN THE CNS, IN THE
PERIPHERY, WE WILL MAKE THESE
VECTORS SO THAT CAN BE
ADMINISTERED THROUGH THE SAME
ROUTE OF AND ADMINISTRATION, AND
IMPORTANTLY FOR THE FDA, AND FOR
THE PRECLINICAL REGULATORY
PROCESS, USE THE IDENTICAL
PRODUCTION MANUFACTURING AND
PURIFICATION METHODS SO THE ONLY
THING THAT WILL BE DIFFERENT AS
I WAS MENTIONING IN THE CONTEXT
OF A PLATFORM IS THAT THESE 4
DRUGS WILL HAVE DIFFERENT GENE
CONTRUCTS INSIDE OTHERWISE THEY
WILL BE IDENTICAL AND THIS
SHOULD SHOW THE ECONOMY OF SCALE
USING IDENTICAL PRECLINICAL
PLGHTS BUT USING THAT TO CARRY
DIFFERENT PAY LOADS TO ADDRESS
DIFFERENT DISEASES.
SO, THE GOAL, NUMBER 1, IS TO
MAKE THIS REALLY AN OPEN BOOK, A
PUBLIC METHODOLOGY THAT CAN BE
WIDELY DISSEMINATED AND ANYBODY
COULD FOLLOW ALONG WITH THEIR
OWN GENE THERAPY STRATEGIES
WITHOUT ANY STRINGS ATTACHED SO
IT'S PART OF THAT GOAL TO USE
REAGENTS AND PROCESSES INCLUDING
MANUFACTURING PROCESSES THAT ARE
FREE INTELLECTUAL PROPERTY
CONSTRAINTS, SO THEREFORE ON TOP
OF SCIENCE, THERE PONENT BE ANY
ISSUES ABOUT HAVING TO PAY VERY
COSTLY LICENSING FEES WHICH
CURRENTLY IS QUITE COMMON.
AND SO IMPORTANTLY, AS I SAY, WE
WILL MAKE ALL THE METHODS AND
PROTOCOLS, THROUGH THE AAV
PACKAGES AND SUBMIT TO THE FDA
PUBLIC AND WE WILL BE POSTING
ON OUR WEBSITE IN REALTIME AS
WELL AS FDA FEEDBACK.
THIS IS A REALLY IMPORTANT
COMPONENT OF NEW DRUG
DEVELOPMENT THAT IS GETTING FDA
FEEDBACK ALONG THE WAY, AS YOU
PRIMATES PAIR TO FILE AN IND
PACKAGE WITH THE FDA AND THAT
FEEDBACK AND VERY UNCOMMON TO
HAVE THAT SHARE, AND WE ARE
DELIGHT THAD FDA AGREED TO ALLOW
US TO SHARE THEIR FEEDBACK TO
OUR REGULATORY FILINGS ON OUR
WEBSITE AS WELL.
THAT'S THE GENERAL IDEA OF THE
PAVE GT PROGRAM AND I COULDN'T
RESIST THIS SLIDE, THIS JOKING
SHOWS MY AGE, NO 1 YOUNGER THAN
I WOULD KNOW WHAT THIS IS BUT IF
THERE'S ANYONE AS OLD AS I AM
THAT USED TO WORK ON CARS YOU
WOULD RECOGNIZE THE CHILTON
MANUEL OR MANUELS OF THIS SORT.
SO IN THE OLD DAYS BEFORE CARS
AND TRUCKS HAD MICROCHIPS AND
SUCH, YOU BEING WORK ON YOUR OWN
CAR AND SO--SO WE OFTEN THINK OF
PAVE GT PROGRAM AS NOT OF THE
MOST ADVANCED MOST AMAIDZING
GENE THERAPY VECTOR GENOME OR
BUT RATHER A GENE THERAPY VECTOR
WILL THAT BE GOOD FOR
EVERYTHING.
SO OR FOR EVERYONE ARE, SO THAT
THE GENE THERAPY VECTOR IS A
DRUG THAT ALMOST EVERYONE CAN
AFFORD, IT CAN TAKE ANY PAY LOAD
TO ALMOST ANYWHERE AND YOU CAN
GET ALL THE PARTS DOWN AT THE
CORNER STORE, AND YOU WILL HAVE
A MANUEL LIKE THE CHILTON MANUEL
THAT SHOWS YOU EXACTLY HOW TO
DEVELOP, MAKE AND REPAIR EVERY
SINGLE ASPECT OF THIS GENE
THERAPY VECTOR.
SO AGAIN, REALLY THE WATCH WORD
FOR AGT, IS ACCESSIBILITY
PARTICULARLY TO THE COMMERCIAL
SECTOR WOULD BE VERY UNLIKELY TO
PLAY A MAJOR ROLE.
SO I KNOW WE'RE RUNNING OUT OF
TIME.
JUST GIVE YOU A COUPLE MINUTES
ABOUT THE SCIENCE AND MORE AND
MORE OF THIS WILL COME OUT IN
PUBLICATIONS AND OUR WEBSITE,
BUT AS YOU IMAGINE, ALTHOUGH I
TRIED TO CONVEY THE IDEA OF THE
PAVE GT INITIATIVES, YOU KNOW AS
THOUGH IT WAS A SIMPLE IDEA,
IT'S ACTUALLY QUITE A
COMPLICATED PROCESS AND QUITE A
LARGE SCALE PROJECT SO AS I
MENTIONED, WE'RE DEVELOPING 4
GENE THERAPIES AT THE SAME TIME
IN PARALLEL, AND THESE ARE
DIVIDED UP INTO 2 PAIRS.
