WE'RE GOING TO GET STARTED.
IT'S MY PLEASURE TO WELCOME ALL
OF YOU TO OUR WORKSHOP ON
GENETIC STRATEGIES TO TREAT THE
EPILEPSIES.
SO THE IDEA FOR THIS WORKSHOP
STARTED A COUPLE OF YEARS AGO AT
AES, WHERE I WENT TO SEVERAL OF
THE PATIENT ADVOCACY SATELLITE
MEETINGS, AND EVERYBODY WAS
SAYING WE WANT GENE THERAPY FOR
OUR GENETIC EPILEPSY.
AND SO WE STARTED PLANNING THIS
AND FINALLY WE'RE ALL HERE, SO
THANKS TO EVERYONE FOR JOINING
US HERE TODAY, BOTH ONLINE, WE
HAVE QUITE A NUMBER OF PEOPLE
ONLINE AND PEOPLE HERE IN THE
ROOM.
SO IT'S MY PLEASURE TO FIRST
INTRODUCE DR. WALTER KOROSHETZ,
DIRECTOR OF NINDS, WHO'S GOING
TO OPEN THE WORKSHOP WITH SOME
INTRODUCTORY COMMENTS.
WALTER?
>> GOOD MORNING, FOLKS.
GOOD MORNING TO PEOPLE ONLINE.
APPRECIATE EVERYONE'S COMING AND
JOINING WITH THE GROUP, WHICH I
THINK IS GOING TO BE TALKING
ABOUT REALLY ONE OF THE MAIN
CHALLENGES FOR THE FUTURE, BUT A
LOT OF WORK HAS GONE IN TO
GETTING OURSELVES IN PLACE TO
KIND OF TAKE ON THIS CHALLENGE,
AND THAT'S TRYING TO GET
STRATEGIES TO TREAT THE GENETIC
EPILEPSIES.
SO SOME OF THIS MAY BRING BACK
SOME PAINFUL MEMORIES TO PEOPLE
ABOUT THE REALLY AMAZING
PROJECTS THAT WENT ON TO
IDENTIFY GENETIC CAUSES IN THE
EPILEPSIES, AND THIS TOOK
PROBABLY THOUSANDS OF PEOPLE
WORKING ON PROJECT, INCLUDING
TENS OF THOUSANDS OF SUBJECTS,
PEOPLE WITH EPILEPSY WORKING
TOGETHER TO COLLECT THE GENETIC
INFORMATION TO PHENOTYPE THE
PATIENT, AND THIS WAS DONE IN
WHAT WAS OUR FIRST CENTER
WITHOUT WALLS FOR EPILEPSY,
WHICH IS A PROGRAM THAT WE FOUND
TO BE SO SUCCESSFUL THAT WE
CONTINUED IT NOT ONLY IN
EPILEPSY, WE'RE TRYING TO MOVE
IT INTO SOME OF OUR OTHER GRANT
MECHANISMS AS WELL.
WE ALSO HAD -- CWOW WAS LOOKING
AT THE VERY TRAGIC PROBLEM OF
SUDDEN UNEXPLAINED DEATH IN
EPILEPSY, A PROJECT TRYING TO
GET AT HOW WE MIGHT PREVENT
EPILEPSY IN A CONDITION THAT MAY
LEAD TO TRAUMATIC BRAIN INJURY
THAT'S GOT A HIGH RISK FOR
DEVELOPING EPILEPSY.
CLEARLY THAT WOULD BE ONE OF THE
HOLY GRAILS OF TRYING TO GET
CONTROL OF THIS PROBLEM WOULD BE
DEVELOP PREVENTIVE STRATEGIES.
THEN IN TERMS OF WORKING UP THE
GENE FINDINGS, WHICH ARE MANY,
WE HAVE TWO CWOWs, ONE LOOKING
AT THE ION CHANNEL EPILEPSIES
AND THE OTHER LOOKING AT THE
NON-ION CHANNEL VARIANTS THAT
ARE RELATED TO EPILEPSY.
AND SO CLEARLY ON THE GENETIC
SIDE, THERE'S A CLEAR KIND OF
LINEAR PATH FROM IDENTIFYING THE
ABNORMALITIES, TRYING TO MATCH
THEM UP WITH A PHENOTYPE, TRYING
TO THEN GO DOWN AND UNDERSTAND
WHAT THE MECHANISM OF THE
DIFFERENT GENETIC FORMS AND THEN
WHAT WE'LL BE TALKING ABOUT
TODAY IS HOW DO YOU ACTUALLY
TREAT THOSE.
SO I THINK THE GOOD NEWS IS THAT
WE'VE MADE A LOT OF PROGRESS.
THE BAD NEWS IS THAT WE'VE GOT A
LOT OF TARGETS TO PURSUE, AND IN
SOME INSTANCES, THERE'S NO
SUBSTITUTE FOR GOING REALLY IN
DEPTH AND VERY SPECIFIC GO AFTER
ONE MUTATION, WHAT DOES DO, WHAT
IS THE BEST WAY TO AMELIORATE
IT.
IT WOULD BE NICE, HOWEVER, IF WE
COULD KIND OF PARCEL THINGS
TOGETHER AND UNDERSTAND A
COUPLE -- SOME TREATMENTS THAT
MIGHT AFFECT MULTIPLE DIFFERENT
FORMS OF THESE EPILEPSIES, BUT
THE SUCCESS OF THAT REMAINS TO
BE SEEN, SUCCESS MEANING
SOMETHING BETTER THAN WHAT'S
ALREADY -- THAT'S HAPPENED WITH
SMALL MOLECULES.
AND THEN I THINK I'LL END UP
WITH THE IDEA THAT AS FOLKS HERE
HAVE BEEN LOOKING AT THE GENETIC
MECHANISM OF EPILEPSY, SOME
FOLKS IN THE EPILEPSIES, A LOT
OF FOLKS OUTSIDE THE EPILEPSIES
THAT HAVE BEEN TRYING TO DEVELOP
WAYS OF TREATING GENETIC
DISORDERS AND AGAIN, THEY FACE A
SIMILAR PROBLEM IN TERMS OF
SPECIFICITY AND ONE GOING RIGHT
AFTER ANOTHER, BUT THAT SEEMS TO
BE SOMETHING THAT WE'RE GOING TO
HAVE TO FACE IN ALL THE RARE
DISEASES, EPILEPSY IS A MODEL
BUT YOU'RE JOINING IN A LARGER
CROWD.
SO A COUPLE THINGS ARE STILL
GOING ON.
SO THERE ARE STUDIES LOOKING AT
THE GENETICS, LOOKING AT THE
CONTRIBUTION OF COPY NUMBER
VARIANTS AND GENETIC
ARCHITECTURE OF EPILEPSY.
THIS SLIDE IS A LITTLE OUT OF
PLACE BUT THERE WAS ANOTHER
RECENT STUDY PUBLISHED BY THE
INTERNATIONAL LEAGUE AGAINST
EPILEPSY CONSORTIUM FOR COMPLEX
EPILEPSIES LOOKING AT THE
GENETIC GENERALIZED EPILEPSIES
AND IDENTIFYING 26 LOCI SPECIFIC
FOR FAMILIAL GENETIC EPILEPSY,
AND I THINK THE POINT OF THIS
PAPER, WHICH I THOUGHT WAS
IMPORTANT, IS THAT IF YOU TAKE
ALL THE EPILEPSIES TOGETHER AND
YOU LOOK, YOU HAVE SO MUCH NOISE
THAT OFTENTIMES YOU MISS THINGS,
BUT IF YOU CAN REALLY GET THE
PHENOTYPING DOWN, THAT THINGS
WILL POP UP THAT ARE SIGNIFICANT
AND IMPORTANT TO FOLLOW UP ON.
THIS PAPER ALSO LOOKED AT SOME
OF THESE VARIANTS THAT THEY
FOUND ARE IN PATHWAYS AND THEY
TRIED TO MATCH THOSE PATHWAYS UP
TO PARTICULAR DRUGS, SOME OF
WHICH ARE USED IN EPILEPSIES,
SOME OF WHICH ARE NOT.
BUT AGAIN, IT'S ANOTHER THEME
THAT WHEN -- AND THIS HAS
HAPPENED CERTAINLY IN OTHER
GENETIC -- I THINK I'LL MENTION
ONE -- ONCE YOU HAVE A MECHANISM
SOMETIMES YOU DO GET A CLUE AS
TO WHAT DRUG IS GOING TO BE
WORKING.
SO IN TERMS OF TREATMENT,
THERE'S KIND OF REALLY NOVEL
TREATMENTS AND THEN THERE'S
BETTER USE OF TREATMENTS THAT
ARE AVAILABLE NOW, SOME OF WHICH
IN THE EPILEPSY SPACE, SOME OF
WHICH MAY NOT BE.
SO THERE'S ANOTHER STUDY, I
THINK THIS IS ONE WHERE THEY
FIND PEOPLE WITH SEIZURES AND
PEOPLE WITH KNOWN EPILEPSY GOING
OUT AGAIN, PHENOME-WIDE-EYED FIX
OF COPY NUMBER VARIANTS AND
LOOKED AT THE NUMBERS HERE.
THEN IN LOOKING AT THE
PARTICULAR CHANNELS THAT CAUSE
EPILEPSY, THIS IS ONE OF
MULTIPLE EXAMPLES, A POTASSIUM
CHANNEL, LOOKING AT PEOPLE WHO
HAVE MUTATIONS IN THIS POTASSIUM
CHANNEL AND THE TAKE-HOME POINT,
OF COURSE, IS THAT THERE'S MANY
DIFFERENT PHENOTYPES THAT YOU
SEE WHERE PEOPLE HAVE THE SAME
MUTATION.
HERE THEY LOOK AT THE STRUCTURE
OF THE CHANNEL AND IDENTIFY SOME
KIND OF CLUSTERING OF PHENOTYPES
ASSOCIATED WITH PARTICULAR
MUTATIONS IN THE CHANNEL, SO THE
ISSUE WITH THE CHANNELS, OF
COURSE, IS THAT SOMETIMES
THERE'S LOSS OF FUNCTION,
SOMETIMES THERE'S GAIN OF
FUNCTION MUTATIONS IN THE SAME
CHANNEL, SOMETIMES THERE WILL BE
MODIFICATIONS IN EITHER
DIRECTION, AND THOSE MAY BE
SPECIFIC FOR THE MUTATION, NOT
JUST THE CHANNEL THAT'S
AFFECTED.
SO AGAIN, ANOTHER LEVEL OF
SPECIFICITY ONCE YOU HAVE THE
CHANNEL DOESN'T MEAN THAT YOU
HAVE THE TREATMENT.
YOU NEED TO KNOW WHAT THAT
DEFECT IS DOING AND DIFFERENT
DEFECTS IN THAT CHANNEL DO
DIFFERENT THINGS.
THEN AGAIN A WHOLE BUNCH OF
REPORTS THAT HAVE COME UP FROM
THE CWOWs LOOKING AT THE
MUTATIONS THAT HAVE COME UP FROM
THE BIG GWAS STUDIES AND THE BIG
GENETIC STUDIES, AND THEN THE
QUESTION IS A COUPLE OF IDEAS ON
WHAT WE MIGHT BE THINKING OF
GOING FORWARD, SO I WAS
INTRIGUED BY HEARING THIS AT THE
AMERICAN EPILEPSY SOCIETY A
COUPLE YEARS AGO.
THE IDEA HERE IS THAT THIS IS
SOMETHING THAT WOULD CUT ACROSS
ANY EPILEPSY CAUSED BY
SYNCHRONOUS VERY ABNORMAL
SYNCHRONOUS FIRING.
THE BRAIN DOESN'T USUALLY IN ITS
NORMAL ACTIVITY, IT DOESN'T
USUALLY DO ANYTHING THAT LOOKS
LIKE EPILEPSY.
EPILEPSY IS A VERY PECULIAR
STATE, CIRCUIT STATE, AND SO THE
QUESTION IS, IS THERE A WAY TO
KIND OF INTERFERE SO THAT STATE
IS NEVER ENGAGED.
AND THE STATE IS CHARACTERIZED
BY JUST UNBELIEVABLY ROBUST
SYNCHRONOUS FIRING, WHICH WILL
BE ASSOCIATED WITH THINGS LIKE
REALLY TREMENDOUS ACTIVATION
OF -- NOTHING QUITE LIKE
EPILEPSY, I DON'T THINK.
ANYWAY, IN THIS PROJECT, WHAT
THEY DO IS THEY HAVE A GENE
THERAPY FOR POTASSIUM CHANNEL,
AND THIS POTASSIUM CHANNEL WILL
BE ACTIVATED BY CFOS SO THE
CELLS THAT ARE ACTIVATING THE
SEIZURE WILL TURN ON THIS
CHANNEL AND THE POTASSIUM
CHANNEL WILL SLOW DOWN THE
FIRING RATE AND STOP THE
SEIZURES.
AND THEN IT BASE CLEAR PETERS
OUT AND THE CHANNEL IS GOING
NORMALLY, BUT THAT CHANNEL WILL
BE ACTIVE FOR A WHILE SO IF A
NEW SEIZURE STARTS TO BREW, IT
WILL SHUT DOWN THAT SEIZURE.
IF YOU GO FOR MONTHS WITHOUT
HAVING ANY SEIZURES AND THE
POTASSIUM CHANNEL IS QUIET BUT
THE NEXT SEIZURE WILL ACTIVATE
IT AGAIN AND YOU MIGHT GET
ANOTHER THREE MONTHS OF
ACTIVITY.
BUT IT'S AN IDEA WHICH WOULD USE
GENOMIC THERAPY THAT WOULD BE
VERY POTENT AT BLOCKING THESE
KIND OF REALLY ABNORMAL
ACTIVITY, AND THIS IS IN A
CLOSED LOOP SYSTEM.
SO THIS IS NOT NECESSARILY
GIVING A DRUG.
THIS IS THE SEIZURE ITSELF
ACTIVATES THE TREATMENT.
SO THAT'S KIND OF THE DEFINITION
OF CLOSED LOOP.
OF COURSE WE'RE DOING CLOSED
LOOP IN EPILEPSY WITH
STIMULATION, THIS IS KIND OF A
SIMILAR GENETIC TECHNIQUE.
THERE ARE OTHER TECHNIQUES, AND
THIS IS ONE THAT IS INTRODUCING
AN ARTIFICIAL ACETYLCHOLINE
RECEPTOR THAT IS ACTIVATED BY A
DRUG THAT, AGAIN, WILL QUIET THE
CELLS USING CHEMO GENETIC
APPROACHES I THINK IS ALSO
SOMETHING THAT COULD FOLLOW THAT
SAME KIND OF PATH THAT WE TALKED
ABOUT IN THE PREVIOUS SLIDE, BUT
NOW IT'S A DRUG, WI BUT IT'S A G
THAT HAS GOT MUCH MORE
SPECIFICITY POTENTIALLY, MUCH
MORE GREATER EFFECT SIZE ON
ABNORMAL CELL FIRING WITH ANY
THE SMALL MOLECULE IS GOING TO
BE ABLE TO DO.
THE PROBLEM WITH SMALL MOLECULES
IS THAT YOU CAN STOP ANY SEIZURE
YOU WANT BUT YOU'LL BE
UNCONSCIOUS, ON RESPIRATOR, AND
THAT MAY BE FACETIOUS BUT THE
POINT IS THAT SMALL MOLECULES,
YOU CAN'T GET THE EFFECT SIZE
YOU NEED IN EPILEPSY BECAUSE THE
SIDE EFFECTS HAVE COME FROM
RAISING THE DOSES THAT ARE
NECESSARY TO QUIET THE
ELECTRICAL ACTIVITY THAT
UNDERLIES THE SEIZURES.
BUT THE GENOMIC THERAPIES ALLOW
YOU TO GET AROUND THAT, EITHER
BY TAILORING IT -- WELL,
PARTICULARLY BY TAILORING IT
JUST TO THE CELLS THAT YOU WANT,
AND THEN POTENTIALLY BY
CONTROLLING IT BY THE SEIZURE
ACTIVITY ITSELF FOR A DRUG THAT
ACTIVATES JUST THAT GENE AND
JUST THE SPECIFIC CELL TYPES
THAT YOU WANT.
SO THESE KIND OF THINGS ARE, FOR
US, A NEW OPPORTUNITY TO START
THINKING ABOUT ANTISEIZURE
MEDICATIONS FOR SURE.
SORE THIS IS ANOTHER KIND OF
THERAPY THAT AGAIN IS GOING TO
BE MUCH MORE SPECIFIC THAN ANY
KIND OF SMALL MOLECULE.
THESE HAVE BEEN USED IN PEOPLE,
GENE THERAPIES ARE USED IN
PEOPLE, GENE EDITING IS GOING
INTO PEOPLE SOON.
SO I WOULD SAY THAT THESE KIND
OF TECHNOLOGIES ARE THINGS I
THINK WE SHOULD KEEP OUR EYE ON,
PARTICULARLY FOR THE GENETIC
FORMS OF EPILEPSY WHERE THEY'RE
MOST SUITED FOR PEOPLE IN THE
BEGINNING TO GET A HANDLE ON HOW
WE CAN SAFELY USE THESE
THERAPIES.
WE DON'T KNOW WHAT THEIR EFFECTS
ARE LONG TERM.
THERE ARE CERTAINLY RISKS
ASSOCIATED WITH USING THEM.
SO THE CASES THAT WHERE YOU CAN
ETHICALLY KIND OF UNDERSTAND THE
RISK-BENEFIT RATIO AND HAVE A
DISCUSSION WITH THE FAMILY, IT'S
GOING TO BE IN CLEARLY THE MOST
SEVERE CASES, BUT THESE ARE THE
KIND OF THINGS THAT ARE -- TO
THINK ABOUT IN EPILEPSY BUT
OTHER GENETIC DISEASES THAT ARE
ACTUALLY FURTHER OUT BECAUSE OF
THE NATURE OF THE DISEASE FOR
THINGS LIKE -- ATROPHY WHERE THE
INFANTS ARE DEAD IN A YEAR, THAT
WAS CLEARLY THE FIRST ONE TO
COME TO FRUITION.
THIS IS THE ONE I TALKED ABOUT
WITH THE GWAS.
I GUESS THE OTHER THING WE'RE
LEARNING IS ABOUT THE SOMATIC
MUTATIONS THAT ARE OCCURRING
PARTICULARLY IN THE MESIAL
TEMPORAL LOBE IN EPILEPSY.
CERTAINLY FOLKS IN THIS ROOM
WORKED ON SOMATIC MUTATION AND
FOCAL EPILEPSIES.
I THINK I WAS A LITTLE BIT
SURPRISED ABOUT THE FREQUENCY IN
WHICH THESE HAVE BEEN SEEN IN
MEDIAL TEMPORAL LOBE EPILEPSY.
THE QUESTION IS WHAT STARTED
THEM, CAUSED A FEBRILE SEIZURE,
AND THEN THEY ACTUALLY GIVE RISE
TO EPILEPSY OVER TIME.
BUT AGAIN ANOTHER POTENTIALLY
GENETIC HANDLE THAT MADE ME
THINK OF AS AN ACQUIRED FORM OF
EPILEPSY.
I GUESS ALSO OFFER POTENTIAL
AVENUES FOR TREATMENT, THEY'RE
PROBABLY GOING TO HAVE TO BE
QUITE SPECIFIC, GIVEN THE --
THAT THESE PATHWAYS ARE USED FOR
SO MANY DIFFERENT THINGS IN THE
BRAIN AND THE REST OF THE BODY.
SO NINDS HAS BEEN THINKING KIND
OF FORWARD-WISE, HATS OFF TO
NINA SCHOR AND ADAM HARTMAN IN
TRYING TO THINK ABOUT GENE
THERAPIES GOING FORWARD, SO
WE'VE KIND OF BEEN LOOKING FOR
ANY OPPORTUNITY TO EXPLORE THIS
SPACE FOR NINDS.
WE HAVE OUR OWN NETWORK, WHICH
IS CALLED URGENT, WHICH IS FOR
ULTRA-RARE GENE THERAPY.
WE HAVE A NUMBER OF PROJECTS
ONGOING, MOST OF THESE REALLY
DEVASTATING DISEASES THAT AFFECT
CHILDREN.
THE INTRAMURAL PROGRAM HAS BEEN
INVOLVED IN A GENE THERAPY
PROJECT WITH THE NCATS.
WE ARE ONE OF THE GROUPS THAT
WORK IN A PUBLIC-PRIVATE
PARTNERSHIP RUN BY THE
FOUNDATION FOR NIH TO DEVELOP A
PLATFORM WHERE YOU CAN PLUG IN
THE GENE THAT YOU'RE INTERESTED
IN FOR A BUNCH OF DIFFERENT RARE
DISEASES.
WE'VE GOT, AGAIN, A NUMBER OF
PROJECTS ONGOING THERE.
IN THE
NEURO SPACE.
THEN THE EC EXCITING THING IS
THERE'S A COMMON FUND PROJECT
CALLED SOMATIC CELL GENOME
EDITING.
SOME OF THESE REALLY
FORWARD-LOOKING TREATMENTS
PEOPLE ARE DOING THE WAY OF GENE
EDITING, AND THIS IS REALLY
COMING ALONG.
I THINK IT'S TRICKY, THERE'S
LOTS OF THINGS TO FIGURE OUT,
BUT THE POTENCY OF THESE
TECHNOLOGIES IS REALLY QUITE
AMAZING, AND I THINK WE'RE
SEEING SOME OF THEM COMING TO
FRUITION NOW IN THE EYE, IN THE
LIVER PROBABLY, PROJECTS IN THEO
DELIVER SOMATIC GENE EDITING
TOOL INTO THE BRAIN, $6 MILLION,
IF ANYBODY IS INTERESTED.
IT CAN'T BE A GENE, IT CAN'T BE
A VIRUS, IT'S A NON-VIRAL --
LOTS OF THINGS TO TALK ABOUT IN
TERMS OF THAT.
AND URGENT, I MENTIONED THESE
ARE THE PROJECTS WE HAVE ONGOING
NOW, SO LI LYSOSOME STORAGE
DISEASE, A NUMBER OF RARE
GENETIC -- ALS, TRYING TO GET 11
DIFFERENT -- FOR 11 DIFFERENT
VARIANTS THAT CAUSE RARE ALS
FORMS.
SO IT'S A REALLY INTERESTING
AREA THAT WE'RE, I THINK,
TALKING ABOUT TODAY.
REALLY EXCITED ABOUT THE FUTURE
OF THESE GENETIC THERAPIES, AND
CLEARLY IN THE EPILEPSY SPACE,
GENETIC EPILEPSIES.
SO I JUST WANTED TO MENTION
WE'VE BEEN WORKING WITH THE
COMMUNITY FOR MANY YEARS, WE
FEEL REALLY GOOD THAT THERE'S A
GREAT SPIRIT AND COMMUNITY
EFFORT HERE SHARING, THINKING
TOGETHER, WORKING ON THE
BENCHMARKS TOGETHER AND REALLY
APPRECIATE THE WORK THAT PEOPLE
DO IN THE AUDIENCE HERE.
SO WITH THAT I WANT TO THANK YOU
ALL AGAIN FOR COMING AND HOPING
THAT YOU CAN THINK REALLY HARD
AND GIVE US -- GIVE YOURSELVES
AND NINDS SOME GOOD IDEAS MOVING
FORWARD.
THANK YOU VERY MUCH.
[APPLAUSE]
>> THANK YOU, DR. KOROSHETZ.
SO I JUST WANT TO SET THE STAGE
QUICKLY FOR THE WORKSHOP.
SO THE PURPOSE OF THIS WORKSHOP
IS TO BRING INVESTIGATORS
TOGETHER WHO HAVE DEVELOPED
GENETIC STRATEGIES TO TREAT
NEUROLOGICAL DISEASES, SO YOU
WILL HEAR FROM SEVERAL SPEAKERS
TODAY, MANY SPEAKERS TODAY AND
TOMORROW WHO ARE NOT WORKING ON
THE EPILEPSIES, BUT ARE WORKING
ON OTHER NEUROLOGICAL DISORDERS,
AND THIS IS ON PURPOSE, SO THAT
WE CAN LEARN FROM THEM WHAT HAS
WORKED, WHAT HAS NOT WORKED,
WHAT THEIR EXPERIENCE HAS BEEN
TO DEVELOP THESE GENETIC
STRATEGIES.
THE GOALS ARE REALLY TO EXPLORE
STATE OF THE ART STRATEGIES FOR
TREATING GENETIC DISEASES AND
SPECIFICALLY FOR FUTURE
DISCUSSIONS ON THE GENETIC
EPILEPSIES.
DISCUSS THE PROGRESS, PITFALLS
AND LESSONS LEARNED FROM
NEUROLOGICAL TRIALS AND
TREATMENTS, IDENTIFY
CONSIDERATIONS FOR DESIGNING AND
IMPLEMENTING THERAPIES TO TREAT
THE EPILEPSIES, AND DISCUSS THE
CRUCIAL ISSUES BEYOND JUST
DEVELOPING THE TREATMENT, AND
THAT WILL BE DISCUSSION FOUR,
WHERE WE'LL REALLY EXPLORE
ETHICAL ISSUES, PERSPECTIVES
FROM PARENTS AND INDIVIDUALS
WHOSE CHILDREN HAVE PARTICIPATED
IN GENETIC THERAPY CLINICAL
TRIALS.
SO I'D LIKE TO TAKE THIS
OPPORTUNITY TO THANK THE
ORGANIZING COMMITTEE.
THE ORGANIZING COMMITTEE WAS
COMPOSED OF MANY INDIVIDUALS
FROM NINDS BUT A SPECIAL THANK
YOU TO LAURIE, HEATHER, ANNE AND
DAN, OUR EXTRAMURAL
INVESTIGATORS WHO WERE PART OF
THE ORGANIZING COMMITTEE AND WHO
YOU WILL HEAR FROM AS MODERATORS
OF THE SESSIONS TODAY AND
TOMORROW.
A SPECIAL THANKS TO ANDREW CHEN,
WHO'S ON OUR NINDS STAFF, FOR
HIS HELP THROUGHOUT THIS WHOLE
PROCESS AS WELL AND A SPECIAL
SHOUT OUT TO ROSE LI AND
ASSOCIATES, THE RLA STAFF.
THIS WORKSHOP WOULD NOT BE
POSSIBLE WITHOUT ALL OF YOUR
HELP TO WORK WITH US ON THE
TRAVEL, THE LOGISTICS,
EVERYTHING AROUND MAKING THIS
WORKSHOP POSSIBLE.
SO WITH THAT, I WOULD LIKE TO
INTRODUCE OUR FIRST SPEAKER, OR
SPEAKER THIS MORNING, SIMON
FROST.
SIMON IS PART OF THE TIBER
CAPITAL GROUP HERE IN THE D.C.
AREA, BUT HE'S NOT GOING TO BE
TALKING ABOUT FINANCES TODAY, I
DON'T THINK, OR MAYBE
INDIRECTLY, BUT IT'S MY PLEASURE
TO INTRODUCE SIMON TO TALK ABOUT
ACTION POTENTIAL, AN EFFORT TO
DEVELOP GENETIC STRATEGIES FOR A
RARE NEUROLOGICAL DISEASE.
WELCOME, SIMON.
>> I THINK I MIGHT BE A LITTLE
TALL FOR THE MICROPHONE.
APOLOGIES.
BUT I'M SIMON FROST.
I KNOW YOU'VE HEARD ABOUT THE
DIAGNOSTIC ODYSSEY IN RARE
DISEASES MANY TIMES BEFORE,
SO -- AND MY FAMILY'S STORY
REALLY ISN'T THAT MUCH DIFFERENT
FROM MANY OTHERS BUT I'M GOING
TO TRY TO TELL THE STORY JUST A
LITTLE BIT DIFFERENTLY TODAY.
IN MY DAY JOB, I'M AN ECONOMIST.
AND I LIKE TO TALK ABOUT
NUMBERS.
SO I'M GOING TO TALK ABOUT SOME
ASTRONOMICAL NUMBERS.
AND SOME QUANTUM PHYSICS.
SURPRISE.
SO ALL OF YOU KNOW THIS
EQUATION.
IT TELLS US AMONGST OTHER THINGS
THAT THE POTENTIAL ENERGY IN THE
UNIVERSE EQUALS THE MASS OF ALL
OF THE COMPONENTS OF THE
UNIVERSE MULTIPLIED BY AN
ENORMOUS CONSTANT SQUARED.
NOW, I DO WANT TO POINT OUT
QUICKLY THAT EINSTEIN HAD NO
BUSINESS SQUARING THAT CONSTANT.
THAT'S KIND OF THE POINT OF THE
CONSTANT.
BUT I THINK HE WAS TRYING TO
SCREW WITH OUR HEADS.
I THINK HE WAS TRYING TO POINT
OUT JUST HOW MIND-BLOWINGLY
MASSIVE THESE NUMBERS ARE.
NOW, AS YOU KNOW, E, THE
CONSTANT, REPRESENTS THE SPEED
OF LIGHT, AND THE SPEED OF LIGHT
IS 670 MILLION MILES AN HOUR.
WHEN YOU SQUARE THAT, YOU GET
ALMOST 450 QUADRILLION MILES AN
HOUR, WHICH IS OBVIOUSLY AN
ASTRONOMICAL NUMBER.
NOW IT DOESN'T STOP THERE.
WE HAVE ONE SEPTRILLION STARS,
THAT'S A TRILLION, TRILLION
SOLAR SYSTEMS.
THAT'S MORE SOLAR SYSTEMS THAN
GRAINS OF SAND ON EARTH.
IT'S 10 TRILLION SOLAR SYSTEMS
FOR EVERY PERSON THAT HAS EVER
LIVED.
AND IF YOU TAKE ALL OF THOSE
SOLAR SYSTEMS, THE MASS THAT
MAKES UP ALL OF THOSE SOLAR
SYSTEMS AND YOU MULTIPLY IT BY
THAT ENORMOUS CONSTANT, SQUARED,
YOU GET RATHER AN ASTRONOMICAL
NUMBER THAT IS THE POTENTIAL
ENERGY IN THE UNIVERSE.
WE LIVE IN AN INCONCEIVABLY
LARGE COSMOS AND WE'RE INFAN
TESS MEDICALLY SMALL.
WE HAVE ABOUT AS MUCH
SIGNIFICANCE AS A SINGLE ATOM
HAS IN THE ENTIRE HUMAN BODY.
HOW DO WE POSSIBLY CONCEIVE OF
SUCH NUMBERS?
HOW DO WE FIND THE SIGNIFICANCE
IN A UNIVERSE LIKE THAT?
NOW I HAVE AN ANSWER, AND I'M
GOING TO SHARE IT.
AND I PROMISE IT'S NOT GOING TO
INVOLVE ANY MORE QUANTUM
PHYSICS.
BUT IT IS GOING TO INVOLVE A
LITTLE BIT OF HISTORY.
SO IN CASE YOU DIDN'T KNOW, THE
EARTH IS OLD.
IN FACT, IT'S FOUR AND A HALF
BILLION YEARS OLD.
AND EVER SINCE THE BEGINNING OF
TIME, NUCLEIC ACIDS AND AMINO
ACIDS AND PEPTIDES HAVE BEEN
LINING UP TO FORM HUMAN BEINGS,
AND OVER THAT TIME, THEY HAVE
LINED OF 3.2 BILLION NUCLEAR
TILES TO FORM THE HUMAN GENOME
AND MAYBE MORE IMPORTANTLY,
30 MILLION NUCLEOTIDES TO FORM
THE EXOME IN THE RIGHT ORDER AND
24,000 PROTEIN CODING GENES.
IF YOU'RE INTENSELY SHARP WITH
IT, YOU WOULD HAVE NOTICED THAT
THOSE NUMBERS ARE STARTING TO
GET PROGRESSIVELY SMALLER.
I THINK EINSTEIN MIGHT HAVE
NOTICED THAT TOO.
AND SINCE EINSTEIN WAS AROUND
SINCE 1956 WE'VE SEEN A TRILLION
FOLD INCREASE IN COMPUTING
POWER.
EINSTEIN CAME UP WITH THESE
REALLY ELEGANT ASTRONOMICAL
EQUATIONS USING A TRILLIONTH OF
THE POWER THAT WE HAVE TODAY.
THE COMPUTING POWER.
NOW, WE LIVE IN THE AGE OF A.I.
AND SUPERCOMPUTERS.
IF YOU HAVE AS MUCH NEANDERTHAL
DNA AS I DO, YOU STILL USE AN
EXCEL SPREADSHEET.
WHEN I LOOK AT MY FAVORITE EXCEL
SPREADSHEET, I SEE THAT IT HAS
MORE THAN A MILLION ROWS, MORE
THAN 16,000 COLUMNS, IN OTHER
WORDS, MORE THAN 60 BILLION
CELLS.
WHICH IF I PUT A SINGLE
NUCLEOTIDE IN EACH OF THOSE
CELLS I CAN FIT FIVE HUMAN
GENOMES INTO A SINGLE -- OF AN
EXCEL SPREADSHEET.
2 1/2 GENOMES IF YOU HAPPEN TO
BE DEPLOYED, EVEN -- JUST MADE
UP KNOWS HOW TO FIDDLE AROUND
WITH EXCEL SPREADSHEETS.
FINALLY, SOME BIOLOGY.
I WANT TO CONTRAST THE NUMBERS
THAT WE SEE IN RARE DISEASES
WITH THE ASTRONOMICAL NUMBERS
THAT I JUST TALKED ABOUT.
WE ONLY HAVE ABOUT 10,000 RARE
DISEASES.
THAT MEANS THAT IF YOU SPEND THE
NEXT FOUR OR FIVE HOURS LISTING
ALL OF THEM, YOU'LL GET RIGHT TO
THE END OF THE LIST.
AS LONG AS THEY'RE NOT ALL CAL
CALLED HEMOPHILIA OF CHILDHOOD.
THE GOOD NEWS IS THAT WE HAVE
TSH 80% OF ALL OF THOSE RARE
DISEASES ARE GENETIC AND MOST OF
THOSE ARE MONO GENETIC.
THAT'S A BEAUTIFUL THING BECAUSE
IT GIVES US TARGETS.
NOT JUST THE ROSETTA STONE OF
RARE DISEASES BUT THE ROSETTA
STONE OF HUMAN BIOLOGY.
IT GIVES US A WAY AS A SOCIETY
TO USE GENOTYPE DATA AS A
FOUNDATIONAL DATASET, AND TO
BUILD ON TOP OF THAT A DEEP
PHENOTYPIC UNDERSTANDING OF
HUMAN BIOLOGY.
IT GIVES US A WAY TO BREAK
GENETIC DISEASES DOWN TO THEIR
UNDERLYING COMPONENTS, DOWN TO
THEIR MOLECULAR BASIS, AND TO
IDENTIFIED THE STRUCTURE
FUNCTION PROBLEMS WITH HE FACE
WITH OUR 24,000 OR SO PROTEIN
ENCODING GENES.
MOST IMPORTANTLY, IT GIVES US A
WAY TO IDENTIFY THERAPEUTIC
TARGETS.
BUT WE PREFER TO DIAGNOSE OUR
PATIENTS CLINICALLY.
AND WE'RE REALLY BAD AT
DIAGNOSING OUR PATIENTS
CLINICALLY.
IN FACT, IT TAKES US 6.3 YEARS
ON AVERAGE TO DIAGNOSE A RARE
DISEASE PATIENT IN THE UNITED
STATES.
CLINICAL DIAGNOSES ARE SIMPLY
NOT WORKING FOR RARE DISEASES.
YET EVEN THOUGH WE'RE
STATISTICICALLY AWFUL AT
DIAGNOSING RARE DISEASES IN THE
U.S., THERE ARE STILL 1 IN 10 OF
US THAT HAVE BEEN DIAGNOSED WITH
A RARE DISEASE.
AND I DON'T NEED EINSTEIN'S HELP
TO CALCULATE WITH A RATIO OF
1 IN 10 ACROSS 8 BILLION PEOPLE
WORLDWIDE, THAT WE HAVE ABOUT
800 MILLION PEOPLE THAT HAVE
RARE DISEASES ON EARTH.
YET THE REST OF THE WORLD IS
EVEN WORSE THAN WE ARE AT
DIAGNOSING RARE DISEASE PATIENTS
AND THE OFFICIAL NUMBER OF
350 MILLION PEOPLE WORLDWIDE,
REFLECTING A PAINFUL GAP OF
450 MILLION PEOPLE AROUND THE
WORLD THAT ARE BEING LEFT
UNDIAGNOSED OR BEING LEFT TO
DIE.
BUT THAT'S NOT ONE OF THE
BIGGEST HUMAN CRIES SEES THAT WE
HAVCRISES AT THEMOMENT, I'M NOT.
NOW THAT GETS ME TO MY FAMILY'S
STORY AND WHAT WE'RE TRYING TO
DO TO TACKLE RARE DISEASES.
THIS IS MY ANNABEL.
WHEN ANNABEL WAS 2 MONTHS OLD
SHE HAD WHAT LOOKED LIKE
EPILEPTIC SEIZURES.
DESPITE NO EEG FINDINGS, SHE WAS
MISDIAGNOSED WITH EPILEPSY.
SHE WAS PUT ON ANTICONVULSANTS,
AND HER EPISODES DIDN'T CHANGE.
EVERY THREE DAYS OR SO, SHE
WOULD HAVE SPELLS OF SEVERELY
REDUCED CONSCIOUSNESS.
SHE WOULD HAVE BOUTS OF
PARALYSIS THAT WOULD LAST FOR UP
TO 10 DAYS.
SHE WOULD HAVE PAINFUL DYSTONIA.
ONE NIGHT, I MUST HAVE HEARD
SOMETHING ON MY BABY MONITOR
NEXT TO MY BED AND I RUSHED TO
ANNABEL'S ROOM, SHE HAD VOMITED,
SHE WAS CHOKING, AND SHE WASN'T
BREATHING.
I TRIED TO SCOOP OUT HER MOUTH
WITH MY FINGERS.
I TRIED TO GIVE HER BACK BLOWS,
I EVEN TRIED THE HEIMLICH
MANEUVER ON THIS TINY
2-YEAR-OLD.
IT MUST HAVE BEEN ABOUT A MINUTE
BUT IT FELT LIKE AN ETERNITY
BEFORE I MANAGED TO CLEAR HER
AIRWAY AND GET HER TO BREATHE.
THIS DIDN'T SEEM LIKE EPILEPSY.
MY WIFE AND I TRAVELED THE
COUNTRY, TALKING WITH EVERY
NEUROLOGIST THAT WE COULD FIND,
AND WE FOUND ONE OF THE BEST AT
THE BOSTON CHILDREN'S HOSPITAL,
DR. PHIL PEARL.
BY SHEER LUCK, DR. PEARL HAD
JUST AGAIN TO A CONFERENCE ON
AHC.
WHAT HE SAW IN ANNABEL WAS
EERILY SIMILAR.
THE ORDERED THE GENETIC TESTS
AND LO AND BEHOLD, SHE CAME BACK
WITH A DE NOVO MUTATION WITH THE
GENE MOST ASSOCIATED WITH A HC.
A DISEASE THAT ONLY HAS A
THOUSAND PATIENTS WORLDWIDE.
IF ANNABEL WERE A STATISTIC,
SHE'D BE 1 IN A MILLION.
SO WE SPENT TWO YEARS OF
ANNABEL'S SHORT LIFE FUMBLING
AROUND WITH GENETIC DIAGNOSES.
NOW TWO YEARS IN NORMAL LIFE IS
DWIGHT A LONGQUITE A LONG TIME U
HAVE A CHILD SICK AS ANNABEL
WAS, TWO YEARS FEELS LIKE AN
ETERNITY, AND THIRDLY, IT COULD
HAVE BEEN AVOIDED.
WE COULD HAVE AVOIDED THE
EXPENSIVE HOSPITAL VISITS, WE
COULD HAVE AVOIDED GIVING HER
THE ANTIEPILEPTICS THAT PROBABLY
HURT HER MORE THAN HELPED HER,
WE COULD HAVE DONE WHOLE GENOME
SEQUENCING WHEN SHE WAS BORN OR
AFTER HER FIRST MAJOR EPISODE
AND WE COULD HAVE DIAGNOSED HER
IN 6.1 DAYS LIKE THESE CHILDREN
WERE, OR LIKE THESE CHILDREN
WERE.
SADLY, ANNABEL WAS ONE OF THE
LUCKY ONES, IT TOOK US JUST
2 YEARS, WHEREAS I SAID BEFORE,
IT TAKES ALMOST 6.3 YEARS ON
AVERAGE TO DIAGNOSE A RARE
DISEASE PATIENT IN THE U.S.
BUT THAT GENETIC DIAGNOSIS GAVE
US REAL HOPE, AND IT GAVE US A
DIRECTION TO POINT OUR RESEARCH
EFFORTS TO IT, AND THAT'S ALL WE
NEEDED.