SO IT'S 2 PLUS 2 MODEL AND THE
REASON IS THAT THERE ARE A
NUMBER OF DISEASE STATES,
INDICATION THAT ESSENTIALLY
COULD COME TO BE, COULD ARISE
FROM DIFFERENT KINDS OF
MUTATIONS IN DIFFERENT GENES
THAT GIVE YOU MORE OR LESS THE
SAME DISEASE.
SO THIS IS WHAT WE'RE TRYING TO
ACHIEVE IN TERMS OF
DEMONSTRATING THE ECONOMY OF
SCALE AND DEVELOPING GENES FROM
THE VERY INCEPTION THROUGH
FREQUENT DEVELOPMENT ALL THE WAY
INTO CLINICAL STUDIES.
SO, WE'RE LOOKING AT 2 LIVER
DISEASES AND 2 ORGANIC
[INDISCERNIBLE], AND 2 CNSs, 2
CONGENITAL MY O SINNIAS, THOSE
ARE IN COLLABORATIONS, THOSE ARE
CLOS COLLABORATORS CHUCK
VENDITTI, AT THE HUMAN GENOME
AND CARSON BONNEMANN AT NINDS,
SO THEY'RE WORKING WITH US AND
DOING ALL THE HEAVY LIFTING FOR
THE GENE THERAPY CONSTRUCTS FOR
THESE 4 DISEASES, THE 2
MYASTHENIAS, AND THE 2 IND
PACKAGES.
SO DOING ALL THE
CHARACTERIZATIONS FOR THE PHARMA
CODE, KINETIC PROPERTIES AND
PROPERTIES OF THE GENE VECTORS,
SCALING THEM UP FOR
MANUFACTURING AND SHOWING THAT
THEY CAN BE MANUFACTURED HERE
AND FORMULATED INTO THE PRODUCTS
THAT THEY NEED TO BE AND
IMPORTANTLY TO SHOW IN
TOXICOLOGY STUDIES THAT THESE
GENE VECTORS SHOULD BE SAFE AND
ALONG THE WAY, BUILDING THE
REGULATORY FILINGS THAT WILL BE
NECESSARY FOR INITIAL
DISCUSSIONS WITH THE IND AND
THEN FOR A FINAL SUBMISSION OF
THE IND PACKAGE TO THE FDA, SO
IN OUR SHOP, [INDISCERNIBLE]
SCIENTISTS AND PROJECT MANAGERS,
IN OUR GROUP THAT ARE LEADING
THIS PROJECT ALONG WITH THE
OTHER 60 SCIENTISTS WE HAVE IN
OUR GROUP AND ALONG WITH A
NUMBER OF COMMERCIAL RESEARCH
ORGANIZATIONS AND COMMERCIAL
MANUFACTURING OPERATIONS, CROs
AND CMOs THAT ARE DOING THE
BULK OF THE LARGE SCALE
MANUFACTURING WORK.
AS THESE VECTORS ARE FINISHED,
THEN WE GO BACK TO CHUCK AND
CARSTEN, AND SO AS PART OF THE
ECONOMY OF SKILL, THEY ARE GOING
TO BE CONDUCTING UMBRELLA TRIALS
THAT IS TO USE THE SAME CLINICAL
PROTOCOL WITH THE SAME CLINICAL
END POINTS TO EVALUATE BOTH
PAIRS OF THESE VECTORS IN THE PC
CA, AND MAAD, ARE DIFFERENT
GENES AND DIFFERENT GENE
MUTATIONS BUT THEY CAUSE
DISEASES THAT MANIFEST SIMILAR
FASHION.
AND SO WE'RE HOPING THAT IN THE
NEXT YEAR OR 2, TO START THOSE
CLINICAL STUDIES EXPW WE'RE
EXCITED ABOUT WHERE WE ARE,
WHICH IS A LITTLE BIT ON THE
EARLY END BUT REALLY HITTING OUR
STRIDE.
I ONLY SHOWED 4 PICTURES THERE,
AND IN THIS SLIDE, STILL ONLY
SHOWING A FRACTION OF ALL THE
PEOPLE THAT ARE CONTRIBUTING
VERY CRITICALLY, TO THIS WORK.
OUR GROUP AT NCATS, OUR VARIOUS
GROUPS ADDED NCATS, NOT ONLY OUR
BRANCH THAT I TOLD YOU ABOUT BUT
THE OFFICE OF RARE DISEASES
RESEARCH, YOU CAN SEE PJ'S PHOTO
IN THE MIDDLE OF THAT BOX IN THE
UPPER CENTER, AND A LOT OF THIS
AS I MENTIONED, OR HINTED AT HAS
TO DO WITH LICENSING ISSUES,
INTELLECTUAL PROPERTY, SO, THE
ROLL OF OF OUR OFFICE OF
STRATEGIC ALLIANCES AND THAT AND
NHGRI AND NINDS HAVE BEEN QUITE
CRITICAL, VERY CRITICAL AS WELL.
THERE ARE CHUCK AND CARSTEN AND
FOLKS FROM THEIR GROUP AS WELL
AS OUR CLINICAL DIRECTOR AT
NICHD.