SO ON THE PLANE ON THE WAY HOME
FROM BOSTON CHILDREN'S HOSPITAL,
MY WIFE AND I STARTED TO READ
RESEARCH PAPERS ABOUT AHC.
WHEN WE GOT HOME, WE HIRED A
SCIENTIST WHO IS AN INCREDIBLE
PERSON WHO WORKED HERE AT THE
NIH, STUDYING RARE NEUROLOGICAL
DISEASES IN C. ELEGANS.
BETWEEN THE THREE OF US, WE READ
MANY HUNDREDS OF PAPERS.
SO ONCE WE -- WHAT WE FOUND OUT
VERY EARLY ON WAS THAT
ATH1A3 CODES FOR THE ALPHA
SUBUNIT OF THE SODIUM POTASSIUM
PUMP.
WE LOOKED AT ALL OF THE DISEASE
ASSOCIATED VARIANTS, AND YOU CAN
SEE THERE ARE 220 OF THEM.
SUPER IMPOSED ON TO THE 3D
PROTEIN.
WE SAW AS DR. KOROSHETZ WAS
SAYING THAT THERE WERE HOT SPOTS
ASSOCIATED WITH THE PROTEIN
WHERE MOLECULAR CHANGES COULDN'T
BE TOLERATED.
WE UNDERSTOOD QUICKLY THAT THE
SODIUM POTASSIUM PUMP PUMPS OUT
OF NEURONS THREE SODIUM IONS AND
PUMPS IN EVERY CYCLE AGAINST THE
CONCENTRATION GRADIENT TO CREATE
AND MAINTAIN THE ELECTRICAL AND
CHEMICAL IMBALANCES IN THE BRAIN
THAT ALLOW NEURONS TO FIRE AND
KEEP FIRING.
WE ALSO UNDERSTOOD VERY QUICKLY
THAT THIS PARTICULAR PROTEIN
AFFECTS HIGH FREQUENCY NEURONS
LIKE GABAMINERGIC NEURONS MORE
THAN MOST OTHER NEURONS.
IT DOES EXPRESS MOSTLY IN
NEURONS.
ANY CHANGES TO THE CYCLE RATES
OF THESE PUMPS HAVE A REAL
EFFECT ON SYMPTOMS IN PATIENTS.
WE ALSO UNDERSTOOD VERY QUICKLY
AND EARLY ON THAT THERE WERE
SOME REAL OPPORTUNITIES TO LOOK
AT OTHER PARTICULAR MUTATIONS IN
OTHER GENES.
IT WAS A SIGNIFICANT OVERLAP
BETWEEN OUR DISEASE AND OTHER
DISEASES ASSOCIATED WITH THESE
GENES, SODIUM CHANNELS,
POTASSIUM CHANNELS, A REAL
OPPORTUNITY FOR A PLATFORM
APPROACH TO THERAPY DEVELOPMENT
AND RESEARCH.
WE CREATED A STRATEGIC FRAMEWORK
FOR RESEARCH, LOOKING AT
RESEARCH PROJECTS BOTH
SEQUENTIALLY AND IN PARALLEL.
WE LOOKED FOR SHORTCUTS, WAYS
THAT WE MIGHT BE ABLE TO FIGURE
OUT WHETHER OR NOT A PARTICULAR
THERAPEUTIC WOULD WORK WITHOUT
HAVING TO UNDERSTAND THE FULL
MECHANISTIC OPERATIONS OF THE
PUMP.
WE CREATED A CIRCULAR HYPOTHESIS
TESTING METHODOLOGY WHERE WE
WOULD LITERALLY TAKE THE TIES ON
WELL DOCUMENTED REVISED
HYPOTHESES EVERY STEP OF THE
WAY.
WE IDENTIFIED THERAPEUTIC
OPTIONS, AND LIKE SO MANY OTHER
DISEASES, THERE WERE ESSENTIALLY
ONLY FOUR AVAILABLE TO US.
GENE THERAPIES LIKE AAB MEDIATED
GENE THERAPY, KNOCKDOWN OPTIONS
LIKE ASOs, GENE EDITING, BASE
EDITING, PRIME EDITING
ESPECIALLY, AND DRUG SCREENS.
WE PURSUED ALL OF THEM IN
PARALLEL.
WE ALSO IDENTIFIED THE
PRE-CLINICAL TOOLS THAT WE HAD
AVAILABLE, AND WE CENTRALIZED
THEM.
ADDING MANY MOUSE MODELS, CELL
LINES, ASSAYS AND DATA ALONG THE
WAY, AND MAKING SURE THAT THEY
WERE AVAILABLE TO ALL
RESEARCHERS WHO WANTED OR NEEDED
THEM.
WE WERE TRYING TO CATALYZE
RESEARCH, AND IT WORKED BETTER
THAN WE EVER COULD HAVE IMAGINE
DOLLARS.
WE WORKED WITH MANY STRATEGIC
PARTNERS, ESPECIALLY THOSE FOLKS
ON THE SCREEN.
NOW, I SAY "WE" A LOT, BUT I
THINK YOU KNOW THAT THE REAL
FIREPOWER CAME FROM PEOPLE AT
THESE INSTITUTIONS WITH ME, MY
WIFE NINA AND DR. NATALIA MORSCH
WORKING AS A HUB TO CONNECT THE
DOTS.
NOW I AM HERE TO TELL YOU
SOMETHING REALLY IMPORTANT.
NONE OF THIS WAS NOVEL.
NONE OF THIS WAS
GROUND-BREAKING.
THIS WAS US REINVENTING THE
WHEEL FOR YET ANOTHER RARE
DISEASE, AND WE KNEW IT.
BUT WE ALSO KNEW WE DIDN'T HAVE
ANY OTHER OPTIONS.
WE HAD TO DO IT OURSELVES.
NOBODY WAS GOING TO HELP US.
THIS IS THE CASE FOR MANY, MAYBE
MOST, OF THE OTHER 10,000 RARE
DISEASES.
BUT EVEN REINVENTING THE WHEEL,
EVEN FOLLOWING THOSE TRIED AND
TESTED PARTS OF THERAPEUTIC
DEVELOPMENT FOR OTHER SUCCESSFUL
THERAPIES, LED US TO AMAZING
RESULTS.
WE'VE SEEN A RESCUE IN VITRO AND
IN VIVO USING OUR AAV-MEDIATED
GENE THERAPIES.
WE'VE SEEN A COMPENSATING
MECHANISM WHERE IF WE KNOCK OUT
THE MUTANT ALLELE, WE SEE AN
INCREASED NUMBER OF PROTEINS
THAT ALMOST GETS TO WILDTYPE
LEVELS.
WE'VE IDENTIFIED SEVERAL
CANDIDATE COMPOUNDS, TESTING
THOSE IN VIVO AND IN VITRO AT
THE MOMENT, AND PROBABLY MOST
EXCITINGLY AND MOST RECENTLY,
WE'VE SEEN SIGNIFICANT
ADVANCEMENTS IN GENE EDITING,
ESPECIALLY PRIME EDITING, WITH
OUR COLLABORATION WITH THE LU
LAB AT THE BROAD INSTITUTE.
SO WE SPENT THE LAST FIVE YEARS
SYSTEMATIZING OUR RESEARCH,
CENTRALIZING OUR TOOLS LIKE OUR
ANIMAL MODELS, OUR CELL LINES
AND OUR SAs, AND WE'VE BEEN
MAKING THEM FREELY AVAILABLE TO
ANYBODY WHO WANTS TO MEET THEM,
IN THE MEANTIME, CONNECTING
CRITICAL SCIENTISTS AND SCALING
OPERATIONS.
NOW SCALING OPERATIONS IS NOT
SOMETHING THAT MOST FOLKS IN THE
RARE DISEASE WORLD KNOW HOW TO
DO.
THESE FOLKS ARE ALL TRYING
DESPERATELY TO SAVE THEIR DYING
CHILDREN.
THEY DON'T HAVE THE EXPERIENCE,
THE MONEY, THE EXPERTISE TO BE
ABLE TO PUT TOGETHER SCIENTIFIC
PLANS THAT ARE SOPHISTICATED.
SO I'M TRYING TO FIGURE OUT A
WAY THAT WE CAN REINVENT THE
WHEEL TOGETHER FOR AS MANY RARE
DISEASES AS POSSIBLE IN
PARALLEL.
IN THE PROCESS OF THINKING ABOUT
SCALING, BACK TO CHRIS AUSTIN,
WHO I THINK A LOT OF YOU KNOW,
APPROACHED ME TO JOIN THE --
ACCELERATION BOARD AT THE NIH
WHERE WE MIGHT BE ABLE TO THINK
ABOUT MORE APPROACHES TOGETHER.
AND I'VE BEEN TRYING EVER SINCE
TO FIGURE OUT WAYS TO ACCELERATE
THE PATH TOWARDS A MORE
WIDESPREAD PLATFORM-BASED
APPROACH.
TO ACCOMPLISH THIS, I'VE TRIED
TO PUT TOGETHER HIGH QUALITY
CENTRALIZED DATA FOR RARE
DISEASES AND MAKE THOSE DATA
AVAILABLE TO HIGH POWERED
ANALYTICS USING A.I. AND
SUPERVISOR COMPUTERSSUPERVISUPEL
SPREADSHEETS.
THE IDEA IS TO GATHER
CENTRALIZED GENOTYPE AND
PHENOTYPE DATA TO BREAK DISEASES
DOWN TO THEIR MOLECULAR BASIS.
TO CATEGORIZE DISEASES WITH
COMMON SYMPTOMS AND COMMON
PATHWAYS INTO LARGER CO-RESEARCH
UNITS AND TO BUILD THAT ROSETTA
STONE THAT I WAS TALKING ABOUT
BEFORE TO DECODE RARE DISEASES
IN HUMAN BUY OSM BIOLOGY.
RECENTLY I'VE HELPED TO LEAD THE
FORMATION OF A COALITION FOR THE
GENOMEIC ANSWERS FOR CHILDREN'S
HEALTH ALLIANCE, ALLOWING
MEDICAID TO PAY FOR WHOLE GENOME
SEQUENCING FOR ALL RARE DISEASES
FOR PATIENTS THAT NEED IT OR
PATIENTS WITH RESPECT TO GENETIC
DISEASES.
AND VERY IMPORTANTLY, TO
CENTRALIZE THOSE DATA TO BE ABLE
TO ACCESS THOSE AND USE THEM TO
CREATE THAT ROSETTA STONE.
NOW AS A RARE DISEASE COMMUNITY,
I THINK WE COULD VERY SOON HAVE
THE PUZZLE PIECES TOGETHER THAT
WE NEED TO CREATE A BLUEPRINT
FOR MANY O OTHER RARE DISEASES O
FOLLOW, TO REPLICATE,
EXTRAPOLATE THE SUCCESS WE'VE
SEEN BOTH JOINTLY AS SEPARATELY
IN THE RARE DISEASE WORLD UP TO
THIS POINT, TO CREATE THOSE
PLATFORMS FOR MANY OTHER
DISEASES TO BE STUDIED
SIMULTANEOUSLY, AND TO TREAT AS
MANY PATIENTS AS POSSIBLE
ULTIMATELY.
WITH THE ADVANCED AN Y ANALYTICL
TOOLS WE NOW HAVE AND GIVEN THE
ASTRONOMICAL MATHEMATICAL
PROBLEMS WE'VE ALREADY SOLVED AS
HUMANITY WITH COMPUTER POWER
THAT WAS A TRILLION OF WHAT WE
HAVE TODAY, I THINK THESE
NUMBERS SHOULDN'T BE
INTIMIDATING ANYMORE.
WE'RE TALKING ABOUT JUST 10,000
RARE DISEASES.
WE'RE TALKING ABOUT JUST 24,000
PROTEIN CODING GENES.
WE ARE NOT TALKING ABOUT A
TRILLION TRILLION SOLAR SYSTEMS,
WE'RE NOT TALKING ABOUT THE
SPEED OF LIGHT SQUARED.
THESE NUMBERS ARE ACHIEVABLE.
WE JUST NEED A COORDINATED PLAN.
WE CAN EITHER KEEP REINVENT
BEINVENTINGTHE WHEEL OR WE CAN A
SYSTEMATIZED CENTRALIZED
WHEEL-MAKING FACTORY THAT CAN
HELP UP TO 800 MILLION PEOPLE
TODAY, AND MAYBE AN ASTRONOMICAL
NUMBER TOMORROW.
AND WHILE WE DO LIVE IN AN
INCONCEIVABLY VAST COSMOS, AND
WHILE WE ARE INFAN TESS
MEDICALLY SMALL, I THINK THAT
ALL OF US IN THIS ROOM HAVE THE
OPPORTUNITY TO CHANGE THE FUTURE
FOR HUMANITY, AND I THINK THAT'S
PERHAPS WHE WHAT REALLY COUNTS.
THANK YOU.
[APPLAUSE]
>> THANK YOU VERY MUCH, SIMON.
BEFORE I INTRODUCE THE MODERATOR
OF THE FIRST SESSION, JUST SOME
LOGISTICS FOR HOW THE WORKSHOP
IS GOING TO RUN.
SO EACH SPEAKER WILL HAVE 20
MINUTES PLUS 5 MINUTES FOR
CLARIFYING QUESTIONS, AND THEN
THERE WILL BE A PANEL DISCUSSION
AT THE END.
FOR ALL OF THE MEMBERS --
SPEAKERS WITHIN THAT SESSION.
SO HERE IN THE ROOM, I IF YOU HE
A QUESTION, PLEASE GO TO THE
MICROPHONE.
IT'S ON THE SIDE OF THE ROOM.
WE'LL ALSO HAVE A ROVING
MICROPHONE FOR PEOPLE WHO WANT
TO ASK QUESTIONS.
ONLINE, YOU CAN RAISE YOUR HAND,
AND WE WILL MAKE SURE THAT WE
CALL ON YOU AND YOU'LL BE ABLE
TO UNMUTE AND TURN ON YOUR
CAMERA SO THAT YOU CAN ASK YOUR
QUESTION AND INTERACT DIRECTLY.
THE CHAT IS OPEN FOR PEOPLE
ONLINE WHO WANT TO OPEN UP
DISCUSSION AND MAKE COMMENTS IN
THE CHAT.
WE WON'T BE TAKING QUESTIONS
FROM THERE, SO PLEASE JUST -- IF
YOU HAVE A QUESTION, RAISE YOUR
HAND.
JUST A COUPLE OF OTHER THINGS,
THE RESTROOMS ARE OUT THE DOOR
AND TO THE LEFT.
DURING THE BREAKS AND AT LUNCH,
PLEASE TAKE A LOOK AT THE
POSTERS ON THE TABLES AND
THERE'S ALSO A DEDICATED POSTER
SESSION FROM 1:00 TO 2:00.
THE ROOM ADJACENT TO THIS ROOM
IS AVAILABLE FOR ANYONE WHO MAY
NEED TO SKIP OUT AND DO A PHONE
CALL OR TAKE A ZOOM MEETING,
WHATEVER YOU NEED TO DO, BUT
THAT ROOM IS AVAILABLE.
JUST ASK AT THE FRONT DESK OR
JUST MOSEY OVER THAT WAY.
SO WITH THAT, IT'S MY PLEASURE
TO INTRODUCE DAN LOWENSTEIN FROM
THE UNIVERSITY OF CALIFORNIA,
SAN FRANCISCO WHO'S GOING TO
MODERATE THE FIRST DISCUSSION.
WELCOME, DAN.
>> THANK YOU, VICKY.
THANKS FOR ALL WHO ARE ATTENDING
HERE AND ARE JOINING US
VIRTUALLY ONLINE.
IT'S A PLEASURE TO BE PART OF
THE PLANNING GROUP THAT'S PUT
THIS TOGETHER, AND JUST TO GIVE
A LITTLE BIT OF CONTEXT BEFORE
THE SPECIFICS OF THIS FIRST
SESSION, THE ARC OF HISTORY,
SCIENCE, ANYTHING, CAN BE
DEFINED BY DIFFERENT POINTS
ALONG THAT PATH.
AND TO SEE FOLKS GATHERED HERE
AND THOSE OF YOU AGAIN WHO ARE
WITH US VIRTUALLY, CERTAINLY
REMINDS ME OF WHAT I'VE SEEN IN
MY LIFETIME, WHICH -- IT TRULY
IS EXTRAORDINARY.
WE CAN GO BACK WHEN IT COMES TO
THE PROGRESS THAT WE'VE MADE IN
EPILEPSY AND GENETICS TO 1989,
THE FIRST I' IDENTIFICATION OF A
LOCUS WAY BACK THEN CONNECTED TO
WHAT TURNED OUT TO BE A
POTASSIUM CHANNEL DISORDER.
1995 OR SO, OUR WONDERFUL
FRIENDS IN MELBOURNE AND
CONNECTED SCIENTISTS WERE ABLE
TO IDENTIFY THE FIRST TRUE
EPILEPSY GENE ASSOCIATED WITH AN
AUTOSOMAL DOMINANT FRONTAL LOBE
EPILEPSY, AND THIS PARTICULAR
WORKSHOP REMINDS ME OF THE
WORKSHOP THAT WAS -- I THINK IT
WAS 2009, WHICH WAS A FOCUS ON
TRYING TO UNDERSTAND WHERE WE
WERE WITH THE GENETICS OF
EPILEPSY.
YOU'VE ALREADY HEARD FROM
DR. KOROSHETZ, THIS THEN LED TO
THE RECOGNITION THAT WE WERE AT
A MOMENT IN TIME, A POINT IN
TIME WHERE WE COULD MAKE SOMELY
SIGNIFICANT PROGRESS IF WE CAME
TOGETHER AND CREATED THE KINDS
OF TEAMS TO FORM THE CENTERS
WITHOUT WALLS AND THAT THEN LED
TO EPI4K, EPI25 AND COUNTLESS
OTHER GROUPS OF, AGAIN,
MULTIDISCIPLINARY TEAMS
THAT HAVE MADE SPECTACULAR
ADVANCES IN THE GENETICS OF
EPILEPSY.
TO GO FROM 1989, WHERE THERE WAS
A LOCUS, TO NOW HAVING THE
IDENTIFICATION OF TARGETS AND
THE CLEARCUT IMPACT THAT IT'S
HAD ON THE PRACTICE OF MEDICINE,
ON THE CARE OF CHILDREN AND
OTHERS SUFFERING FROM EPILEPSY
HAS BEEN NOTHING SHORT OF
SPECTACULAR.
SO OUR GATHERING TODAY, I THINK,
HAS THE PROMISE OF ANOTHER ONE
OF THOSE IDENTIFIABLE POINTS IN
TIME.
BECAUSE WE ARE -- NO QUESTION,
WE ARE AT THE PLACE WHERE WE CAN
NOW DEVELOP MORE AND MORE
EFFECTIVE THERAPIES AND CURES
RELATED TO WHAT WE'VE UNDERSTOOD
IN THE GENETICS OF EPILEPSY.
SO IN THIS FIRST SESSION, THE
PLANNING COMMITTEE AS YOU'VE
ALREADY HEARD, IT WAS EASY TO
RECOGNIZE THAT WE NEED TO RELY
ON FOLKS OUTSIDE OF OUR FIELD TO
TRY TO UNDERSTAND WHAT WE'RE
TRYING TO DO IN A VERY
COMPLICATED, CHALLENGING
PROBLEM, AND THAT IS GENETIC
THERAPIES RELATED TO BRAIN
DISORDERS, SPECIFICALLY
EPILEPSY.
AND AS WE'VE BEEN THINKING ABOUT
THIS, I THINK THAT THERE ARE
THREE AREAS THAT WE NEED TO
CONTEND WITH THAT ALL OF US ARE
AWARE OF BUT I JUST WANT TO
EMPHASIZE THEM.
THREE ASPECTS OF GENE THERAPIES
FOR EPILEPSY THAT ARE
PARTICULARLY, PARTICULARLY
CHALLENGING.
THE FIRST ONE IS DEALING WITH
THE BLOOD BRAIN BARRIER.
A LOT OF THE MOST IMPORTANT
ADVANCES IN GENE THERAPY TO DATE
IN OTHER DISEASES HAVE NOT HAD
TO CONTEND WITH THAT.
ALTERING, FOR EXAMPLE, THE
HEMATOPOIETIC SYSTEM OR ALTERING
AN IDENTIFIABLE CANCER OUTSIDE
OF THE BRAIN.
WE'RE IN A WHOLE DIFFERENT
UNIVERSE WHEN IT COMES TO TRYING
TO GET GENE THERAPIES
EFFECTIVELY ACROSS THE BLOOD
BRAIN BARRIER.