SO AGAIN, THIS IS JUST A SUBSET
OF PLAYERS THAT HAVE TO COME
TOGETHER TO MAKE THIS BIG
PROJECT WORK AND WE'RE HOPING
THAT IN THE END BY CONDUCTING
ALL OF THIS, DEVELOPMENT OF 4
GENE THERAPY VECTORS IN THE
PUBLIC DOMAIN, AND TO MAKE ALL
THE FILINGS AND EVEN THE FDA
FEEDBACK PUBLIC, THIS WILL
REALLY SERVE TO FACILITATE A
MUCH BROADER AND CHEAPER AND
APPROACHABLE PROPOSITION FOR THE
RARE DISEASE COMMUNITY SO THAT
OVER TIME GENE THERAPY AND IN
THIS PARTICULAR CASE WILL BE
MUCH MORE ACCESSIBLE TO ACADEMIC
SCALE WORK AND TO RARE DISEASES
BUT LOW, LOW, NUMBERS OF
PATIENTS AND IN THE END,
OBVIOUSLY THE GOAL IS TO REALLY
TRY TO MOVE THIS GRAPH A BIT, SO
THAT THE 500 DRUGS THAT ARE
APPROVED CURRENTLY THAT IS
ALMOST CREEPING UP YEAR BY WREER
THIS COULD BE 1 OF THE WAYS IN
WHICH WE COULD MAKE A REAL DENT
IN THE FRACTION OF DISEASES THAT
HAVE FDA APPROVED TREATMENTS.
SO THAT'S A THUMB NAIL SKETCH OF
THE PAVE GT PROGRAM.
I HAND IT OVER TO MY COLLEAGUE
T. J. BROOKS NEXT AND HAPPY TO
ANSWER ANY QUESTIONS AT THE END
OF THE HOUR.
THANK YOU DON
THESE ARE LEARNING OBJECTIVES I
WILL TALK ABOUT OR THE BGTC AND
BRIEFLY AT THE END IS TALKING
ABOUT OPPORTUNITIES FOR THE NIH
AND THE SOMATIC CELL GENOME
EDITING PROGRAM THEY THINK WILL
BE OF INTEREST TO THIS SLIDE.
SO THIS IS THE BGTC AND
ORGANIZED BY THE FOWBDATION FOR
THE NIH WHICH VERY IMPORTANTLY
IS NOT PART OF THE NIH AND THAT
HAS IMPLICATIONS FOR HOW WE CAN
DO THIS THERE YOU CAN SEE THE
GROUP, MIERS, PETER MARKS, AT
FDA WHO WAS REALLY INVOLVED IN
SPEARHEADING THIS PROGRAM AND
GETTING IT OFF THE GROUND WITH
GREAT MANAGEMENT AND
PARTICIPATION FROM COURTNEY AND
BRAD FROM THE NIH.
NEXT SLIDE.
SO THE GOALS OF THE BGTC ARE IN
SOME WAYS SIMILAR TO THOSE OF
PAVE GT WHICH IS TO AAV
TECHNOLOGY MORE ACCESSIBLE
PARTICULARLY FOR DISEASES OF NO
COMMERCIAL INTEREST.
ACCELERATE THE POTENTIAL OF THE
STREAMLINE OF CLINICAL AND
PREPRODUCT TESTING AND
FACILITATE SCIENTIFIC AND
REGULATORY ADVANCE THAT WILL
BENEFIT THE WHOLE FIELD OF AAV
GENE THERAPY AND ULTIMATELY
BRING GENE THERAPIES TO
INDIVIDUALS IN NEED SOONER.
NEXT SLIDE.
SO THERE'S BASICALLY 2
COMPONENTS TO THE BGTC AND WE
ALL A BASIC BIOLOGY COMPONENT ON
THE TOP WHICH IS FOCUSED ON NOT
JUST A BASIC BIOLOGY OF AAV IN
GENERAL, BUT MORE SPECIFICALLY
TO ENHANCE VECTOR GENERATION AND
ALSO ENHANCE THERAPEUTIC GENE
EXPRESSION IN PEOPLE AND THERE'S
ALSO A CLINICAL COMPONENT THAT
IS FOCUSED ON WHAT WE CALL
BESPOKE CLINICAL APPLICATIONS,
IN THIS CASE, IT'S REALLY
ANOTHER WAY OF SAYING DISEASE OF
NO COMMERCIAL INTEREST, WE'RE
TRYING TO STANDARDIZE VARIOUS
ASPECTS OF THE PROJECT AND TO
COME UP WITH A PATHWAY TO START
UF AAV GENE THERAPY CLINICAL
TRIALS MORE EFFICIENTLY.
NEXT SLIDE.
AND THESE 2 EFFORTS ARE RELATED
TO EACH OTHER, ULTIMATELY WE
ANTICIPATE THAT THEY ENHANCING
VECTOR GENERATION WILL IMPACT
VECTOR MANUFACTURING AND
ANALYTICS IN THE CLINICAL
COMOPPOSITE BEHAVIORIAL
PHENOTYPE AND THEN THE SIMILARLY
WE HOPE THAT ENHANCING GENE
EXPRESSION IN PATIENTS CAN BE
INCLUDED IN SOME OF OUR CLINICAL
TRIALS.
TO THE EXTENT THAT WE CAN
IDENTIFY WAYS TO IMPROVE BOTH OF
THOSE STEPS.
NEXT SLIDE.
SO AS WE'RE SETTING UP BCGT,
WITH THIS, WE HAD A LOT OF
PARTICIPANTS WITH INDUSTRY AND
ACADEMIA INVOLVED AND SOME HICK
UPS WITH COVID, BUT WE THOUGHT
ABOUT A WAY TO,A PROVE AAV
VECTOR PRODUCTION WOULD BE TO
FOCUS ON THE INDIVIDUAL STEPS
INVOLVED IN MAKING AAV GENE
THERAPIES AND THAT WOULD INCLUDE
THE STEPS INVOLVED FROM PUTTING
THE THERAPEUTIC GENE CONSTRUCT
AND THE HELPER VIRUSES AND
THINGS INTO CELLS AND THEN WHAT
HAPPENS TO THOSE CONSTRUCTS IN
THE CELLS AND KIND OF IDENTIFY
EACH INDIVIDUAL STEP AND SEE IF
WE CAN OPTIMIZE EACH 1 OF THOSE
INDIVIDUAL STEPS SEPARATELY.
AND WE PUT OUT A REQUEST FOR
PROPOSALS FOR APPLICATIONS IN
THE COMMUNITY ON HOW TO DO THIS
THAT REQUEST WAS CLOSED ON
FEBRUARY 18th.
NEXT SLIDE.
AND WE THOUGHT OF DOING
SOMETHING SIMILAR FOR IMPROVING
AAV GENE EXPRESSION TO THINK OF
ALL OF THE STEPS THAT HAPPEN
AFTER TARGET CELL IS INFECTED
WITH A THERAPEUTIC AAV CONSTRUCT
ALL THE WAY THROUGH THE PROCESS
OF PRODUCING THE THERAPEUTIC
GENE WHICH OF COURSE IS WHAT IS
NEEDED TO GET TO THERAPEUTIC
EFFICACY, IF YOU LOOK AT EACH 1
OF THOSE STEPS INDIVIDUAL LEE,
CAN WE OPTIMIZE EACH 1 OF THEM.
AND HERE AGAIN, WE HAD FUNDING
OPPORTUNITIES THAT WERE OPENED
UP AND NEXT SLIDE.
AND SO THE WHYED WE HAD IS TO
ASK THE COMMUNITY FOR HIGH
THROUGH PUT SCREENING COMPATIBLE
ASSAYS TO OPTIMIZE EACH OF THOSE
MECHANISTIC STEPS, WITH THE IDEA
THAT ONCE WE'VE GOTTEN THOSE
ASSAYS WE WOULD CARRY OUT HIGH
THROUGH PUT SCREENING EFFORTS
USING FOR EXAMPLE, WHOLE GENOME
SCREENS TO IMPROVE AAV VECTOR
GENERATION, OR SCREENING
APPROVED DRUGS IN TARGET CELLS
FOR THE CLINICAL TRIALS, FOR THE
PROJECTS ON ENHANCING
THERAPEUTIC GENE EXPRESSION AND
WE PLAN TO DO THIS WORKING WITH
THE NCATS INTRAMURAL HIGH
THROUGH PUT SCREENING FACILITY
BUT WE ALSO WROTE THESE FUNDING
OPPORTUNITIES TO BE OPEN TO
OTHER NOVEL APPROACHES AS WELL
TO CAST A VERY WIDE NET TO THE
COMMUNITY REALIZING THAT A GOAL
TO THESE--THE ULTIMATE RESULTS
OF THESE EFFORTS WERE ALL GOING
TO BE PUT INTO THE PUBLIC DOMAIN
AND THAT'S A VERY IMPORTANT
ASPECT OF THIS PUBLIC PRIVATE
PARTNERSHIP.
WE TRIED TO MAKE THE WHOLE THING
IN THE PRECOMPETITIVE SPACE SO
WE COULD PUT ALL THE DATA AND
ALL THE RESULTS INTO THE PUBLIC
DOMAIN TO BENEFIT THE WHOLE
COMMUNITY AND THAT OF COURSE IS
OBVIOUSLY GOING TO LIMIT THE
KIND OF APPLICATIONS WE GET TO
THE EXTENT THAT PEOPLE ARE
WORKING ON THINGS WHERE THEY'RE
VERY CONCERNED ABOUT
INTELLECTUAL PROPERTY AND THEY
WOULD OBVIOUSLY NOT APPLY AND WE
DID UNDERSTAND THAT AND DO
UNDERSTAND THAT.
NEXT SLIDE.
SO THE APPLICATIONS WERE
RECEIVED IN FEBRUARY AND WE'RE
STARTING THE REVIEW PROCESS OF
THEM.
AS WE GO THROUGH THEM WE'RE
IDENTIFYING YOU KNOW DIFFERENT
PROJECTS AND PLAN TO HAVE A
FORMAL REVIEW IN THE NEXT FEW
WEEKS OR SO, I WOULD LIKE TO
MENTION THERE IS A POSSIBILITY
THAT WE MAY END UP RELEASING
ADDITIONAL FUNDING
OPPORTUNITIES.
SO THOSE OF YOU WHO THINK YOU
MIGHT HAVA AN INTEREST IN THIS
AND MAY HAVE MISSED THE FIRST 1
THERE'S POSSIBILITY OF
ADDITIONAL FUNDING OPPORTUNITIES
IN THE FUTURE.
NEXT SLIDE.