THE SECOND IS THE NEED FOR EARLY
INTERVENTION FOR MANY OF THE
EPILEPSIES, BECAUSE IN THE
GENETIC DISORDERS, THEY MANIFEST
EARLY, THE NETWORK HAS ALREADY
BEEN SET UP TO A CERTAIN EXTENT,
AND WE NEED TO BE ABLE TO
INTERVENE EARLY ENOUGH AND AS
YOU'LL HEAR FROM ONE OF OUR
SPEAKERS, WE INVITED TIPPI
SPECIFICALLY BECAUSE SHE'S BEEN
THINKING ABOUT THAT.
AND THEN FINALLY, AND THIS ONE
VEXES ME PERHAPS THE MOST, AND
THAT IS, HOW DO WE COME UP WITH
HIGH FIDELITY TARGETING OF THE
VERY COMPLEX AND MESHED SYSTEM?
THE IMMUNE SYSTEM IS PROBABLY
THE EQUIVALENT COMPLEX SYSTEM
THAT EXISTS IN THE BODY COMPARED
TO THE NERVOUS SYSTEM, BUT IT'S
A LITTLE BIT DIFFERENT.
IT'S DISPERSED, IT CAN BE
SEPARABLE, AT LEAST OUTSIDE OF
THE BRAIN, WHEREAS WITHIN THE
BRAIN, THE CIRCUITRY IS A HECK
OF A LOT MORE NOT ONLY COMPLEX
BUT ALSO ENMESHED WITHIN OTHER
NEURONAL SUBTYPES AS WELL AS
OTHER CELL TYPES, AND SHE'S
GOING TO HELP US UNDERSTAND
THAT.
SO THAT'S THE CONTEXT.
I'M GOING TO DESCRIBE OUR THREE
SPEAKERS.
MANY OF YOU KNOW THEM BUT THESE
ARE SPECTACULAR FOLKS WHO WE'VE
CONVINCED NEED TO COME FROM FAR
AND WIDE TO JOIN US.
BEV DAVIDSON IS A WELL-KNOWN
RENOWNED GENETICIST AND
NEUROSCIENTIST WHO'S CURRENTLY
SERVING AS THE CHIEF SCIENTIFIC
OFFICER AT CHILDREN'S HOSPITAL
OF PHILLY AND PROFES PROFESSOR E
UNIVERSITY OF PENNSYLVANIA.
HER WORK HAS BEEN FOCUSING ON
MECHANISMS OF NEURODEGENERATIVE
DISEASES AND DEVELOPING GENE
THERAPY APPROACHES TO TREAT
CONDITIONS SUCH AS HUNTINGTON'S
DISEASE AND OTHER INHERITED
NEUROLOGICAL DISORDERS.
HER RESEARCH HAS REALLY BEEN
INSTRUMENTAL IN ADVANCING THE
USE OF RNA INTERFERENCE AND GENE
EDITING TECHNOLOGIES TO SILENCE
DISEASES AND COMING UP WITH NEW
THERAPEUTIC APPROACHES.
SHE'S A MEMBER OF THE NATIONAL
ACADEMY OF MEDICINE, WHICH AMONG
OTHER THINGS IS PART OF THE
RECOGNITION OF HER REMARKABLE
CONTRIBUTIONS.
WE'LL HEAR FROM TIPPI MCKENZIE
ON LINE, PROFESSOR OF SURGERY AT
THE UNIVERSITY OF CALIFORNIA
SAN FRANCISCO AND A LEADING
EXPERT IN THE FIELD OF FETAL
SURGERY AND MATERNAL FETAL
MEDICINE.
HER RESEARCH HAS BEEN AIMING TO
UNDERSTAND AND TREAT CONGENITAL
DISEASES THROUGH PRENATAL
INTERVENTIONS.
SHE'S REALLY ADVANCED THE FIELD
OF IN UTERO STEM CELL
TRANSPLANTATION AND GENE
THERAPY.
AND CO-DIRECTS A CENTER AT UCSF
ON MATERNAL FETAL PRECISION
MEDICINE.
AND THEN FINALLY, FYODOR URNOV,
WHO IS A PROFESSOR OF MOLECULAR
AND CELL BIOLOGY AT THE
UNIVERSITY OF CALIFORNIA,
BERKELEY.
AND A LEADING SCIENTIST IN THE
FIELD OF GENOME EDITING.
I HAPPEN TO KNOW FY ODOR QUITE
WELL BECAUSE I HAD THE
OPPORTUNITY TO SERVE AS A MEMBER
OF THE SCIENTIFIC ADVISORY BOARD
AT THE INNOVATIVE GENOMICS
INSTITUTE, THE IGI BASED AT
BERKELEY, AND FYODOR IS JUST A
REMARKABLE SCIENTIST WHO HAS
BEEN FOCUSING ON DEVELOPING AND
APPLYING CRISPR-BASED
TECHNOLOGIES FOR THERAPY
PURPOSES.
HIS RESEARCH HAS BEEN PIVOTAL IN
ADVANCING THE PRECISION AND
APPLICATION OF CRISPR TREATING
APPROACHES FOR TREATING GENETIC
DISORDERS.
HE'S ACTIVELY INVOLVED IN THE
ETHICAL CONSIDERATIONS AND
POLICY DISCUSSIONS SURROUNDING
THE USE OF GENOME EDITING AND
HAS HAD MANY, MANY RECOGNITIONS,
MOST RECENTLY BEING YOUR I THINK
PH.D. ALMA MATER AT BROWN, ONE
OF THE HIGHEST HONORS THAT THEY
GIVE TO THEIR ALUMNI AND THEIR
SCIENTISTS.
SO THOSE ARE THE THREE SPEAKERS
THIS MORNING.
YOU'LL HEAR FROM ANNE PODURI
THE NUMBER ONE RULE IN MY FIELD
WHICH IS CLINICAL GENE ID ITING
IS NEVER, EVER, EVERY GIVE
FAMILIES FALSE HOPE.
THERE ARE SEVERAL FAMILIES IN
THE ROOM, INCLUDING THE FAMILY
THAT JOINED ME ON THIS TRIP.
SO I SPENT A LOT OF TIME
THINKING ABOUT HOW TO -- SORRY,
ACTUALLY MY NORMAL LEVEL OF
SPEECH IS VERY LOUD.
I JUST DIDN'T WANT TO OVERWHELM.
HOW DOES THIS SOUND WHERE YOU
ARE?
ALL RIGHT.
I'M GOING TO FAIL THE
INTELLIGENCE TEST.
HOW DO I ADVANCE THE SLIDE?
AH-HA!
THE THINGIE WORKS.
SO LOOK, MY GOAL IS TO GIVE YOU
A JUNE 2024 DEFINITIVE REALITY
SNAPSHOT.
WE ARE SERIOUS PEOPLE GATHERED
TO TREAT A VERY SERIOUS DISEASE.
HERE ARE MY DISCLOSURES.
SOME OF THEM WILL BE RELEVANT AS
I SPEAK.
THE GENE EDITING FIELD HAS HAD A
LANDMARK MOMENT.
WE HAVE AN APPROVED MEDICINE.
FOR SICKLE CELL DISEASE, NO LE
LESS.
I HAD THE MO NOR OF INTRODUCING
GENE EDITING AT THE ADVISORY
COMMITTEE MEETING THAT APPROVED
THIS MEDICINE, AND I SHOWED THAT
VERSION OF THE SLIDE IN WHICH I
PUT OUT THE TRAJECTORY OF MY
FIELD THAT BEGAN WORK -- WITH A
NON-WORKING POINTER BECAUSE THIS
IS NOT A POINTER.
NO WORRIES, I'LL JUST WAVE.
AT THE VERY, VERY END IS WORK
DONE IN 1994 THAT STARTED GENE
EDITING.
MY COLLEAGUES ESTABLISHED THE
TREATMENTS OF CLINICAL GENE
EDITING IN 2005 AND NAMED THE
TECHNOLOGY, THE WORLD COMPLETELY
CHANGED, THEY COMPARE IT FROM
GOING FROM LPs TO SPOTIFY,
CRISPR GENOME MEDICINE AND NOW
WE HAVE AN APPROVED MEDICINE.
THAT'S VICTORIA GRAY, THE FIRST
SUBJECT TO BE -- SO I STAND
BEFORE YOU TO SAY THE NEXT 10
YEARS WILL NOT FEATURE A LINEAR
GROWTH OF THE FIELD BUT WILL
FEATURE AN EXPONENTIAL GROWTH OF
THE FIELD AND I WILL SUPPORT THE
STATEMENT THAT 100% OF MY FOCUS
TODAY IS TO WEAPONIZE THE
POSITIONS OF THE PHYSICIAN
SCIENTISTS AND SCIENTISTS ROOM
WITH HOW DO YOU DO A CRISPR JEAN
EDITING TRIAL FOR EPILEPSY IN
THE NEXT FIVE YEARS.
THE REASON FOR MY DATABASED
OPTIMISM COMES WITH A PARALLEL
TRACK MUTUALLY REINFORCING
INNOVATION IN THE TOOLBOX OF
CLINICAL TRACK RECORD OF EDITING
AND I WILL REVIEW THE FIRST TWO
AND I'M NOT GOING TO REVIEW THE
THIRD BECAUSE I KNEW I WAS GOING
TO IF AFTER BEV DAVIDSON SO I'M
NOT GOING TO TRY TO SHOOT THE
SHOT AFTER CAITLYN CLARKE.
THIS IS SOME DATA THAT ALSO JUST
CAME OUT AND THE BOTTOM LINE IS
AS BEV JUST SHOWED, THE BRAIN IS
TRANSDUCIBLE IN WAYS WE HAVE
NEVER DREAMT OF, AND I AGREE
WITH DR. KOROSHETZ, HOW DOES
THIS THING DO IT?
WELL, AS MY EX-INDUSTRY SELF IN
KIND OF AN AWKWARD WAY DOESN'T
CARE.
IN THE SENSE IF I CAN GET THE
PAYLOAD THERE AND IF I CAN SHOW
IT'S SAFE AND TOLERATED IN
NON-HUMAN PRIMATES, THEN I CAN
SPEAK WITH THE AGENCY.
BUT I AGREE THE QUESTION OF HOW
THIS HAPPENS IS A REALLY
IMPORTANT ONE.
SO MY JOB IS TO REVIEW WITH YOU
GENOME EDITING, AND I WANT TO
THANK DR. KOROSHETZ AND I WANT
TO THANK THE NIH, FOR HAVING
FUNDED A UNIQUE FIRST IN CLASS
FIVE-YEAR, $170 MILLION EFFORT
ON PUTTING CRISPR INTO PEOPLE.
IT'S CALL THE SOMATIC GENOME
EDITING CONSORTIUM.
THANK YOU, DR. KOROSHETZ, FOR
YOUR LEADERSHIP.
I'M NOT GOING TO REVIEW GENE
EDITING IN THE ABSTRACT.
I'M GOING TO REVIEW GENE EDITING
FOR THE BRAIN FUNDED BY THE NIH
BY PEOPLE IN THIS INSTITUTE AND
YOU CAN LEVERAGE EVERY SINGLE
SILL BOL OF EVERYTHING I'M ABOUT
TO DESCRIBE EVEN THOUGH NONE OF
THESE PROGRAMS ARE TREATING
EPILEPSY, BECAUSE FOUNDATIONALLY
AS I'M ABOUT TO EXPLAIN, CRISPR
IS A PLATFORM.
SO I'M GOING TO START FROM THE
TOP WHICH IS A PROJECT LED BY
JENNIFER DOUDNA AT MY IN INSTITE
AND I'M GOING TO INTRODUCE THE
WAY THE EDITING IS BEING DONE
THROUGH THE PRISSMM OF ONGOING
CLINICAL TRIALS FOR CRISPR.
SO YOU CAN UNDERSTAND HOW THIS
IS AN ITERATIVE PROGRESS, ONE
TRIAL BUILDS ON ANOTHER AND THEN
BUILDS ON THE NEXT.
SO THE IDEA OF GENE EDITING IS
YOU CREATE A DOUBLE STRAND
BREAK, NO, THEY DO NOT KILL
CELLS IF YOU DO THEM RIGHT,, SO
AT THIS POINT, WHAT DO YOU MEAN?
I READ IN THE POPULAR MEDIA THAT
TARGETS CAUSE CANCER AND KILL
PEOPLE.
IF YOU WORK WITH THE RIGHT
PEOPLE, WHETHER IN ACADEMIA OR
IN INDUSTRY, THEY WILL DELIVER
TO YOU A GENE EDITOR WITH SINGLE
LOCUS DEMONSTRABLE SPECIFICITY
IN IMD-GRADE MODELS WITH NO OFF
TARGETS ABOVE THE LIMIT OF
DETECTION.
IT IS A TECHNICALLY SOLVED
PROBLEM.
DOES THIS MEAN THE EDITOR WILL
BE SAFE IN HUMANS?
NOBODY KNOWS.
I WILL SAY AT THE VERY END, THE
ONLY WAY TO FIND OUT THAT
SOMETHING IS SAFE -- BUT I HEAR
THOSE OF YOU CURRENTLY SAYING
NOW IS NOT THE TIME FOR CRISPR
BECAUSE -- TARGET SOMETHING.
PERISH THE THOUGHT.
IN PHASE 3 WITH A DOUBLE STRANT
BREAK TO DO GENE DISRUPTION,
IN -- SUBJECTS.
THIS BRAND NEW TECHNOLOGY CALLED
CRISPR, WHICH ONE DAY MAY
HAVE -- ARE YOU JOKING?
765 SUBJECTS IN A PHASE 3 TRIAL.
HOW DID THEY GET THAT FAR?
THEY USED NON-VIRAL DELIVERY,
WITH A NANOPARTICLE,
SYSTEMICALLY ADMINISTERED
WITH -- TO DELIVER, IDENTIFIES
THE DTR GENE, A MU TAN FORM OF
WHICH CAUSE THE
NEURODEGENERATION AND HARD
DEGENERATION AND KNOCKS THE GENE
OUT.
WHAT'S REALLY IMPACTFUL IS THIS,
THERE'S A COMPLETE UNCOUPLING OF
THE PHARMACOKINETICS AND
PHARMACODYNAMICS.
THE EDITOR BY PHARMACOKINETIC
STUDIES LASTS FOR 72 HOURS.
THE PHARMACODYNAMICS ARE AS LONG
AS PEOPLE HAVE LOOKED.
SO WHAT YOU'RE LOOKING AT HERE
AT THE SUBJECTS FOR TWO
DIFFERENT COHORTS ARE DOSED AT
DAY ZERO, AND THEN YOU MONITOR
THE SERUM BIOMARKER IN THE
BLOODSTREAM OF THE TARGET GENE
BEING KNOCKED OUT, OUT TO 24
MONTHS.
THEY HAVE ACHIEVED 96% WHOLE
GENOME SINGLE GENE KNOCKOUT WITH
NO DETECTABLE OFF TARGET
EFFECTS.
SPRTLSEPARATELY, THEY HAVE KEPT
EVERYTHING THE SAME, THEY
CHANGED ONE THING, 20
NUCLEOTIDES IN THE GUIDE RNA,
THE TARGET OF DIFFERENT -- THE
ROUTE OF ADMINISTRATION IS THE
SAME.
THE BIOMARKER IS DIFFERENT.
BUT CRISPR IS A PLATFORM.
YOU GO FROM MEDICINE ONE TO
MEDICINE TWO BY SWAPPING OUT 20
NUCLEOTIDES OF THE GUIDE.
THE SAME IS TREUP TO DEVELOPING
EPIGENETIC STRATEGIES -- TO
CLINICAL PRACTICE.
AT THE HIGHEST DOSE COHORT, OUT
TO 88 WEEKS POST DOSING.
THEY SEE IDENTICAL LEVELS OF
ELIMINATION OF A DIFFERENT SERUM
MARKER.
THIS IS HOW FAR A KNOCKOUT BASED
APPROACH TO CRISPR GENE EDITING
HAS GONE INTO THE CLINIC.
THIS IS ALSO THE APPROACH THAT'S
THE BASIS FOR -- BRINGING US
CLOSER TO THE HEAD, AT LEAST,
HAS DOSED 15 SUBJECTS WITH AAV,
AND AGAIN I THANK BEV AND THE
FIELD OF AAV FOR HAVING GIVEN
THUS TOOL IN WHICH THEY'RE
CREATING TWO DOUBLE STRAND
BREAKS TO ELIMINATE THE
PATHOGENIC VARIANTS WHICH
CREATES LOSS OF VISION.
THE RESULT FROM THIS COHORT WERE
JUST PUBLISHED IN THE NEW
ENGLAND JOURNAL.
BY THE WAY, VICKY HAS MY SLIDES
SO ANYONE, PLEASE, YOU'RE
WELCOME TO MY SLIDES.
THE BOTTOM LINE S THERE IS CLEAR
PRELIMINARY EVIDENCE OF EFFICACY
AND -- UNFORTUNATELY THEY
DROPPED THE PROGRAM BECAUSE IT'S
NOT COMMERCIALLY VIABLE BECAUSE
THERE ARE ONLY 300 PATIENTS AND
EVEN IF THEY PRICE IT AT
$3.5 MILLION A PATIENT, THEY
WON'T BE ABLE TO MAKE MONEY.
I'M NOT TRYING TO BE -- BUT
THAT'S WHAT THEY JUST DID.
JENNIFER AND HER WONDERFUL TEAM
HAS NOW FUNDED THE CONSORTIUM TO
TAKE OVER THE NEXT FOUR YEARS TO
THE CLINIC THIS APPROACH OF A
DOUBLE CUT USING EITHER AAV OR
INNOVATIVE METHODS OF DELIVERY,
PROBABLY INTRAPARENCHYMAL AT
LEAST INITIALLY TO EXCISE
PATHOGENIC REPEATS IN THE BRAIN
OF SUBJECTS WITH EITHER HD OR
C9 -- OR ALS.
WHY AM I TELLING YOU THIS?
BECAUSE WE CAN ENGINEER A GENE
EDITOR THAT WILL ELIMINATE A
PATHOGENIC GAIN OF FUNCTION
VARIANT IN AN EPILEPSY CAUSING
GENE, ALEVE-SELECTIVELY. ALLELEH
HIGH EFFICIENCY AND SPECIFICITY,
100% OF THE REGULATORY INTO
MANUFACTURING LEARNINGS FROM OUR
PROJECTS ARE AVAILABLE TO
EVERYONE IN THIS ROOM.
THIS IS A FEDERALLY FUNDED
EFFORT.
WE ARE FUNDED TO BE THE RISING
TIDE.
BUT THEODORE, THIS IS HUNT TINGE
TONS AND HD AND ALS.
WHAT DOES THAT HAVE TO DO WITH
EPILEPSY?
EVERYTHING.
THE DISEASE END POINTS ARE
DIFFERENT BUT HOW YOU MAKE THE
VIRUS IS THE SAME, HOW YOU DO
THE SAFETY IS THE SAME,
EVERYTHING IS THE SAME EXCEPT
THE DISEASE-SPECIFIC MODEL.
SO YOU CAN TAKE 90% OF THE INK D
AND THE PATH TO IT AND DO A
GLOBAL SEARCH REPLACE.
THEY HAVE GONE FROM TGR -- NEXT.
THEY HAVE A REMARKABLE PROJECT
TO USE THE SECOND VERSION OF
GENE EDITING WHICH IS CALLED
BASE EDITING.
THEY ARE FUNDED TO DO BASE
EDITING FOR FIRST SPINAL
MUSCULAR ATROPHY -- I DON'T HAVE
TO TELL THIS AUDIENCE WHAT THE
SEIZURE SPECTRUM IS IN GIRLS AND
WOMEN WITH TOURETTE'S SYNDROME.
SO WHAT IS BASE EDITING?
I DON'T WANT TO GO THROUGH THIS
BECAUSE IT WILL JUST PUT
EVERYONE TO SLEEP.
BUT HERE IS WHAT I NEED YOU TO
UNDERSTAND.
IT IS A WAY TO REPAIR POINT
MUTATIONS.
IT IS ALSO A WAY TO CREATE POINT
MUTATIONS IF YOU WANT TO DO THAT
AND I IT DOES NOT INVOLVE A DOUE
STRAND BREAK.
IF YOU NEED TO REPAIR A
CAUSATIVE MUTATION, IT'S A
REALLY GOOD WAY TO DO THIS.
SO IT IS IN THE CLINIC, IT IS IN
THE CLINIC FOR HEART DISEASE NO
LESS.
VERVE HAS TAKEN A MESSENGER RNA
ENCODING BASE EDITOR AND GUIDE
RNA AND IT SOUNDS AWFULLY
LIKE -- BECAUSE CRISPR IS A
PLATFORM.
BUT INSTEAD OF TARGETING TTR,
THEY TARGETED PCS K-9, HARBORING
A BASE EDITOR.
AND SO THAT'S THE PRECISE CHANGE
ON THE RIGHT YOU SEE HERE, JUST
ONE BASE PAIR CHANGE WHICH
KNOCKS OUT PCS K-9.
THIS IS THE CLINICAL RELEVANCE,
FOLKS, THAT THE HIGHEST DOSE
COHORT SUBJECT EXPERIENCE IS 60%
REDUCTION IN SERUM CHOLESTEROL.
I EMPHASIZE, THIS IS NOT A
MOUSE.
THIS IS A NEW ZEALANDER.
THAT'S WHERE THEY'RE DOING THE
TRIAL.
THEY HAVE AN OPEN IND IN THE
UNITED STATES.
CRITICALLY TO THE POINT OF
UNCOUPLING PHARMACOKINETICS TO
PHARMACODYNAMICS.
THIS IS A DIFFERENT BIOTECH,
DIFFERENT EDITOR, COMPLETELY
DIFFERENT DISEASE BUT THE
PHENOMENON IS THE SAME.
THE DURABILITY OF THE
PHARMACODYNAMIC EFFECT OUT TO
180 DAYS POST DOSING IS
COMPLETELY UNCOUPLED FROM THE 7H
THE DRUG SUBSTANCE LIVES IN THE
BLOODSTREAM OF THE SUBJECT.
WHY AM I TELLING YOU THIS WITH
RESPECT TO NEUROLOGIC DISEASE?
BECAUSE THEY'RE FUNDED BY THE
SOMATIC CELL GENOME -- I CONSULT
FOR FRANK BENNETT AND I TRULY
WORSHIP HIM.
I KNOW MANY OF YOU KNOW WHAT THE
LIFETIME COSTS ARE OF TREATING A
SUBJECT WITH SMA WITH SPIN RAH
IS A.
I KNOW YOU KNOW.
NOT A JOKE.
SO WHILE IT HAS SAVED 14,000
CHILDREN, THE HEALTHCARE
ECONOMICS ARE DIFFICULT.
THIS AIMS TO BE A ONE AND DONE
AND THAT'S A BIG THEME FOR
CRISPR TOOLS.
SO THEY PUBLISHED NON-CLINICAL
EFFICACY IN SCIENCE SO I WON'T
GO THROUGH THIS, BUT I WANT TO
EMPHASIZE TO THIS COMMUNITY THAT
THE WAY IT'S CONFIGURED IS TO
LEVERAGE THE PLATFORM NATURE OF
CRISPR AS AN APPROACH AND TO
HAVE INVESTIGATORS FIRST TREAT
SUBJECTS ON ONE COHORT, IN THIS
CASE, THIS WOULD BE FOR SMA, AND
THEN REPURPOSE IT FOR A
DIFFERENT NEUROLOGIC DISEASE AND
IN THIS CASE, THEY'RE GOING TO
GO FOR -- I IMAGINE MANY OF YOU
HAVE SEEN THE STAGGERING REPORTS
SHOWING TWO SUBJECTS WITH
TOURETTE'S SYNDROME WHO WERE
DOSED WITH AAE CONTROLLABLE --
THEY HAVE EXPERIENCED AN
IMPROVEMENT THAT NEUROLOGISTS
HAVE NEVER SEEN, LIZ I KNOW IS
IN THE AUDIENCE IS VERY PROUD OF
THIS.
I AM NOT GOING TO SAY A SINGLE
WORD ABOUT IT EXCEPT MY JAW WAS
ON THE FLOOR, I'M JUST A PH.D.,
BUT YOU'RE IN THE GENES CLINIC,
THIS IS THE PLATFORM THIS
PLATFORM WILL STAND ON, AND THEY
WILL HAVE A SEIZURE END POINT IN
THEIR TARGET PROFILE, THEY WILL
HAVE A SE SEIZURE END POINT IN
THEIR CLINICAL TRIAL DESIGN.
THEY WILL HAVE BIODISTRIBUTION
DATA IN THE BRAIN.
YOU WILL BE ABLE TO LEVERAGE ALL
OF THAT FOR A CRISPR TRIAL FOR
EPILEPSY.
THERE'S ALSO PRIME EDITING.
IT'S IN PRINCIPLE, AND THIS
PERSON WHO GAVE THIS VERY MOVING
TALK AT THE BEGINNING MENTIONED
PRIME ET EDITING.
IN PRINCIPLE, IT'S A MORE
VERSATILE MUTATION REPAIR
METHOD.
IN PRACTICE, IT'S VERY FINICKY,
YOU HAVE TO APPROACH IT WITH
CARE.
IT IS ABOUT TO ENTER THE CLINIC
FOR A BLOOD DISEASE, CHRONIC
GRANULOSIS DISEASE, BY THE WAY,
HARRY MALEK AT THE NIH IS THE
WORLD'S LEADER ON THIS.
THE POINT I WANT TO MAKE IS THE
PAPER ON THE LEFT.
THIS IS FROM THE INVENTOR OF THE
PRIME EDITING, DAVID LU, HERE
THEY DID FAIRLY PLAIN VANILLA
DELIVERY OF PRIME EDITOR TO THE
MOUSE BRAIN.
THE BAR GRAPH ON THE RIGHT THAT
YOU CAN'T REALLY SEE, WHICH IS A
GOOD THING, BASICALLY MEASURES
BASE PRIME EDITING EFFICIENCY IN
VARIOUS TISSUES OF THE MOUSE
BRAIN.
THIS IS A 2023 STUDY DONE WITH
2021 TECHNOLOGY.
I CAN ASSURE YOU STANDING ON THE
SHOULDERS OF THE KIND OF DATA
THAT BEV DAVIDSON JUST SHOWED
YOU THAT WE'RE GOING TO GET TO
HIGH DOUBLE DIGITS PRIME EDITING
WITH SYSTEMIC ADMINISTRATION OF
NON-HUMAN PRIMATES VERY, VERY
SOON.
SO THIS WILL BE TREATED BY BASE
EDITING BECAUSE OF SOME
LIMITATIONS WE HAVE.
THERE IS PRIME EDITING
ACCELERATING VERY, VERY FAST.
FINALLY, SONIA VALLABH WHO NEEDS
NO INTRODUCTION TO THIS AUDIENCE
IS FUNDED TO DO SOMETHING ABOUT
THE PRION DISEASE THAT KILLED
HER MOTHER IN THIS DEVASTATING
WAY, MAY KILL HER BECAUSE SHE'S
40 YEARS OLD AND WE DON'T KNOW
HOW MUCH LONGER SHE HAS.
I HAD BREAKFAST WITH HER A FEW
WEEKS BAG.
BACK.
AND THE TECHNIQUE THEY'RE USING
IS YET ANOTHER ADDITION TO THE
CRISPR TOOLBOX, WHICH IS EPI
EDITING.
I NEED TO DISCLOSE A CONFLICT OF
INTEREST, I AM THE SCIENTIFIC
CO-FOUNDER, TECHNOLOGY COMPANY
THAT SEEKS TO MAKE COMMERCIAL
MEDICINES OFF EPI EDITING, BUT
MY EMOTIONAL CONFLICT OF
INTEREST IS EVEN LARGER.
BASICALLY NO DOUBLE STRAND
BREAKS, NO GENETIC CHANGES, IT'S
THE ABILITY TO INACTIVATE OR
ACTIVATE GENES AS WELL.
I'M NOT GOING TO GO THROUGH
TECHNICAL DETAILS EXCEPT TO SAY
THAT YOU CAN CUE THE DURATION OF
THE EFFECT SHORTER OR LONGER,
AND CRITICALLY, IT GIVES YOU THE
OPPORTUNITY FOR ALLELE-SELECTIVE
ACTIVATION OR INACTIVATION OF
GENE EXPRESSION.
AND I'M SURE THIS IS FINISHING
ALL SORTS OF PUZZLES IN YOUR
HEAD WITH RESPECT TO HOW THAT
CAN BE RELEVANT TO BOTH GAIN OF
FUNCTION AND LOSS OF FUNCTION
MUTATION IN EPILEPSY.
SO I'M GOING TO IN THE INTEREST
OF TIME SKIP THROUGH THIS AND
JUST GET STRAIGHT TO THIS.
THIS IS A PARTIAL LIST OF
COMPANIES THAT ARE
COMMERCIALIZING EPIGENOME
EDITING.
ONE OF THEM, ENCODED, HAS AN
OPEN IND FOR EPIGENOME EDITING,
AND THEIR NON-CLINICAL EFFICACY
IN MOUSE AND THEIR SAFETY AND
BIODISTRIBUTION IN NON-HUMAN
PRIMATE IS PUBLISHED.
BECAUSE I DON'T WORK ON
EPILEPSIES I'M NOT GOING TO
REVIEW A SINGLE PIECE OF THESE
DATA EXCEPT TO TELL YOU THAT
THEY'RE BUILDING AN ENGINEERED
TRANSCRIPTION FACTOR THAT AIMS
TO ACTIVATE THE REMAINING COPY
AND THEY'RE USING A PROMOTOR
THAT IS SPECIFIC TO INHIBITORY
INTERNEURONS.
I DON'T KNOW HOW TO SPELL IT SO
I'M NOT GOING TO EMBARRASS
MYSELF BUT I'M JUST SAYING TO
YOU WHAT THEY'RE DOING.
AND I DON'T KNOW ANYTHING ABOUT
MOUSE MODELS OF EPILEPSY BUT
MANY OF YOU DO.
SO IF YOU ARE INTERESTED IN HOW
AN EXISTING BIOTECHNOLOGY
COMPANY IS DEPLOYING EP GINO EPE
EDITING FOR A SPECIFIC
CONGENITAL SEIZURE DISORDER,
AGAIN THEY HAVE AN OPEN IND.
WHY AM I TELLING YOU THIS?
WELL, BECAUSE SONIA HAS A GRANT
TO DO THIS FOR PRION DISEASE.
THIS WOULD INVOLVE
ADMINISTRATION OF AN AAV THAT
HARBORS AN EPI EDITOR THAT WILL
SILENCE THE MUTANT ALLELE.
THAT KILLED HER MOM AND SO
EVERYTHING THAT THEY LEARN FROM
THIS EFFORT, YET AGAIN, WILL BE
UNDER THE RIGHT TERMS PUBLICLY
AVAILABLE INFORMATION, AND MOST
CERTAINLY AVAILABLE TO ANYONE IN
THIS ROOM WHO WISHES TO THINK
ABOUT EPI EDITING FOR THEIR
FLTHEIRLABOR OF EFFORTS.
I SAID TO HE BEGINNING THE
CLINICAL TRACK RECORD AND
DELIVERY WILL CONTINUE TO DRIVE
CRISPR PROGRESS.
SPECIFICALLY I TOLD YOU WE
STARTED WITH CLASSICAL EDITING,
AND THEN WE TRANSITIONED TO BASE
EDITING.
EPI EDITING.
IT CAN ONLY GROW.
I MENTIONED WE HAVE AN APPROVED
MEDICINE.
BUT I ALSO SAID THAT CRISPR IS A
PLATFORM THAT UNTIL YOU HAVE THE
PHASE 3 TRIAL WITH 765 SUBJECTS,
AND ALL THEY DID IS CHANGE 20 --
I MENTIONED THAT PLATFO
PLATFORMABILITY -- THE FACT THAT
A DIFFERENT COMPANY USES THE
SAME DELIVERY TO TREAT A
COMPLETELY DIFFERENT DISEASE.
MOST IMPORTANTLY, I TOLD YOU
ABOUT THE PROGRAM THAT IS LED BY
THIS INSTITUTE, THE SOMATIC CELL
GENOME CONSORTIUM COLLABORATION,
WHICH HAS FUNDED THREE PROGRAMS
ALL THE WAY TO IND TO TARGET
MURLT MULTIPLE DISORTS OF THE CL
AND PERIPHERAL NERVOUS SYSTEM
AND EVERY SYLLABLE OF INNOVATION
THAT COMES OUT OF THAT WILL BE
AVAILABLE TO YOU.
INCLUDING -- IN CLOSING, DO YOU
MIND IF I TAKE ONE MORE MINUTE?
FOLKS, I DO NOT WANT TO BE A
DEBBIE DOWNER, I WANT TO BE
DEBBIE REALIST.
THERE IS ONE NEUROLOGIC DISEASE
IIN THE ENTIRE PORTFOLIO OF ALL
THE BIOTECH FOR-PROFIT CRISPR
COMPANIES IN THE WORLD.
ONE.
WHY IS THAT?
IS IT BECAUSE THEY'RE NOT GOOD
TARGETS?
NO.
IT'S BECAUSE CAPITALISM.
AGAIN, I'M NOT TRYING TO BE
ELIZABETH WARREN, I'M JUST
TELLING YOU WHAT IS REALLY
HAPPENING.
INVESTORS ARE INSISTING ON LATE
STAGE CLINICAL ASSETS I AND
NEUROLOGIC DISEASE TRIALS TAKE
LONG.
WHY ARE THEY DOING THAT?
I AM TOLD IT'S BECAUSE MONEY IS
EXPENSIVE RIGHT NOW.
NOW, THERE IS A SERIOUS ANSWER.
BUT WHY AM I TELLING YOU THIS?
I'M TELLING YOU THAT THAT I
BELIEVE THAT NOW IS A UNIQUE
MOMENT IN TIME FOR THE FEDERAL
ACADEMIC AND NON-PROFIT SECTOR
TO STEP UP.
THE FIRST THING YOU MUST
UNDERSTAND, FYODOR, LET'S DO 10
YEARS OF HUMAN PRIMATE STUDIES
BEFORE THINKING ABOUT EPILEPSY.
ABSOLUTELY NOT.
THE ONLY WAY TO FIND OUT HOW TO
SAFELY AND EFFECTIVELY GENE-EDIT
PEOPLE IS TO GENE-EDIT MORE
PEOPLE.
THAT APPLIES TO GENE THERAPY AS
WELL AND REMEMBER, GENE THERAPY
STARTED HERE, AT THE NIH, PETE
ROSENBERG IN 1989.
AND IN THAT 35-YEAR HISTORY OF
THE FIELD, NOT A SINGLE SEVERE
ADD DIVERSITY EVENT THAT WE SAW
ON TRIALS OF GENE THERAPY OR
GENE EDITING WERE PREDICTED FROM
ANY NON-CLINICAL STUDIES.
SO IF ANYONE IN THE ROOM THINKS,
LET'S DOSE A LOT MORE MONKEYS
BEFORE WE ARE COMFORTABLE DOSING
HUMANS, FOLKS, RESPECTFULLY, YOU
ARE DELUDING YOURSELF BY
THINKING YOU'RE MAKING THE
THERAPY SAFER BY DOSING MORE
MONKEYS.
I'M NOT SAYING YOU SHOULDN'T
DOSE MONKEYS.
I'M SAYING THE REAL -- THAT WILL
EMERGE WILL ONLY EMERGE IF YOU
DO THE CLINICAL TRIAL.
ANSO IF YOUR GOAL IS TO USE CRIR
TO TREAT EPILEPSIES, PROGRAMS
CAN BE BUILT -- AND THIS IS MY
MOST IMPORTANT STATEMENT OF THE
DAY -- RIGHT NOW.
NOT FOUR YEARS FROM NOW.
THAT TAKE ON SPECIFIC TARGETS IN
THE EPILEPSY SPACE, THAT GANTT
CHART THEM OUT WITH MILESTONES
AND GO/NO-GO GATES, AND
DR. KOROSHETZ, TIM AND CHRIS
WILL GLADLY SEND YOU THOSE GANTT
CHARTS FOR THE FIVE PROGRAMS
THAT THEY ARE CURRENTLY
MANAGING.
AND THEN YOU PUT THEM THROUGH
REGULATORY REVIEW, USING THE
FRAMEWORK THAT THE CONSORTIUM
HAS ESTABLISHED, TO ADVANCE TO
IND AND CLINICAL TRIALS.
LAST QUOTE, THIS IS THE QUOTE I
ALWAYS END MY TALKS ON, AMANDA
GOGORMAN SAID AT PRESIDENT BIDES
INAUGURATION, WHY SHOULD THE
FEDERAL GOVERNMENT DO THIS, WHY
SHOULD THE ACADEMICS AND
NON-PROFITS DO THIS?
WELL, BECAUSE WE'RE POWERFUL.
AND THE WAY TO LIVE MOST --
THANK YOU.
[APPLAUSE]
>> WE'RE A LITTLE BIT OVER BUT
CAN WE TAKE TWO OR THREE
QUESTIONS?
WE'RE GOING TO THEN HAVE A
BREAK.
THE MICROPHONES WORKING?
WHILE YOU'RE READING THAT, I
HAVE A QUESTION FOR YOU.
WHAT EXPLAINS THE PROLONGED
PHARMACODYNAMIC EFFECT?
>> SO THE PROLONGED
PHARMACODYNAMIC EFFECT AS BEST
AS WE CAN TELL BY LITERALLY
GENOTYPING NON-HUMAN PRIMATES,
IS THAT THE EDITED ALLELES DO
NOT GENETICALLY REVERT.
SO -- AND FURTHERMORE, THE
EDITED CELLS DO NOT EPITOSE.
THAT WAS THE BIG FEAR.
BUT IF THE EDITED CELLS WOULD
EPITOSE AND WOULD BE OVERGROWN,
THEN THE PHARMACODYNAMICS WOULD
PLUMMET.
BUT STRIKINGLY, THE EDITED CELLS
PERSIST.
AND SO THE KNOCKOUT ALLELES JUST
HAVE NOWHERE TO GO.
BUT I WANT TO BE CLEAR, WE WERE
ALL AFRAID THAT YOU WOULD GET
80% EDITING AT TWO MONTHS AND
THEN 4% EDITING AT A YEAR,
BECAUSE YOU KNOW, EDITING IS
TOXIC.
THAT'S NOT WHAT WAS SEEN IN
CLINICAL TRIAL.
I'M GLAD YOU ASKED.
IT WAS A KEY CONCERN, FRANKLY.
VICKY, IS THERE A QUESTION
ONLINE?
JUST READ IT?
>> QUESTION FROM --
>> AS I LIKE TO SAY IN SUCH
SITUATIONS, NO DISRESPECT TO
ANYONE, WE CAN CHANGE A SINGLE
BASE PAIR IN THE HUMAN GENOME
BUT CERTAINLY AT THE GENOMICS
INSTITUTE WHERE WE DO THAT, WE
STRUGGLE WITH AAGs ALL THE
TIME.
BEV DAVIDSON HAS IT FULLY UNDER
CONTROL.
I KNOW, I KNOW, DR. DAVIDSON IS
SAYING, GET YOUR STUFF -- LET'S
GO.
YES.
I MEAN, LOOK AT THE
BIODISTRIBUTION YOU SAW IN THE
NHP BEV JUST SHOWED.
GOT IT, VICKY?
>> WE'RE HAVING PROBLEMS
UNMUTING THE PERSON.
WE'RE INVITING HIM TO UNMUTE.
CAN YOU UNMUTE?
>> SO CAN THAT PERSON ASK DURING
THE PANEL?
>> YES, WE CAN COME BACK.
>> OKAY.
WITH NO DISRESPECT.
>> WHY DON'T WE DO THAT.
>> OKAY.
SORRY.
>> ANY OTHER QUESTIONS IN THE
ROOM?
NO?
SO WE'RE SCHEDULED TO NOW TAKE A
BREAK.
WE'LL BE BACK IN 11 MINUTES OR SO.
THANKS AGAIN.
>> OKAY, WE'RE GOING TO START
UP.
IF YOU COULD TAKE YOUR SEATS,
PLEASE, AND DR. TIPPI MACKENZIE
IS GOING TO PRESENT.
TIPPI -- I THINK SHE'S IN
EUROPE, SO SHE HAD TO -- BECAUSE
OF THE TIME ISSUE, SHE'S
RECORDED HER PRESENTATION, BUT
IS POTENTIALLY AVAILABLE FOR THE
Q & A.
SO IF YOU COULD ALL PLEASE TAKE
YOUR SEATS.
AND SHE'S ON ZOOM.
GREAT.
SO LET'S START THE RECORDED PART AND TIPPI IS LISTENING IN.
HI EVERYONE.