SO 1 OF THE THINGS WE'RE DOING
WITHIN THE MANUFACTURING WORK
STREAM OF THE BGTC IS TO SEE IF
YOU CAN DEVELOP A MINIMAL SET OF
QUALITY ATTRIBUTES THAT WOULD BE
USED TO DETERMINE IF A AN AV,'S
MANUFACTURED IN PHASE, YOU MIGHT
THINK THAT THE FACT THAT THE
IDEA OF DIFFERENT SETS OF DATA,
DEMONSTRATE SAFETY, OF SAFETY
ATTRIBUTES, SO, WORKING WITH A
GROUP OF INDIVIDUALS FROM BOTH
PUBLIC AND PRIVATE ENTITIES AT
THIS MINIMAL SET.
MEETING EVERY OTHER WEEK NOW TO
KIND OF NARROW IT DOWN, IT'S A
SURPRISINGLY, COMPLICATED
PROCESS BUT I THINK WE'RE MAKING
GOOD PROGRESS ON IT, AND WE'RE
REALLY FOCUSED ON THINGS THAT
WOULD BE INDEPENDENT OF THE
TYPE, SORT OF STANDARDIZED TYPES
OF ASSAYS YOU DOA THAT WOULD BE
RELEVANT ANY AAV THAT WOULD GO
INTO HUMANS, THINGS LIKE FOR
EXAMPLE, DETERMINING THAT IT'S
STERILE.
THE HOPE IS THAT WE CAN
ULTIMATELY COME UP WITH THIS
MINIMAL SET OF ATTRIBUTES AND
THEN WE WILL HAVE A DISCUSSION
WITH THE F, DIDA TO GET THEIR
FEEDBACK, AND AGAIN WITH THE
GOAL OF DEVELOPING SORT OF A
STANDARD HERE THAT CAN BE USED
BY OTHER INVESTIGATORS, NOT ONLY
WITHIN THE UNITED STATES, BUT
EVEN IN ON THE COUNTRIES AS
WELL.
AND THEN OF COURSE WE WILL USE
THOSE ATTRIBUTES IN OUR OWN
CLINICAL TRIALS WITHIN THE GGTC
AND THIS IS 1 TIEWNLT WHERE I
THINK WE CAN HAVE SOME ACTION
WITH PAVE GT AS WELL.
THE NEXT SLIDE.
SO THE IDEA OF THE CLINICAL
PROGRAM IS REALLY AGAIN SIMILAR
TO PAVE GT IS TO NOT TRY TO DO
ANYTHING NEW AND CUTTING EDGE
WITH REGARD TO THE VECTORS, WE
WANT TO SPECIFICALLY USE THE
VECTORS THAT HAVE BEEN USED
PREVIOUSLY FOR AAV GENE THERAPY
TRIALS WHERE THERE'S APPROVED
INDs, WE WANT TO WORK WITH
MANUFACTURES WHO HAVE MADE
VECTOR AND GOTTEN INDs AND
BASICALLY TAKE THOSE SAME
PROCESSES, AND PUT DIFFERENT
THERAPEUTIC GENES IN AND
ULTIMATELY COME UP WITH A
THERAPEUTIC STREAMLINE PLATFORM
TO GET TO CLINICAL TRIALS AND
REALLY TO TRY TO ALSO TAKE
ADVANTAGE OF MASTER FILES AND
PREVIOUS DATA THAT THESE
DIFFERENT MANUFACTURES WILL HAVE
IN EXPERIENCE WITH THE FDA.
AND SO WE ANTICIPATE THAT VECTOR
MANUFACTURING WITHIN THE
VTT WILL BE DONE BY SOME OF THE
COMMERCIAL PARTNERS THAT ARE
PARTICIPATING IN THE PROGRAM.
AND WE ENVISION HAVING A LIMITED
NUMBER OF AAV SEROTYPES, THESE
WILL BE 1S THAT HAVE ALREADY
BEEN USED IN CLINICAL TRIALS AND
A LIMITED NUMBER OF DELIVERY
MODALITIES TO TRY TO GET
DIVERSITY OF TISSUES TO INSURE
THAT THIS CLINICAL TRIAL
PIPELINE IS AS BROAD AS WE CAN
POSSIBLY MAKE IT.
NEXT SLIDE.
SO TO DO THE CLINICAL TRIAL
WOULD BE LOOKING FOR PERHAPS 5
OR 6 DISEASES THAT HAVE A HIGH
LIKELIHOOD OF CLINICAL SUCCESS
FOR AAV GENE THERAPY TO BE
SELECTED BY THE STEERING
COMMITTEE AND SO, WE WOULD BE
THINKING BASICALLY OF YOU KNOW
SINGLE GENE DISORDERS, VERY
IMPORTANTLY THESE HAVE TO BE
DISEASE WHERE THERE'S NO
COMMERCIAL INTEREST.
WE WOULD LIKE TO HAVE DISEASES
WITH THE CLINICAL OUTCOMES CAN
BE ASSESSED IN A FAIRLY SHORT
PERIOD OF TIME, ALREADY
ASSEMBLED PATIENT GROUPS,
CLINICAL INVESTIGATORS, ET
CETERA.
AND TO RUN THESE PROGRAMS AND
BASED ON DEVELOPING THEM,
ULTIMATELY COME UP WITH THE
STANDARDIZED PROCESS FOR
STARTING OFF CLINICAL TRIALS
EMPLOY AND SO THE WAY WE'VE DONE
THIS IS BASICALLY PUT OUT A
FUNDING OPPORTUNITY AND ASK THE
COMMUNITY TO SUBMIT THEIR
PROPOSED DISEASES FOR
CONSIDERATION.