THANK YOU SO MUCH FOR THE
INVITATION TO PRESENT, AND I
APOLOGIZE FOR NOT BEING ABLE TO
BE THERE IN PERSON.
MY NAME IS TIPPI MACKENZIE.
I'M A PROFESSOR OF SURGERY AT
UCSF AND I DIRECT OUR STEM CELL
INSTITUTE, AS WELL AS
CO-DIRECTING OUR CENTER FOR
MATERNAL-FETAL PRECISION
MEDICINE, WHERE WE TRY TO
DEVELOP NEW THERAPIES FOR
FETUSES WITH GENETIC DISEASES.
THESE ARE MY DISCLOSURES.
SO I'M VERY EXCITED ABOUT
TELLING YOU ABOUT INNOVATIONS IN
FETAL THERAPY AND HOW THESE
COULD BE RELEVANT FOR TREATING
PATIENTS WITH GENETIC CAUSES OF
EPILEPSY.
SO FETAL SURGERY IS A FIELD THAT
WAS INVENTED AT UCSF IN THE
1980s, AND HAS BEEN
DISSEMINATED ALL OVER THE WORLD
NOW, WHERE PEOPLE CAN DO OPEN
FETAL SURGERY FOR CONDITIONS
SUCH AS SPINA BIFIDA, AND I'M
SHOWING YOU A SPINA BIFIDA
REPAIR HERE, AS WELL AS
LAPAROSCOPIC SURGERIES IN THE
FETUS, WHICH WE CALL FETOSCOPIC,
CATHETER BASED INTERVENTIONS TO
DRAIN FLUID COLLECTIONS, ET
CETERA, AND WE HAVE AN AMAZING
WAY OF GETTING INTO THE FETAL
UMBILICAL VEIN, USUALLY JUST
WITH ULTRASOUND GUIDANCE, AND
THIS ACTUALLY HAS BEEN AROUND
SINCE THE 1960s TO GIVE BLOOD
TRANSFUSIONS FOR PATIENTS WHO
HAVE RH INEXAT ABILITY BETWEEN
THE MOTHER AND THE FETUS.
AND THE ABILITY TO GIVE A
SYSTEMIC INVEUTION ALLOWS US TO
CONSIDER SEMI STILL
TRANSPLANTATION, ENZYME
REPLACEMENT THERAPY OR, IN THE
FUTURE, GENE THERAPY OR GENOME
EDITING AND COLLECTIVELY WE CAN
REFER TO THESE AS FETAL
MOLECULAR THERAPIES.
YOU MAY WONDER WHY NOT WAIT
UNTIL BIRTH.
OF COURSE WE'RE TRYING TO
PREVENT IRREVERSIBLE ORGAN
DAMAGE.
BUT IN ADDITION TO THAT, THE
FETAL ENVIRONMENT OFFERS
NUMEROUS ADVANTAGES BIOLOGICALLY
FOR THE SUCCESS OF SUCH
THERAPIES, SUCH AS HAVING A MORE
PERMEABLE BLOOD BRAIN BARRIER
LIKELY UP UNTIL THE END OF THE
SECOND TRIMESTER, A UNIQUE
IMMUNE SYSTEM THAT ALLOWS US TO
TOLERIZE TO NEW ANTIGENS SUCH AS
TRANSGENE ENCODED PROTEINS,
ACCESSIBLE STEM CELL
POPULATIONS, AS WELL AS A SMALL
SIZE THAT ALLOWS US TO REALLY
DECREASE THE MANUFACTURING COST
OF A NEW THERAPY.
WE USUALLY DOSE AROUND 400 OR
500 GRAMS OF FETAL WEIGHT.
THERE ARE RATIONALE FOR TREATING
CONDITIONS IN ALL OF THESE
DIFFERENT SYSTEMS.
FOR THE CNS SPECIFICALLY, WE
THINK A LOT ABOUT SMA OR
ANGELMAN, OF COURSE THEY MUST
ALL BE SEVERE AND EARLY ONSET
AND HAVE A GOOD GENOTYPE
PHENOTYPE CORRELATION BECAUSE BY
DEFINITION WE'RE TREATING A
GENOTYPE THAT WE'VE DETECTED ON
THE FETUS WITHOUT HOPEFULLY --
YES.
SO THIS IS THE TOOLKIT FOR
PRENATAL THERAPY OF CNS
DISEASES.
SO WE CAN HAVE PRETEENS OR SMALL
MOLECULES, GENE REPLACEMENT
THERAPY OR GENOME EDITING.
IN THE CURRENT REALM WE'RE
CURRENTLY FOCUSING ON THERAPIES
FDA-APPROVED FOR CHILDREN FOR
APPLICATIONS FOR PRENATAL
THERAPY.
SO IN TERMS OF THE PIPELINE OF
PLEK RAR FMOLECULAR THERAPIES AE
HAVE EXPERIENCE WITH SOME STEM
CELL TRANSPLANTATION THAT'S LESS
RELEVANT FOR TODAY SO I WON'T
REALLY TALK ABOUT THAT.
WE HAVE AN ONGOING CLINICAL
TRIAL FOR IN UTERO ENZYME
REPLACEMENT THERAPY IN LYSOSOMAL
STORAGE DISEASES.
I THINK THAT IS LIKELY RELEVANT
SO I WILL TALK A LITTLE BIT
ABOUT OUR EXPERIENCE, AND THEN
WE AND OTHERS ARE REALLY WORKING
ON PRE-CLINICAL MODELS FOR
PRENATAL GENE THERAPY, USING
ASOs, AAV GENE REPLACEMENT OR
GENOME EDITING.
AND I'LL PAUSE AND SAY THAT THIS
FIELD IS NOT AT ALL ABOUT
EDITING IVF EMBRYOS.
WE'RE REALLY THINKING ONLY ABOUT
EDITING SOMATIC CELLS IN A
SECOND TRIMESTER FETUS.
SO LYSOSOMAL STORAGE DISEASES,
AS YOU ALL KNOW, ARE GENETIC
DISEASES CAUSING DEFICIENCIES IN
CRITICAL LYSOSOMAL ENZYMES, AND
WE FIRST GOT INTERESTED IN THEM
BECAUSE SOME OF THEM CAN PRESENT
WITH HYDROPS, FOR EXAMPLE, ON
MPS7 AND HAVE IN UTERO DEMISE.
ALTHOUGH THERE ARE SOME
POSTNATAL THERAPIES SUCH AS
RECOMBINANT ENZYME REPLACEMENT
THERAPY OR STEM CELL TRANSPLANT,
THERE IS STILL RATIONALE IN THAT
YOU CAN POTENTIALLY PREERCHT IN
UTERO DEMISE, INDUCE TOLERANCE
TO THE MISSING ENZYME, IN WHICH
IMMUNE REACTIONS CAN BE LIMITED
IN SOME CONDITIONS SUCH AS POM
PAY DISEASE, YOU CAN DELIVER
ENZYME TO THE BRAIN AT LEAST
DURING THE PERIOD THAT THE BLOOD
BRAIN BARRIER IS PERMEABLE AND
PREVENT ONGOING ORGAN DAMAGE.
SO WE FIRST DID THIS IN MICE, OF
COURSE, AS YOU DO, SO IN
MPS7 MICE, WE SAW THAT IN UTERO
INFUSIONS OF THE ENZYME IMPROVE
SURVIVAL, DECREASE STORAGE.
THEY DID PENETRATE INTO
MICROGLIA IN THE CNS, IMPROVE
BONE LENGTH AND IMPORTANTLY,
INDUCE TOLERANCE TO THEIR COME
NENT PROTEIN.
THAT'S PUBLISHED SO I WON'T GET
INTO IT.
PRIOR TO AEMPLOYING FOR AN IND,
WE ALSO STARTED PERFORMING A
SURVEY OF PATIENT GROUPS WITH --
WE'VE HEARD AN OVERWHELMING YES
TO FETAL THERAPY AND WE'VE HAD
AN IND SINCE 2020.
AND THE CLINICAL TRIAL WAS
LAUNCHED A FEW YEARS AGO.
SO IT'S THE PEARL TRIAL.
WE WERE ABLE TO GET A PLATFORM
IND TO TREAT PATIENTS WITH EIGHT
DIFFERENT CONDITIONS, ALL OF
THESE HAVE AN FDA-APPROVED IV
FORMULATION OF THE ENZYME.
AND THE WAY IT WORKS IS USUALLY
THE DIAGNOSIS IN A FETUS IS MADE
IN FAMILIES WHERE THEY ALREADY
KNOW THEY'RE CARRIERS, THEY
MIGHT HAVE HAD A PREESKT
AFFECTED PREGNANCY OR A CHILD,
AND ONCE THE DIAGNOSIS IS
CONFIRMED AND THE PATIENT MEETS
ENROLLMENT CRITERIA, WE DO THE
ENZYME INFUSIONS EVERY TWO TO
FOUR WEEKS BECAUSE THAT'S THE
HALF-LIFE OF THE ENZYME THROUGH
THE UMBILICAL VEIN, AND THEN
AFTER BIRTH, WE DO STANDARD OF
CARE ENZYME REPLACEMENT THERAPY,
OF COURSE, BUT THEY'RE ELIGIBLE
FOR OTHER CLINICAL TRIALS OF
GENE THERAPIES OR STEM CELLS,
AND THEN WE'RE DOING A FIVE-YEAR
FOLLOW-UP.
IT'S A PHASE ONE TRIAL SO OUR
PRIMARY OBJECTIVES ARE SAFETY
AND FEASIBILITY, BUT THE
SECONDARY OBJECTIVES, OF COURSE,
ARE EFFICACY, SO ARE WE
DECREASING THE METABOLIC
BYPRODUCTS, THE GAGS, ARE WE
INDUCING TOLERANCE TO THE
PROTEIN AND ALSO LOOKING AT
LONG-TERM OUTCOMES.
SO THE WAY WE DO THIS ULTRASOUND
GUIDED INJECTION IS -- WELL, DRG
MFM WHO DOES ALL OF THESE IN
ADDITION TO THE IN UTERO
TRANSFUSIONS.
AND SO AT THE POINT OF ENTRY OF
THE NEEDLE INTO THE UMBILICAL
VEIN, YOU CAN DRAW BACK A LITTLE
BIT OF BLOOD AND THAT'S REALLY
USEFUL FOR CHECKING TROUGH
LEVELS AND SUBSEQUENT INFUSIONS,
CHECKING AP ANTI-DRUG ANTIBODIES
WELL AS UNDERSTANDING WHETHER
WE'RE MAKING A DIFFERENCE IN
DISEASE-SPECIFIC BIOMARKERS.
IT'S OF COURSE A TECHNICALLY
DELL CAN'T PROCEDURE, SO WE
ALWAYS COUNSEL FAMILIES THAT
THERE IS A RISK OF PRETERM
DELIVERY, OR EVEN IN UTERO
DEMISE.
WE THINK THE RISK IS LESS THAN E
LESS THAN 1% SIDE OF IT.
SO OUR FIRST EXPERIENCE WAS WITH
A FAMILY WHOSE THIRD FETUS WAS
DIAGNOSED WITH INFANTILE ONSET
POMPE DISEASE.
THE CRIM NEGATIVE IOPD, WHICH IS
THE MORE SEVERE VERSION, AND THE
SIBLING 1 HAD BEEN DIAGNOSED AT
8 MONTHS, SUFFERED FROM IMMUNE
REACTIONS TO THE ENZYME AND DIED
AT 29 MONTHS.
SIBLING TWO WAS PRENATALLY
DIAGNOSED AND HAD PALLIATIVE
CARE, SO THE PATIENTS WERE VERY
MOTIVATED TO SEEK KIND OF A
DIFFERENT TREATMENT PLAN FOR THE
THIRD PREGNANCY.
THE RATIONALE FOR THE IN UTERO
THERAPY WAS THE NON-SEVERE
PHENOTYPE IN THIS FAMILY.
THEY'D HAD EARLY ONSET
CARDIOMYOPATHY AS WELL.
THIS WAS AN INNATIONAL
COLLABORATION KIND OF IN THE
HEAT OF THE PANDEMIC WITH
COLLEAGUES AT CHILDREN'S
HOSPITAL OF EASTERN ONTARIO AND
DUKE, WHERE WE DID NON-DIRECTIVE
COUNSELING, THE PATIENT RECEIVED
SIX DOSES OF THE ENZYME INFUSION
AND HAD A TERM DELIVERY AND IS
NOW TWO YEARS OLD AND DOING
WELL.
WE DID SEE A BENEFIT IN THE
CARDIOMYOPATHY.
SO I'M SHOWING YOU HERE PRENATAL
ECHOCARDIOGRAMS FROM SIBLING 2,
THE AFFECTED FETUS WHO WAS NOT
TREATED, AND YOU SEE THAT
THERE'S A THICKENING OF THE
SEPTUM BETWEEN THE RIGHT AND
LEFT VENTRICLE HERE, THE Z SCORE
WAS 7.
WHEREAS IN THE IP UTERO-TREATED
PATIENT, THE SEPTAL THICKNESS
WAS NORMAL.
AT BIRTH THE PATIENT HAD NORMAL
CK LEVELS, COMPARING THEM TO A
NEWBORN SCREENING, A COHORT OF
CRIM NEGATIVE IOPD PATIENTS, YOU
CAN SEE THAT THEY ALL START WITH
HIGHER THAN NORMAL CK LEVELS.
AND CONSISTENT WITH THAT, WE DID
SEE A MOTOR BENEFIT IN OUR
PATIENT WHO HAD NORMAL
MILESTONES AS OPPOSED TO TWO OUT
OF THE FOUR OF THE NEWBORN
DIAGNOSED PATIENTS WHO HAD MOTOR
DELAYS.
AND OUR PATIENT WALKED AT 11
MONTHS.
SO WE'VE SINCE TREATED THREE
PATIENTS, AND THERE ARE ALSO TWO
MORE IN UTERO RIGHT NOW.
WE HAVEN'T HAD, THANK GOODNESS,
ANY SAFETY EVENTS.
EACH PATIENT RECEIVED THREE TO
SIX IN UTERO INFUSIONS.
THEY WERE ALL BORN AT TERM AND
THEY'RE ALL RECEIVING POSTNATAL
ENZYME THERAPY.
AND WE ARE SEEING MARKERS OF
EFFICACY IN ADDITION TO THE
RESCUED PREDICTED ORGAN
DYSFUNCTION, WE'RE SEEING NORMAL
BIOMARKERS IN NEWBORN SCREENING,
AND A DECREASE EVEN IN THE FETAL
BLOOD GAGs OVER TIME AND
RESCUE OF PLACENTAL STORAGE.
THE NEUROLOGICAL TESTING IS
ONGOING.
AND WE'RE CONTINUING TO ENROLL
PATIENTS.
SO ENZYME REPLACEMENT THERAPY,
OF COURSE, MAY BE PROMISING BUT
IT'S NOT A DEFINITIVE CURE, SO
MARCHING SLOWLY INTO MORE
DEFINITIVE THERAPIES, MOVING ON
TO THE GENE THERAPY PORTION OF
THE TALK.
SO FIRST GENE THERAPY LIGHT,
ANTISENSE OLIGONUCLEOTIDES.
WE'VE DONE SOME STUDIES IN
ANGELMAN SYNDROME IN MICE.
ANGELMAN SYNDROME AS YOU ALL
KNOW IS A SEVERE GENETIC DISEASE
CHARACTERIZED BY DELAY AS WELL
AS SEIZURES.
AND THE GENETICS OF IT IS REALLY
INTERESTING.
SO IN THE UBE3A GENE, IN
NEURONS, THE PATERNAL ALLELE IS
SILENCED, SO YOU CAN PRESENT
WITH ANGELMAN'S SYNDROME IF
THERE'S A MA TERN LOSS OF MATERF
FUNCTION.
THE SILENCING OF THE PARENTAL
ALLELE -- THE UB3 A ANTISENSE.
PEOPLE HAVE DESIGNED ANTISENSE
OLIGOS TO INHIBIT THE
UBA3 ANTISENSE AND REINSTATE THE
PATERNAL ALLELE EXPRESSION.
SO YOU CAN STUDY THIS REALLY
NICELY IN A MOUSE MODEL WHERE
THERE'S A UB3AYFP, SO WE DID
EXPERIMENTS WHERE WE BRED THE
YFP ON THE PATERNAL SIDE AND TO
THE RESULTANT PUPS WE DELIVERED
AN ANTISENSE OLIGOTO SEE HOW
WELL WE COULD REINSTATE PATERNAL
ALLELE EXPRESSION, SO WAKING UP
OF THAT ALLELE CAN BE READ OUT
AS YFP POS TIFL POSITIVITY OF TS
IN ALL THE SUBSEQUENT PLOTS I'M
GOING TO SHOW YOU.
SO THESE ARE THE BRAINS OF IN
UTERO INJECTED ANIMALS.
HERE WE'VE DONE AN INTRACRANAL L
INJECTION, WE INJECTED THE LEFT
VENTRICLE, YOU CAN SEE THEM ALL
LIGHT UP WITH THE METHYLENE BLUE
HERE.
NEGATIVE CONTROLS, NOTHING IS
GREEN AND MATERNAL ALLELE
POSITIVE CONTROLS, ALL THE CELLS
ARE GREEN AND INTRACRANIAL
INJECTION AT BOTH A 1 AND
2.5-MICROGRAM DOSE DOES RESULT
IN YFP EXPRESSION IN BOTH
CORTICAL AND HIPPO CAM PAL
NEURONS AND THAT'S QUANTIFIED
HERE.
WE ALSO DID SIMILAR EXPRESSIONS
NOW IN ANGELMAN KNOCKOUT MICE
WHERE WE'VE BREAD BRED THE KNON
THE MATERNAL SIDE AND INJECTED
INTRACRANIALLY.
YOU CAN SEE WITH ANGELMAN, WE
CAN SEE LOOKING AT UB3A PROTEIN
EXPRESSION, WE CAN SEE THE
EXPRESSION RESTORED IN THE
CORTEX ON THE HIPPOCAMPUS.
THIS DID TRANSLATE INTO SOME
IMPROVEMENTS, ALTHOUGH SUBTLE
ELEMENT IN FEAR CONDITIONING AS
WELL AS -- TRAINING IN ANGELMEN
MICE THAT WERE TREATED WITH ASO.
WE ALSO THEN WANTED TO SEE,
INTRACRANIAL INJECTIONS SOUND
PRETTY SCARY, ALTHOUGH WE CAN
DPO TDOTHE SPINA BIFIDA REPAIRSR
NEUROSURGEON HAS REASSURED US IT
SHOULD BE REASONABLY SAFE TO
OFFER IN HUMANS, WE WANTED TO
SEE IF AN AMNIOTIC FLUID
INJECTION CAN ACTUALLY DO THE
SAME THING IN THE PERIOD BEFORE
THE BLOOD BRAIN BARRIER HAS
CLOSED.
SO HERE WE'RE INJECTING IN FETAL
MICE IN THE AMNIOTIC FLUID, AND
YOU CAN SEE WE CAN GIVE A MUCH
HIGHER DOSE, SO HERE THEY COULD
TOLERATE A 20-MICROGRAM DOSE.
AND WHEN YOU COMPARE THE
INTRAAMNIOTIC HERE TO THE
INTRACRANIAL, THERE'S A LOT MORE
GREEN IN BOTH THE CORTEX AND THE
HIPPOCAMPUS, AND THAT IS
QUANTIFIED HERE, THE
INTRAAMNIOTIC COMPARED TO THE
INTRACRANIAL.
WE DID SOME WORK TO TRY TO
FIGURE OUT HOW DOES THE ASO
ACTUALLY ENTER THE CNS.
SO HERE WE'VE DONE RNA IN SITU
HYBRIDIZATION USING A PROBE
AGAINST THE BACKBONE OF THAT
ASO, AND YOU CAN SEE ALL THE
PINK IS THE INJECTED CELLS THAT
HAVE TAKEN UP ASO.
WE SEE A LOT IN THE DORSAL
PALLIDUM -- AND WE DETECTED ASOO
POSITIVITY IN THE RESPIRATORY
EPITHELIUM.
THE OLFACTORY EPITHELIUM
POTENTIALLY GOING THROUGH THE
CRIBRIFORM PLATE AS WELL AS THE
CORE YOID PLEXUS SO POTENTIAL
ROUTES OF ENTRY INTO THE CNS OF
THE ASO.
SO WHEN WE LOOK AT THE FETUS AS
A WHOLE, RED IS HOT, BLUE IS
COLD, WE WERE EXCITED ABOUT THE
GREEN NEURONS IN THE BRAIN, BUT
YOU CAN SEE THE BRAIN IS KIND OF
THE LEAST OF IT.
AND THERE'S A LOT OF ASO
PENETRATION INTO THE LUNG, THE
HEART, THE LIVER AND THE GI
TRACT.
AND THAT'S QUANTIFIED HERE.
SO WE'RE REALLY EXCITED ABOUT
USING THE INTRAAMNIOTIC ROUTE TO
DELIVER THERAPEUTIC RNAs
INCLUDING ASOs, NOT JUST FOR
CNS DISEASES BUT POTENTIALLY FOR
SOME OTHER SYSTEMIC DISEASES AS
WELL.
AND SO OUR USUAL PROTOCOL FOR
TRYING TO FIGURE OUT IF
SOMETHING WORKS CLINICALLY, OF
COURSE, IS TO DO A MOUSE STUDY
AND THEN A SHEEP STUDY.
SO WE'VE BEEN CL COLLABORATING W
WITH BIOGENERA BIOGEN TO USE ANO
SIMILAR TO NUSINERSEN USED IN
PATIENTS WITH SPINAL ATROPHY IN
SHEEP, AND THIS IS -- WE'VE DONE
BOTH INTRAAMNIOTIC INJECTIONS,
AS WELL AS SOME INTERCYST SISTER
MA MAGNA INJECTIONS WITH OUR
FETAL NEUROSURGEON DR. GUPTA AND
THAT'S SHOWN HERE.
SHEEP HAVE VERY SMALL
VENTRICLES, SO WE HAD TO DO
CHRCISTERNA MAGNA INJECTIONS.
YOU CAN SEE WHEN WE LOOK IN THE
SPINAL CORD FOR THE ASO, AND
THIS IS NOW IN ELI E ELISA FORE
ASO, AT THE MEDIUM AND HIGH
DOSE, WE'RE SEEING WHAT WE'VE
BEEN TOLD LEVELS OF 1 TO 10 ARE
SORT OF IN THE THERAPEUTIC
RANGE.
SO THIS IS ENCOURAGING.
OF COURSE WHEN YOU DO THE
INTRACRANIAL INJECTION, WHICH IS
SORT OF OUR POSITIVE CONTROL IN
THIS EXPERIMENT, YOU GET MUCH
HIGHER LEVELS.
AND JUST LIKE IN THE MOUSE
STUDY, ALTHOUGH WE'RE SEEING
SOME DISTRIBUTION INTO THE
SPINAL CORD, A LOT OF THE
DISTRIBUTION SEEMS TO BE IN SOME
OF THE OTHER ORGANS AS WELL.
SO WE THINK THIS IS ENCOURAGING
BUT OBVIOUSLY WE NEED SOME MORE
WORK, ESPECIALLY BECAUSE THIS
TOOL COMPOUND HAS NOT BEEN USED
IN HUMANS AT THIS POINT.
WE'RE ALSO THINKING VERY
CRITICALLY ABOUT CAN YOU DO GENE
REPLACEMENT THERAPY JUST GIVEN
THAT MANY PATIENTS ARE NOT GOING
TO HAVE DISEASES OR SPECIFIC
MUTATIONS THAT ARE AMENABLE TO
ASO THERAPY.
SO WE'VE COLLABORATED WITH
NOVARTIS IN OBTAINING AN
AAV9-GFP VECTOR THAT'S SIMILAR
TO ZOLGENSMA USED IN CHILDREN
WITH SMA.
THIS TIME USING UMBILICAL VEIN
INJECTIONS IN FETAL LAMBS.
AND AS YOU CAN IMAGINE, THIS
WORKED REALLY WELL USING THE
DOSE-ADJUSTED FOR WHAT INFANTS
WITH SMA WOULD BE GIVEN.
WE SAW WIDESPREAD
BIODISTRIBUTION IN THE CNS, SO
HERE I'M SHOWING YOU GFP AND NEW
END STAINING IN THE CERVICAL,
THORACIC AND LUMBAR SPINAL
CORDS, AND WE'RE EXCITED BY THIS
BECAUSE IN ADDITION TO SMA, OF
COURSE, OTHER NUMEROUS POTENTIAL
INDICATIONS FOR DISEASES THAT
WOULD MAKE SENSE POTENTIALLY TO
TREAT IN UTERO, INCLUDING
POTENTIALLY GENOME ONE, GENOME
TWO, NEUROPATHIC GAUCHER JUST TO
NAME A FEW.
AAV9, OF COURSE, ALSO TRANSDUCES
THE MUSCLE CELLS REALLY WELL,
AND WE SAW THAT HERE, AND SO
POTENTIALLY THIS COULD BE
CONSIDERED AS A STRATEGY FOR
MUSCULAR DISPROPHYS AS WELL.
AND THIS PAPER IS RECENTLY OUT.
SO THAT BROAD BIODISTRIBUTION,
THOUGH, IS A TWO-EDGED SWORD,
AND WITH ANY FIELD, BUT
ESPECIALLY WITH FETAL THERAPY WE
REALLY HAVE TO THINK ABOUT THE
RISKS AND THE BENEFITS AND AS I
MENTIONED WE'RE ABSOLUTELY NOT
INTERESTED IN DOING ANY
HERITABLE EDITING.
SO WE HAVE LOOKED TO SEE WHETHER
THIS AAV9-GFP GETS INTO GERM
CELLS IN COLLABORATION WITH
DIANA LAIRD, AMAZING GERM CELL
BIOLOGIST AT UCSF.
INTERESTINGLY AND UNFORTUNATELY
IN THE OVARIES OF THESE FETAL
LAMBS INJECTED WITH AAV9-GFP, WE
ARE SEEING GFP EXPRESSION.
INTERESTINGLY WE SEE ONLY IN THE
OVARIES AND NOT IN THE TESTES,
SO IT ONLY HAPPENS TO THE FEMALE
LAMBS.
THEN LOOKING AT THE LITERATURE,
THERE IS AN AUTOPSY STUDY OF TWO
INFANTS WHO HAD RECEIVED
ZOLGENSMA AND THERE IS PCR
POSITIVITY FOR VECTOR IN THE GOA
FLADGONADS, SO WE THINK THIS ISN
IMPORTANT CONSIDERATION.
OF COURSE THE AAV SHOULD REMAIN
EPISOMAL SO THIS ISN'T A
HERITABLE GENE PER SE BUT I
THINK THIS WOULD BE CONCERNED IF
AAV WERE USED AS A DELIVERY
VEHICLE FOR A GENOME EDITOR
BECAUSE IN THAT CASE, EVEN IF
THE VECTOR DOESN'T INTEGRATE,
YOU WOULD POTENTIALLY HAVE A
HERITABLE EDITING BECAUSE YOU'VE
DELIVERED A GENOME EDITOR.
AND SO THAT BRINGS US TO WHAT I
THINK IS REALLY THE FUTURE, OF
COURSE, IN VIVO GENOME EDITING,
LIKELY USING LIPID
NANOPARTICLES, ALTHOUGH THE
DELIVERY VEHICLES CONTINUE TO
EVOLVE SO QUICKLY, RIGHT?
AND SO THIS IN OUR LAB IS JUST
IN MICE SO FAR USING THESE CRE
REPORTER MICE TO DELIVER LNPs
DELIVERING CRE MRNA.
WE'RE COLLABORATING WITH A
NUMBER OF LNP EXPERTS INCLUD ANN
USING OUR MOUSE MODEL TO INJECT
THESE LNP-CRE INTO THE FETAL
MOUSE.
WHERE RECOMBINATION EVENTS
BECAUSE OF THE CRE CAN BE READ
OUT AS RED CELLS TURNING GFP
POSITIVE.
SO YOU GET REALLY BROAD
BIODISTRIBUTION AS YOU CAN SEE
HERE, THIS IS A STAINING ABOUT
FOUR DAYS AFTER WE'VE DONE THE
IN UTERO INJECTION.
A LOT OF STAINING IN THE LIVER
AND THE HEART, OF COURSE.
WE'RE REALLY INTERESTED IN
WHETHER THIS CAN BE USED TO
DELIVER A THERAPEUTIC TO
HEMATOPOIETIC STEM CELLS, WHICH
ARE IN THE FETAL LIVER AT THAT
GESTATIONAL AGE AND WE ARE
SEEING SOME HINTS WHEN WE LOOK
AT HSCs FROM THOSE INJECTED
MICE THAT THERE IS SOME
RECOMBINATION EVENTS.
SO WE THINK THAT THIS COULD BE A
PROMISING METHOD FOR SHORT TERM
DELIVERY OF THE GENOME EDITORS
FOR SELECT SOMATIC TISSUES.
THE CNS DELIVERY IS OF COURSE
MORE CHALLENGING AS MANY OF YOU
ARE EXPERTS IN, BUT OF COURSE
THERE ARE NUMEROUS METHODS IN
DEVELOPMENT.
AND THE VISION FOR ALL OF THIS
HONESTLY IS TO DEVELOP A PROGRAM
WHERE WE CAN HAVE A PRENATAL
DIAGNOSIS AND THERAPY FOR
PATIENT WITH SEVERE EARLY ONSET
DISEASES.
SO WOULD HE WOULD BE PERFORMING
EARLY GENETIC DIAGNOSIS.
WE ALREADY HAVE A DIAGNOSTIC ARM
OF OUR GROUP WHO'S DOING WHOLE
EXOME AND WHOLE GENOME
SEQUENCING, FIRST STARTED OUT IN
PATIENTS WITH ULTRASOUND
DETECTED ANOMALIES BUT REALLY
ALSO MOVING INTO PHENOTYPICALLY
NORMAL FETUSES.
ONCE WE CONFIRM THE DISEASE, YOU
OF COURSE DO NON-DIRECTIVE
COUNSELING, WHICH IS REALLY THE
CORNER STONE OF THIS ENTERPRISE,
REALLY PRESENTING THE OPTIONS OF
NOT CONTINUING THE PREGNANCY,
NOT DOING ANYTHING DIFFERENT IN
THE PREGNANCY OR ENROLLING IN A
CLINICAL TRIAL.
AND THEN YOU WOULD MANUFACTURE
THE DELIVERY WITH THE IDEAL
DELIVERY VEHICLE, THE EDITOR
THAT'S OPTIMIZED FOR THE
RELEVANT TISSUE, AND THAT'S
IDEALLY BEEN INACTIVATED FOR
GERM CELLS AND OTHER NON-TARGET
ORGANS.
AND THEN THE INJECTION WOULD BE
INTO THE UMBILICAL VEIN AS WE'VE
REVIEWED.
THIS PROCEDURE IS UNDER LOCAL
ANESTHESIA AND TAKES ABOUT 30
MINUTES.
AND THEN YOU WOULD NEED TO DO
MONITORING OF ON AND OFF TARGET
EDITS, PROBABLY USING CELL-FREE
DNA AND RNA IN MATERNAL AND CORD
BLOOD. AND IN THE FUTURE, IF
THERE'S A NEW MUTATION, YOU
COULD POTENTIALLY DESIGN THE
GUIDE RNAs AND TEST ON PATIENT
CELLS, ALTHOUGH THE TIMELINE OF
THAT FOR PRENATAL APPLICATIONS
IS STILL NOT FAST ENOUGH.
SO IN CONCLUSION FOR ALL OF
THESE DIFFERENT POTENTIAL
THERAPEUTICS, SO IN TERMS OF
PROTEINS OR SMALL MOLECULES, IN
TERMS OF THE ENZYME REPLACEMENT,
THE PROTEIN REPLACEMENT DATA,
DEFINITELY ENCOURAGING BUT EACH
PATIENT NEEDS MULTIPLE INFUSIONS
SO FAR AND IT'S NOT PERMANENT.
ANTISENSE OLIGOS, THE TIMELINE
WOULD PROBABLY BE A SINGLE IN
UTERO INFUSION AND WE'RE VERY
ENCOURAGED TO SEE CNS
PENETRATION EVEN WITH THE
AMNIOTIC FLUID DELIVERY, BUT
THIS NEEDS A LITTLE BIT MORE
WORK BEFORE CLINICAL
APPLICATIONS.
GENE REPLACEMENT THERAPY WITH
AAV, WE ARE, OF COURSE, EXCITED
BY THE EXCELLENT CNS
DISTRIBUTION, BUT AT LEAST FOR
THE AAV9 CAPSID, WE HAVE SOME
CAUTIONARY DATA FOR USE TO
DELIVER GENOME EDITORS.
AND FOR GENOME EDITING, I THINK
IT'S REALLY PROMISING BUT OF
COURSE WE NEED EFFECTIVE
DELIVERY METHODS FOR THE CNS AND
THE MUTATION-SPECIFIC METHODS
MAY BE CHALLENGING FOR THE
PRENATAL TIMELINE.
SO THANK YOU AGAIN SO MUCH.
I'D LOVE TO ACKNOWLEDGE THE
PEOPLE IN MY LAB WHO REALLY MAKE
IT ALL HAPPEN, THE CLINICAL
TRIAL TEAM FOR THE IN UTERO
ENZYME REPLACEMENT THERAPY.
ON ALL OF OUR COLLABORATORS,
BOTH AT UCSF AND AT OTHER
INSTITUTIONS FOR THE THREE
STUDIES THAT ARE PRESENTED, AND
OUR FUNDING SOURCES.
THANK YOU SO MUCH, AND I'LL BE
HAPPY TO TAKE ANY QUESTIONS.
[APPLAUSE]
>> OKAY, THANK YOU SO MUCH,
TIPPI, AND I BELIEVE YOU'RE
ONLINE AND YOU CAN HEAR US?
>> YES, YES, I'M HERE.
THANK YOU SO MUCH, DAN.
>> BEAUTIFUL.
GREAT.
SO MAYBE BEV AND FYODOR, IF YOU
DON'T MIND CAN YOU COME UP HERE?
THIS IS NOW OPEN Q & A FOR
EVERYBODY.
IS FYODOR HERE?
HE'S COMING?
OKAY.
QUESTIONS FOR TIPPI DIRECTLY BUT
ALSO OUR OTHER SPEAKERS.
OKAY.
ANN?
>> HI, TIPPI.
HELLO?
THANKS SO MUCH.
IT'S ANN PODURI.
THIS IS FASCINATING.
I JUST WONDERED IF YOU COULD
TALK US THROUGH A LITTLE BIT
ABOUT WHY YOU'RE TRYING TO AVOID
THE GERM CELLS IN TERMS OF ON
TARGET, OFF TARGET VERSUS NEXT
GENERATION, CHOICE-MAKING AND SO
ON, I'M THINKING IN TEXTING WITH
A NUMBER OF PEOPLE WHO ARE WATCH
ONLINE TOO IN TERMS OF THE
VARIOUS REASONS FOR THAT, BUT IF
YOU COULD TALK US THROUGH THAT,
THAT WOULD BE GREAT.
>> SURE.
YEAH.
I MEAN, I THINK YOU BASICALLY
NAMED THEM.
YOU KNOW, WE DON'T WANT TO MESS
WITH EVOLUTION PRIMARILY.
I FEEL LIKE THERE'S DEFINITELY A
RED LINE AGAINST GOING IN THE
GERMLINE, AND THERE'S A LOT YOU
CAN DO WITH TREATING SOMATIC
CELLS IN THE CURRENT GENERATION,
AND I THINK WE ALSO DON'T KNOW
ENOUGH ABOUT OFF-TARGET EFFECTS,
AND SO HAVING AN OFF-TARGET
EFFECT THAT HAS BEEN CONTINUED
THROUGH THE GERMLINE SUCH THAT
THERE MIGHT BE A CANCER RISK IN
SUBSEQUENT GENERATIONS, ET
CETERA, I THINK I JUST DON'T
THINK IT'S SAFE AND ETHICAL.
>> CAN I JUST ADD ONE THING,
LEGALLY, PETER MARKS, HEAD OF
THE CBER, HE SEES THAT GERMLINE
MODIFICATION AS A NON-STARTER,
JUST BASED ON THE CLIMATE.
IN OTHER WORDS, WE SHOULD JUST
STOP THINKING ABOUT THAT BEING
AN OPTION.
>> [INAUDIBLE]
>> WELL, OKAY.
PEOPLE ASK ME ALL THE TIME,
RIGHT, LIKE IF I COULD GET RID
OF APOE4.
BUP WE CAN TALK ABOUT THAT AT
GREAT LENGTH, BUT THE BOTTOM
LINE IS, IT IS A NON-STARTER
TODAY.
WE CAN TALK ABOUT THE ETHICS,
THE SCIENCE, BUT POLITICALLY AND
LEGALLY, THERE'S A RIDER TO AN
APPROPRIATION BILL, IT A
POLITICAL NON-STARTER.
IT WILL NOT HAPPEN IN THE NEXT
FIVE YEARS IN THIS COUNTRY.
>> CAN I ADD TO THAT TOO, AND I
THINK ONE OF THE BEAUTIFUL
THINGS ABOUT THE CRISPR
TECHNOLOGIES IS THE SPECIFICITY,
SO WHAT WE'RE TALKING ABOUT HERE
IS PASSING ON ON-TARGET EDITING.
TIPPI MENTIONED, YOU KNOW, THE
RISKS OF OFF-TARGET EDITING AND
I THINK, YOU KNOW, AS FYODOR
AMPLIFIED DURING HIS TALK,
THERE'S A LOT OF SAFETY DATA OUT
THERE NOW THAT'S ACCRUING, BUT
WHEN WE LOOK FOR ALL THE OFF
TARGETS EVEN WITH AN ACTIVE
NUCLEASE, IT'S PRETTY RARE.
>> THERE'S A COUPLE QUESTIONS
ONLINE.
SO QUESTIONS FROM JEFF NOABLES,
HAS SPECIFICITY BEEN TESTED IN
IMMATURE DEVELOPING BRAIN?
>> WE HAVE GIVEN OUR VECTORS TO
BILL PORONTO, WHO IS A COLLEAGUE
OF TIPPIS, AND HE HAS PUT THESE
INTO HIS FETAL MODEL SYSTEMS,
AND SO FAR THINGS LOOK PRETTY
GOOD.
IT'S EARLY DAYS, THOSE, BECAUSE
IT'S VERY PRELIMINARY, VERY FEW
ANIMALS, BUT SO FAR WE HAVEN'T
FOUND A SYSTEM IN WHICH THEY'RE
REFRACTORY.
>> ALTHOUGH THE PARADOX, IF I
MAY STEP IN, FROM THE CRISPR
ANGLE IS THE AGENCY DOESN'T LIKE
NONSPECIFIC BIODISTRIBUTION.
SO VERVE, THE COMPANY THAT DID
THE -- DISEASE -- THEY WERE ON
CLINICAL HOLD IN THE U.S. FOR A
YEAR BECAUSE THEY WERE CONCERNED
ABOUT OFF TARGET AND OFF TARGET
TISSUES.
SO STRATEGICALLY FOR THE FIELD
TO KIND OF THE WORK THAT BEV
ALLUDED TO, REALLY IS THE DRIVER
OF ULTIMATE PROGRESS BECAUSE OFF
TISSUE BY DISTRIBUTION WHATEVER
YOUR PAYLOAD IS, THE EASIER A
PATH YOU WILL HAVE THROUGH
REGULATORY REVIEW IN THE U.S.
THAT'S JUST PRACTICALLY A TRUTH
RIGHT NOW.
>> ANOTHER QUESTION FROM BRANDY
THAT SORT OF TIES INTO THIS, HOW
DO YOU ANTICIPATE HANDLING
DISORDERS THAT HAVE MULTISYSTEM
IMPACTS WHERE YOU T DO WANT TO
TARGET MORE THAN THE BRAIN, LIKE
SUPER SCLEROSIS COMPLEX, SURGE
WEBER, ET CETERA?
>> YOU KNOW, WE'VE TALKED ABOUT
THIS AT LENGTH EVEN WITH
INDIVIDUALS IN MY LAB INCLUDED
THAT WORKS IN VARIOUS DISORDERS
KNOWN AS THE LYSOSOMAL STORAGE
DISEASES WHERE THERE'S MANY THAT
ARE BRAIN-CENTRIC BUT THERE'S A
LOT OF THEM THAT TIPPI MENTIONED
ALSO THAT HAVE INVOLVED THE
BONE, INVOLVED THE LIVER,
INVOLVED THE SPLEEN AND INVOLVED
THE BRAIN.
SO THERE, I ACTUALLY THINK THE
PATH FORWARD IS LIKELY GOING TO
BE AN LNP DELIVERY FOR THE PRIF
LAL SYSTEMS AND PROBABLY A MORE
TARGETED AAV FOR THE -- OR YOU
USE SOMETHING THAT, YOU KNOW,
FYODOR SHOWED WITH THE RECEPTOR
TARGETED AAVs BECAUSE THAT
GETS INTO EVERY ORGAN, EVERY
ENDOTHELIAL CELL EXPRESSES THOSE
RECEPTORS.