NEXT SLIDE.
AND SO, YOU OPEN THAT PROCESS,
WE'VE GOTTEN MULTIPLE
SUBMISSIONS AND WE'RE NOT GOING
TO BE TRYING TO DOWN SELECT TO
GET TO A SMALLER NUMBER OF
DISEASES AND ULTIMATELY CHOOSE
THE 5 OR 6 OR SO THAT WE WILL
ULTIMATELY STUDY AND
IMPORTANTLY, THESE WILL HAVE TO
BE PAIR WTD VECTOR MANUFACTURING
FOR DOING THE FIRST IN HUMAN
CLINICAL TRIALS.
NEXT SLIDE.
AND ULTIMATELY COME OUT OF THIS
IS SOMETHING LIKE A MANUEL FOR
AAV GENE THERAPY CLINICAL
DEVELOPMENT, INSIGHTS AND
LEARNINGS THAT FACILITATE THE
SUCCESS OF FUTURE GENE THERAPYS,
INCLUDING IMPROVEMENTS IN AAV
TARGET GENE EXPRESSION,
IMPROVEMENT NEGLIGENCE THE WAY
WE MAKE CLINICAL AAV VECTORS
THIS HARMONIZED AND VALIDATED
SET OF CLINICAL QUALITY
ATTRIBUTES AND STANDARDIZED
REGULATORY SUBMISSION PACKAGE
AND TEMPLATES, IN PARTICULARLY
REALLY UTILIZING EXPLOITING
VECTOR MASTER FILE SO THAT WHEN
NEW DISEASES NEED TO BE
ADDRESSED AND THERAPIES FOR NEW
DISEASE NEED TO BE ADDRESSED
MANUFACTURES CAN RELAY AS MUCH
AS POSSIBLE ON PREVIOUSLY
GENERATED DATA ON THE PRODUCTION
OF THOSE AAV VECTORS.
AGAIN, A VERY SIMILAR IDEA TO
WHAT WE HAVE IN PAVE GT.
NEXT SLIDE.
SO THESE ARE THE PARTNERS WE
HAVE IN THE BGTC, YOU CAN SEE WE
HAVE PARTICIPATION IN MULTIPLE
NIH INSTITUTES AND CENTERS, 11
DIFFERENT ENTITIES, VERY
IMPORTANTLY, WE HAVE THE ACTIVE
PARTICIPATION OF THE FTA CENTER
FOR BIOLOGICS, AND AS I SAID,
PETER MARK SYSTEM INTIMATELY
INVOLVED IN INITIATING THIS
PROGRAM WHICH WAS CRUCIAL FOR
ITS SUCCESS ON THE RIGHT YOU CAN
SEE OUR VARIOUS OTHER PARTNERS
INCLUDING MULTIPLE FOR PROFIT
ENTITIES AS WELL AS NONPROFITS
AS WELL.
SO OVERALL QUITE LARGE
CONSORTIUM.
NEXT SLIDE.
SO THE WAY THE STRUCTURE THAT
WORKS WE HAVE AN EXECUTIVE
COMMITTEE THAT OVERSEES THE BGTC
AND THIS COMMITTEE SEES A LOT OF
OTHER FNIH ACCELERATED MEDICINES
PARTNERSHIP, OUR STEERING
COMMITTEE IS MADE UP OF 50% NIH
AND 50% PRIVATE SECTOR
INDIVIDUALS, AND WE'VE GOT
DIFFERENT AND TRY TO ADDRESS ALL
THE DIFFERENT ASPECTS THAT WE'RE
TRYING TO ACHIEVE AND THEN THE
BGTC.
NEXT SLIDE.
AND SO THIS KIND OF GOES THROUGH
SOME OF THE DIFFERENT COMMITTEE
ROLES AND I WON'T GO THROUGH
THIS IN A LOT OF DETAIL, BUT YOU
CAN SEE HOW WE'RE TRYING TO
DEVELOP THE OVERSIGHT OF THE
BGTC TO INCLUDE THE PERSPECTIVES
AS BOTH THE DEFENDANT AND THE
PRIVATE SECTOR, SINCE THIS IS OF
COURSE A PRIVATE PUBLIC PRIVATE
PARTNERSHIP, AND THERE ARE
ASPECTS OF THIS THAT
WILL--ULTIMATELY ALL OF THE DATA
WILL COME OUT TO THE PUBLIC
DOMAIN BUT WE ANTICIPATE HAVING
ANNUAL MEETINGS AND INCLUDING
SOME THAT WILL OPEN TO THE
PUBLIC SO THE PUBLIC AND THE
COMMUNITY CAN SEE THE PROGRESS
THAT WE'VE BEEN MAKING.
NEXT SLIDE.
AND THESE ARE SOME OF THE
SPECIFIC ROLES AGAIN, I WON'T
DWELL ON THIS FOR THE SAKE OF
TIME.
BUT I WOULD ALSO NOTE DOWN
THERE, WE'VE ALSO INCLUDED IN
THE BGTC, GROUPS REPRESENTING
PATIENTS INCLUDING THE NATIONAL
ORGANIZATION FOR RARE DISEASES,
AND WE'VE GOT A LOT OF THOUGHT
TO THE COMMUNICATIONS INVOLVED
IN THE BGTC SO THAT AS WE DO
MAKE PROGRESS, WE COMMUNICATE
THAT PROGRESS IN WAYS THAT MAKE
SENSE TO THE DIFFERENT
STAKEHOLDERS WHO WILL BE
RECEIVING IT.
NEXT SLIDE.
SO IN TERMS OF THE TIMELINES,
WE'RE NOW IN 2022 AS I SAID
WE'VE GONE PAST, GOTTEN
APPLICATIONS FOR THE DIFFERENT
WORK ALREADY REVIEWING THOSE AND
HOPE TO HAVE PROGRESS IN TERMS
OF IDENTIFYING DISEASES WE WANT
TO STUDY, BY THE END OF APRIL AS
WELL AS MORE PROGRESS ON SOME OF
THE OTHER INITIATIVES, TO
ULTIMATELY GET TO THE POINT
WE'RE STARTING TO SEE RESULTS
AND OF COURSE, WE WILL BE
KEEPING THE COMMUNITY UPDATED AS
WE MOVE THROUGH THIS EFFORT.
NEXT SLIDE.
JUST TO KIND COMPARE THE BGTC
AND PAVE GT BECAUSE THEY SOUND
SIMILAR, THERE ARE CERTAIN
SIMILARITIES BUT THERE ARE
DIFFERENCES IN THE BGTC, WE
CHOSE 4 DISEASES OF INTEREST AND
THE NIH CLINICAL CENTER, AND THE
BGTC AS WE'RE SING PROBABLY 5 OR
6 OR SO WE WILL HAVE A SINGLE
MANUFACTURE OF MAKING ALL 4
VECTORS AND THE BGTC WILL HAVE A
CONSORTIUM IN BOTH CASES WE PLAN
TO MAKE THE INFORMATION AS
PUBLIC ULTIMATELY WITH PAVE GT,
WE PLAN TO DO THAT A LOT MORE, A
LOT SOONER AND A LOT MORE
EXPLICITLY, AND WE HOPE THAT THE
BGTC WE'LL SEE HOW THE TIMING
GOES ON THAT.
AND PAVE GT WILL DO ALL THE WORK
OF THE NIH CLINICAL CENTER,
WHEREAS IN THE BGTC WE
ANTICIPATE DIFFERENT CLINICAL
SITES WHICH MAY IN FACT INCLUDE
THE NIH CLINICAL CENTER, AND
AGAIN THE PAVE GT IS A SINGLE
SEROTYPE AND BGT IS MULTIPLE
SEROTYPES.
NEXT SLIDE.
AND THEN JUST AT THE LAST FEW
MINUTES HERE, I WANTED TO
BRIEFLY MENTION SOME PROGRESS ON
THE NIH SOMATIC CELL GENOME
EDITING PROGRAM, THIS IS 1 THAT
IS FUNDED THROUGH THE NIH COMMON
FUND THAT NCATS IS INVOLVED IN,
COORDINATE ALONG THAT WITH
NINDS, AND MANY OTHER NIH
INSTITUTES AND CENTERS
PARTICIPATING AS WELL.
SO THE PHASE 1 OF THE PROGRAM
WAS DESIGNED TO LOWER THE
BARRIERS FOR THE GENOME EDITING
THERAPIES BY DEVELOPING BETTER
ANIMAL MODELS FOR TESTING GENOME
EDITING READS AND DELIVERY
SYSTEMS.
BETTER WAYS TO ASSESS THAN
BIOLODGEICAL EFFECTS OF GENOME
EDITING A BIG COMPONENT ON
IMPROVING GENOME EDITING OF THE
MACHINERY.
EXPANDING THE HUMAN GENOME
EDITING REPERER TWOAR AND
COORDINATING AND DISSEMINATION
FUNCTION THAT WOULD PUT UP INTO
A PUBLIC TOOL KIT ALL OF THE
DISCOVERIES THAT HAVE BEEN MADE
UNDER THE SCG PHASE 1 PROGRAM.
NEXT SLIDE.
AND IF YOU JUST CLICK THROUGH
THAT, YOU CAN CLICK IT AGAIN,
WE'VE HAD MULTIPLE PUBLICATIONS
THAT WE'VE SUPPORTED THROUGH THE
SCG PHASE 1, MOST OF THEM
FOCUSED ON DEVELOPING BETTER
TOOLS AND INCLUDING THE PRIME
EDITOR THAT WE PROVIDED SOME OF
THE FUNDING FOR AND BETTER
DELIVERY TECHNOLOGIES BUT, NEXT
SLIDE.
THERE IS AN OUTPATIENT SETTING
FOR COMPLON FUND PROGRAMS TO
HAVE MULTIPLE PHASES, UP TO
25-YEAR PHASES SO WE HAVE IN
FACT PROPOSED THE SECOND PHASE
WHICH WILL BE MORE FOCUSED ON
GETTING INTO THE CLINIC WHERE
PHASE 1 WAS REALLY ALL ABOUT
TECHNOLOGY DEVELOPMENT AND 1 OF
THE INITIATIVES WE PROPOSED IN
PHASE 2, AND BETTER DEVELOPMENT
OF BETTER GENOME EDITING ASSAYS
THAT WOULD BE ESSENTIALLY
QUALIFIED OR AT THE LEVEL OF
PRECISION THAT WOULD BE
ULTIMATELY REQUIRED FOR
REGULATORY APPROVAL.
WE WOULD LIKE TO THINK THAT SOME
OF THESE WOULD ULTIMATELY BECOME
PART OF THE STANDARD FDA
APPROVAL PROCESS ALTHOUGH WE
CAN'T KNOW THAT BUT THAT'S A
GOAL.
SO THESE WILL BE 3 YEAR AWARDS
TO DEVELOP THESE NEW ASSAYS.
NEXT SLIDE.
INITIATIVE 2 WILL BE FOCUS
SPECIFICALLY ON IND ENABLING
STUDIES IN DIFFERENT DECS WITH
DIFFERENT TARGET TISSUES.
AND THE GOAL OF THESE AWARDS
WILL BE TO DEVELOP PACKAGES OR
BRING THINGS ALL THE WAY UP TO
THE POINT OF GETTING AN IND
WITHOUT GOING INTO THE CLINICAL
TRIAL WITH THE HOPE THAT ONCE AN
IND IS ATTAINED, THAT WILL MAKE
IT MORE ATTRACTIVE FOR OTHER
ENTITIES TO PICK UP THE IND AND
ULTIMATELY SUPPORT THOSE
CLINICAL TRIALS.
THESE WILL BE 5 YEAR AWARDS.
NEXT SLIDE.
AS YOU TALKED A LOT ABOUT
THERAPEUTIC PLATFORMS, GENOME
EDITING IS BY DEFINITION ALMOST
THERAPEUTIC PLATFORM, SO
INITIATIVE 3 OF THE COMMON FUND
THAT WE ENVISION WILL FOCUS
ACTUALLY ON PLATFORM CLINICAL
TRIALS AND THE IDEA OF
BEING--THIS WILL BE A BI PHASIC
PROGRAM, THE FIRST FACE WILL BE
TO GET AN IND AND THE SECOND
PHASE TO CARRY OUT A CLINICAL
TRIAL WITH THE IMPORTANT
REQUIREMENT THAT THESE CLINICAL
TRIALS WILL HAVE TO INVOLVE MORE
THAN 1 DISEASE, SO THE IDEA
WOULD BE, YOU WOULD HAVE 1
EDITOR, ON 1 DELIVERY SYSTEM,
BUT MORE THAN 1 DISEASE.
AND TO REALLY SEE IF WE CAN
ESTABLISH A CLINICAL TRIAL
PLATFORM FOR GENOME EDITING.
NEXT SLIDE.
COORDINATION CENTER THROUGHOUT
THE SCGE PROGRAM THAT WILL
SUPPORT SEMIANNUAL MEETINGS BUT
ALSO IMPORTANTLY DATA AND
PROTOCOL SHARING AND ULTIMATELY
ACROSS THE BROADER COMMUNITY SO
THAT THE RESULTS OF THESE
EFFORTS CAN BE EXTENDED THROUGH
THE MUCH BROADER COMMUNITY
FOCUSED ON DEVELOPING TREATMENTS
FOR FOR SINGLE GENE DISORDERS,
BOTH RARE AND COMMON IN FACT.
úNEXT SLIDE.
VERY LAST THING I WILL SAY IS I
POINTED THIS OUT, BECAUSE WE
ANTICIPATE--I CAN TALK ABOUT
THIS BECAUSE WE PUBLISHED NOW
THESE NOTICES OF INTENT TO
PUBLIC FUNDING OPPORTUNITIES SO
THESE ARE THESE FORMAL NOTICES
TO,A LETTER THE COMMUNITY THAT
WE WILL BE HAVING THESE FUNDING
OPPORTUNITIES COMING UP AND I
POINT OUT HERE BECAUSE IN THE
PAST NIH INTRAMURAL
INVESTIGATORS HAVE BEEN ABLE TO
APPLY FOR A COMMON FUND PROGRAMS
AND WE ANTICIPATE THAT WILL BE
THE CASE FOR THESE 1S AS WELL,
SO THESE ARE THE NOTICE OF
INTENTS TO PUBLISH THAT PEOPLE
CAN LOOK THROUGH IF THERE'S
INTEREST.
AND I THINK THAT'S MY LAST
SLIDE.
SO I WILL THANK YOU ALL FOR
LISTENING ON BEHALF OF DON AND
MYSELF.
I THINK WE HAVE QUESTIONS
SUBMITTED LATER WE CAN TRY TO
ADDRESS THEM VIA E-MAIL BUT
THANK YOU VERY MUCH.
>> YEAH, THANK YOU DR. BROOKS
AND DR. LO, FOR SHARING REALLY
THOUGHT-PROVOKING PRESENTATIONS
ON THE PAVE GT AND THE BGTC
INITIATIVES, YOU KNOW TO ADVANCE
THESE TECHNOLOGIES WITH THE GOAL
OF PURSUING, THE GOAL OF YOU
KNOW EXPANDING REACHING GENE
THERAPIES FOR MANY MORE PATIENTS
WITH RARE DISEASES, YOU ARE
RIGHT WE HAVE SEVERAL QUESTIONS
BECAUSE OF YOUR PRESENTATIONS,
AND I WILL FORD THEM TO YOU SO
I'M SORRY WE CAN'T ANSWER THEM
HERE BUT I WANT TO THANK THE
BOTH OF YOU AND THE NIH
COMMUNITY FOR JOINING US TODAY
AND I WISH EVERYONE A GREAT
AFTERNOON.
THANK YOU FOR JOINING US.