AS LONG AS YOU CAN MAKE THEM
EFFICIENT ENOUGH TO DO LOW
ENOUGH DOSE WHERE YOU DON'T
DESTROY ALL THE TRANSDUCED
CELLS, I THINK IT BECOMES
SOMEWHAT PRACTICAL BUT WE'LL
HAVE TO SEE.
>> IT'S IMPORTANT TO UNDERSTAND,
PEOPLE SAY FUNCTIONAL CURE FOR
SICKLE CELL DISEASE, BUT I SPEAK
WITH PHYSICIANS WHO TREAT
INDIVIDUALS LIVING WITH SICKLE
CELL DISEASE QUITE A BIT,
INCLUDING JOHN TISDALE HERE,
MARK WALTERS AT CHILDREN'S
OAKLAND, BUT PEOPLE WHO HAVE
RECEIVED THEM FOR SICKLE CELL
DISEASE, THEY STILL HAVE
NECROSIS AND SEVERE PAIN.
IN FACT THEY STILL RECEIVE
PAINKILLERS FOR THEIR PAIN
EPISODES EVEN THOUGH -- THIS IS
ALL GOING TO SAY THAT THE AGENCY
IS COMFORTABLE WITH THE CONCEPT
OF HAVING THE APPROVABLE END
POINT BE NOT AT 100% CURE.
I'M NOT SAYING THAT'S WHAT WE
STRIVE FOR, BUT LET'S FIX ONE
PART OF THE BODY.
BUT I'M JUST SAYING THAT TODAY,
AT THE STAGE WHERE THAT FIELD
IS, SOMETHING THAT POSITIVELY
IMPACTS THE PATIENT'S LIVED
EXPERIENCE IS SOMETHING THAT THE
AGENCY IS COMFORTABLE WITH HAV
HAVING.
>> AND IT ALSO SPEAKS TO THE
IMPORTANCE OF EARLY
INTERVENTION.
>> IF I CAN JUST AMPLIFY BOTH OF
THOSE POINTS, I THINK LYSOSOMAL
STORAGE DISEASES ARE A GREAT
TARGET BECAUSE OF THE CONCEPT OF
CROSS-CORRECTION.
SO IF YOU GET YOUR LNP IN THE
LIVER AND THE HEPATOCYTES ARE
TURNING UP A NORMAL ENZYME, THEN
IT CAN CROSS-CORRECT THE MANY
OTHER CELLS IN THE BODY.
OF COURSE EXCEPT FOR THE CNS.
SO BEV, I REALLY LIKED WHAT YOU
SAID ABOUT SOMETHING SEPARATE
FOR THE CNS, AND I DEFINITELY
AGREE THAT WE DON'T HAVE TO AIM
FOR A 100% CURE AS WE'RE GETTING
STARTED IN THIS FIELD.
>> LAURIE?
>> BEV --
>> I THINK IT'S ON.
>> OKAY.
BEV, I'M WONDERING IF YOU CAN
POSTULATE ON WHAT YOU THINK THE
MECHANISM IS FOR YOUR
CELL-SPECIFIC TARGETING.
BECAUSE I'M THINKING ABOUT
DRAVET SYNDROME, AND IT'S JUST
NOT -- A THAT'S
HAPLOINSUFFICIENT BUT A LOT OF
GENES ARE DIFFERENT IN RESPONSE
TO THAT.
SO WOULD WE GET THERE TARGETING
NEURONS THE WAY YOU'RE THINKING
ABOUT IT IN A DISEASE MODEL?
DO WE KNOW?
>> SO THE QUESTION FOR THOSE IN
THE ROOM THAT PROBABLY HEARD YOU
ONLINE WAS, YOU KNOW, CAN
SOMETHING LIKE I DESCRIBED WORK
FOR DRAVET AND OTHER DISORDERS,
OTHER EPILEPSY DISORDERS
AFFECTING VERY SPECIFIC CLASSES
OF NEURONS.
AND I DO THINK SO.
WE'VE BUILT IN, AS I MENTIONED,
THIS SINGLE CELL APPROACH THAT
THEN CAN IDENTIFY WHAT CAPSIDS
ARE GOING TO WHAT CELLS.
FIRST WE CAN GET THE REGIONAL
SPECIFICITY, YOU KNOW, HERE WE
WANT TO HIT MAYBE THE ENTIRE
TEMPORAL CORTEX OR THE ENTIRE
HIPPOCAMPUS OR BOTH, AND THEN
YOU BEGIN TO IMPLEMENT THE
SINGLE CELL TRANSDUCTION
INFORMATION AND LAYER THAT ON
TOP OF IT.
AND THEN YOU CAN GET THAT
SPECIFICITY.
THE OTHER WAY IS TO GET YOU TO
BASICALLY ALL THE REGIONAL AREAS
THAT YOU WANT TO HIT IN MOST OF
THE NEURONS AND THEN YOU USE THE
PAYLOAD, YOU KNOW, SOME OF THE
BEAUTIFUL WORK COMING OUT OF THE
ALLAN BRAIN ATLAS, FOR EXAMPLE
THAT HAS IDENTIFIED VERY
RESTRICTIVE ENHANCERS THAT CAN
ALLOW FOR EXPRESSION IN SPECIFIC
CLASSES OF NEURONS.
SO I THINK THERE'S WAYS TO
ENGINEER NOT JUST THE CAPSIDS
THAT I'VE DONE BUT ALSO THE
PAYLOADS IN A WAY THAT PROVIDES
THAT LEVEL OF SPECIFICITY AND I
DON'T WANT TO UNDERMINE THOSE
THAT ARE WORKING ON PAYLOAD
ENGINEERING.
I'M ONE OF THEM TOO.
BECAUSE I THINK THERE'S TIMES
WHERE YOU NEED BOTH.
AND MAYBE FOR EDITING, IT'S A
SIMILAR THING, YOU MAY NOT NEED
TO EDIT ALL THESE OTHER CELLS,
ALTHOUGH IT WOULDN'T REALLY
MATTER IF THE GENE'S NOT
EXPRESSED ANYWAY.
BUT FOR GENE REPLACEMENT-TYPE
THERAPIES OR TAKING OUR VECTORS
TO THE LIVER, VECTORIZED
ANTISENSE TECHNOLOGY OR SOME
OTHER WAY TO KNOCK DOWN, I THINK
IT'S IMPORTANT.
>> JUST REALLY QUICKLY, AS I
MENTIONED, I DON'T KNOW HOW TO
SPELL INHIBITORY INTERNEURON,
BUT IF YOU LOOK AT -- PLEASE.
I'M SERIOUS.
I HAVE WIKIPEDIA LEVEL KNOWLEDGE
THAT THEY EXIST.
BUT ENCODED IN THEIR PAPER,
WHICH I MENTIONED, AND ON THEIR
WEBSITE GO ON AND ON FOR PAGES
ABOUT HOW THEY DID ALL OF THESE
SCREENS FOR PROMOTERS THAT DRIVE
PAYLOAD CONTROL, AND THEN THEY
ACTUALLY TALK ACTIVELY ABOUT HOW
THAT IS THE ONLY WAY TO DO THIS
BECAUSE, AGAIN, I'M NOT A --
BIOLOGIST BUT WHERE I'M GOING
WITH THIS IS EXACTLY TO BEV'S
POINT.
SPECIFICITY OF PAYLOAD
EXPRESSION IS A MAJOR DIRECTION
FOR THE FIELD, AND IT SOUNDS
LIKE FROM PEOPLE WHO ACTUALLY
WORK WITH DRAVET, THAT IS
SOMETHING TO DO.
>> AND THEN REMOVING THAT
OFF-TARGET EXPOSURE, AS BOTH
FYODOR AND I ARE TALKING ABOUT
WHERE MOST OF YOUR PAYLOAD GOES
TO YOUR TARGET AND IS EXPRESSING
YOUR TARGET, THERE'S NO REASON
TO TREAT THE SPLEEN, THE KIDNEY
AND THE LIVER WITH YOUR DEAD
CAPSID THAT DOESN'T EXPRESS.
OKAY, IT DOESN'T EXPRESS BUT
IT'S STILL GOING THERE AND
THAT'S NOT GOOD.
>> YES?
>> I HAVE A QUESTION FOR
DR. DAVIDSON.
SO YOU TALK ABOUT YOUR CIRCUITRY
MANIPULATION OF THE AAV, SO WE
KNOW IF YOU HAVE LIKE -- IS THAT
A POSSIBILITY -- SPOT OF
INJECTION THAT IT WILL KEEP --
THAT GOES THROUGH THE -- AND --
THEN GOES TO ALL THESE --
DISEASE --
>> THAT'S WHAT WE THINK IS
HAPPENING.
WE'RE DOING CRISPR SCREENS RIGHT
NOW TO IDENTIFY THE RECEPTOR,
WHICH IT STILL USES THE AAV
RECEPTOR SO WE HAVEN'T KNOCKED
OUT ITS NATIVE BINDING BUT WHAT
WE'VE DONE IS ADD A COMPLEMENT
OF DIFFERENT CO-RECEPTOR, THAT
IS BASICALLY INTRACELLULAR, THAT
IS ALLOWING THESE THINGS TO MOVE
AS THEY ARE.
I WISH I COULD SAY MORE, BUT WE
HAVE 100 CANDIDATE GENES TO
TEST, SO STAY TUNED.
>> A QUESTION ONLINE AND THEN IN
THE ROOM.
>> ANOTHER QUESTION FROM JEFF.
IN ION CHANNELLOPATHY EPILEPSY,
EXCITATION TRANSCRIPTION
COUPLING IS A KEY FEATURE FOR
HEALTHY NEURAL SIGNALING, WHICH
STRATEGY CAN PRESERVE THIS
REGULATION?
WHI
>> YOU MEAN GENE REPLACEMENT
VERSUS GENE YOCKDOWN VERSUS ALL
OF THESE?
I THINK YOU HAVE TO LOOK AT EACH
INDIVIDUAL DISEASE, YOU KNOW, IN
ISOLATION.
FOR EXAMPLE, I WORK WITH
COLLEAGUES AT CHOP WITH
HAPLOINSUFFICIENCY DISORDERS
WHERE GENE REPLACEMENT MAY NOT
MAKE SENSE, BUT WE'RE DEVELOPING
ANTISENT BLOCKING
OLIGONUCLEOTIDES THAT CAN
ESSENTIALLY BLOCK A MIKE --
BINDING SITE, REDUCING MODESTLY
THE LEVEL OF EXPRESSION, THEN
YOU GET TWICE THE EXPRESSION.
SO IN MY OPINION IT DOESN'T MAKE
SENSE FOR GENE THERAPY.
THERE ARE OTHER METHODS YOU
COULD USE AND I THINK THE PRIME
EDITING OF BLOCKING THAT SITE
WITH THE VECTORS THAT I DELIVER
IS A TOTALLY COOL NEW WAY THAT I
ACTUALLY JUST THOUGHT OF AS
FYODOR WAS TALKING AND I WANT TO
WORK WITH HIM TO DEVELOP THAT.
>> THERE YOU GO.
>> JUST QUICKLY, I ALSO WANT TO
TOUCH ON THIS CONCEPT OF EDITING
AS A TOOL TO MAKE ALLELES.
THE SIMPLEST THING FOR US TO DO
IS KNOCK SOMETHING OUT.
IF GETTING RID OF SOMETHING IS
USEFUL FOR EXACTLY THE BIOLOGY
THAT WAS JUST DESCRIBED, BRING
IT ON.
ACTIVATING SOMETHING OR
SILENCING SOMETHING AT THE
ENDOGENOUS LEVEL IS ALSO QUITE
FEASIBLE.
REPAIR OF POINT MUTATION, AGAIN,
I KNOW THERE'S LUNCH AHEAD, THE
CHALLENGE AT THE REGULATORY
LEVEL, PLEASE BEAR WITH ME, IS
IF YOU CHANGE THE GUIDE RNA OF
THE MUTATION THAT AFFECTS CHILD
NUMBER ONE TO A DIFFERENT
MUTATION THAT AFFECTS CHILD
NUMBER TWO, AS OF TODAY, IN THE
FOOD AND DRUG ADMINISTRATION'S
MINDSET, IT'S A DIFFERENT
PRODUCT.
SO YOU HAVE TO REDO A
SUBSTANTIAL NUMBER OF THE
EXPENSIVE NON-CLINICAL STUDIES
EVEN THOUGH IT'S THE SAME
DISEASE, CRISPR IS A PLATFORM,
BLAH, BLAH, BLAH.
WHICH IS WHY FOR ME, AGAIN, I'M
A GENE EDITOR, I WILL BE THE
FIRST ONE TO SAY IF GENE THERAPY
WITH AAV WORKS, USE IT.
FOR ALL THE REASONS THAT I'VE
JUST -- HAVING SAID THAT, THAT
DOESN'T MEAN WE SHOULDN'T BE
TAKING ONSETTINGS WHERE WE NEED
TO REPAIR THE MUTATION ONE BY
ONE.
THE REASON I SAY THIS IS, WE ARE
ACTIVELY WORKING WITH THE FDA,
AGAIN, I KNOW THERE ARE
CLINICIANS IN THE ROOM -- IS TO
START GETTING INDs WOULD BE
BASKETS AND THE BASKET WOULD
HOLD A SYNDROME -- SO WHAT THAT
MEANS IN ENGLISH IS YOU HAVE A
CONSTELLATION OF GENETIC
CONDITIONS WHICH PRESENT VERY
SIMILARLY, DIFFERENT GENES,
DIFFERENT MUTATIONS, BUT THEN
YOU COULD HAVE A BASKET IND
WHERE DIFFERENT GENE EDITORS ARE
PUT INTO THE SAME IND, AND ALLOW
YOU TO TREAT THE PATIENTS AS
THEY COME IN BASIS.
THIS IS NOT YET REALITY, THIS
HAS NEVER BEEN DONE BEFORE, BUT
I JUST WANT TO NUANCE THIS
QUESTION ABOUT HOW YOU RESTORE
THE BIOLOGY.
IN TERMS OF, LIKE, THE LOGISTICS
OF DEPLOYING A MOLECULAR OUTC
OUTCOME, VARYING CHALLENGE AND
REGULATORY BARRIER, DEPENDING ON
WHAT EXACTLY YOU'RE RESEARCHING.
>> OTHER COUNTRIES ARE DOING
THIS, SO SOMEWHAT TIME WE FOLLOW
SUIT.
BASKET TRIAL.
>> YES, BASKET TRIAL, YES.
>> I THINK IT'S BEEN A GREAT
MORNING, A GREAT DISCUSSION.
I HAVE A QUESTION ABOUT GENE
EDITING, AND WHAT PROPORTION OF
NEURONS CAN BE IMPACTED BY GENE
EDITING, WHICH PERCENTAGE OF
CELLS YOU'RE AFFECTING, AND THEN
FOR DIFFERENT DISORDERS, WHAT
PROPORTION OF NEURONS YOU'RE
AFFECTING.
ENS MATIC DEFECTS WHERE YOU NEED
SOME SMALL AMOUNT OF RESIDUAL
ENZYME ACTIVITY MIGHT BE MUCH
EASIER TO ADDRESS, GE
GUILLAIN-BARRE DROME --
>> I'LL START AND THEN I'LL PASS
TO MY COLLEAGUES, BUT FOR
LYSOSOMAL STORAGE DISEASES,
POSTNATALLY AT LEAST, YOU REALLY
NEED MORE THAN 100% EXPRESSION
IN THOSE CORRECTED CELLS IN THE
BRAIN TO ALLOW FOR SUFFICIENT
SECRETION AND A PENUMBRA OF
ENZYME TO BE SECRETED.
IF YOU'RE JUST EXPRESSING WILD
TYPE AMOUNTS, IT WILL JUST
IMPACT A FEW CELLS.
SO I THINK THE GOAL FOR
SOMETHING LIKE A LYSOSOMAL
STORAGE DISEASE IS THAT YOU
WOULD HAVE TO CORRECT A LOT OF
CELLS TO HAVE AN IMPACT ON THOSE
SURROUNDING CELLS AROUND THEM,
BECAUSE YOU WOULDN'T SECRETE
ENOUGH ENZYME TO MAKE MUCH OF A
DIFFERENCE, AT LEAST IN THE
BRAIN.
MOST OF THESE ENZYMES FI BIND V,
VERY BEAUTIFULLY TO THE
EXTRACELLULAR MATRIX, SO IT
TAKES A LOT MORE THAN NORMAL TO
MOVE THEM AROUND.
FOR SOMETHING LIKE HUNTINGTON'S
DISEASE, I THINK EVERY DISEASE,
YOU HAVE TO ASK THIS QUESTION.
IT'S A BEAUTIFUL QUESTION
BECAUSE I THINK AS YOU DEVELOP A
THERAPY FOR A DISORDER, THIS IS
A CRITICAL THING TO KNOW, HOW
MUCH DO I NEED TO CORRECT TO
IMPACT A CHANGE, A MEANINGFUL
CHANGE IN A PATIENT, AND MAYBE
YOU CAN GET SOME INDICATION OF
THAT FROM MODEL SYSTEMS, AND FOR
HUNTINGTONS, I THINK WE NEED TO
CORRECT ABOUT 50% OF THE MEDIUM
SPINY NEURONS IN THE -- THOSE
CELLS ARE MOST IMPACTED BY WHAT
WE NOW KNOW IS SOMATIC REPEAT
EXPANSION WHERE -- THEY START
OFF -- OVER TIME, OVER DECADES,
SOME OF THOSE CELLS END UP WITH
OVER A HUNDRED REPEATS, SO YOU
WOULD WANT TO -- AND YOU'D HAVE
TO GO IN EARLY ENOUGH TO MAKE A
DIFFERENCE, AND THEN THE CELLS
CAN NO LONGER TOLERATE THAT.
SO WE REALLY THINK -- I THINK
THIS IS, AGAIN, SIMILAR TO SOME
OF THE OTHER QUESTIONS, A VERY
SPECIFIC QUESTION.
>> TIPPI, DO YOU WANT TO SAY
SOMETHING ABOUT HOW YOU'RE
THINKING ABOUT THE SORT OF THE
EFFICACY VERSUS CLINICAL BIN
FETS,BENEFITS, AND THEN I'LL SAY
SOMETHING.
>> I AGREE WITH ALL OF THAT, AND
JUST TO ADD THAT THE OTHER
KNOWLEDGE GAP I SEE IS WHEN IN
DEVELOPMENT DO YOU ACTUALLY NEED
THE EXPRESSION THE MOST.
SO FOR EXAMPLE, FOR SMA,
CHARLOTTE SUMNER'S WORK SHOWS
THE SMN EXPRESSION IN NEURONS IS
HIGHEST PRENATALLY, SUGGESTING
THAT PERHAPS THE PRENATAL
CORRECTION IS REALLY THE MOST
IMPORTANT, SO HAVING A TREATMENT
WHERE YOU RESTORE EXPRESSION IN
A CERTAIN CRITICAL DEVELOPMENTAL
TIME WINDOW MAY BE JUST AS
IMPORTANT AS HAVING THE RIGHT
LEVEL OF EXPRESSION, SO I THINK
WE NEED TO THINK REALLY
CAREFULLY THERE.
>> YOUR QUESTION LET'S ME RE-GET
ON MY FAVORITE HIGH HORSE.
AS BEST AS I CAN TELL, THE ONLY
WAY TO ANSWER THIS QUESTION
DEFINITIVELY IS DO THE CLINICAL
TRIALS.
AND I MEAN, NOBODY WANTS TO DO
UNPRODUCTIVE EXPERIMENTS ON
SUFFERING HUMAN BEINGS.
BUT A GREAT EXAMPLE IS SICKLE.
THE WAY WE KNOW THAT 10 TO 20%
REPAIR IS ENOUGH TO REMEDY THE
SICKLE PHENOTYPE IS NOT BECAUSE
WE HAVE SOME DEEP INSIGHT FROM A
MOUSE.
THAT'S A HUMAN EXPERIMENT, WHICH
WAS INADVERTENT.
IT WAS ALLOGENEIC BONE
TRANSPLANTATION.
I LEARNED THAT FROM MARK WALTERS
AND JOHN TISDALE HERE.
WHEN YOU DO AN ALLOGENEIC BONE
TRANSPLANT, IT IS CURATIVE, EVEN
WHEN A SUBJECT IS ONLY 10%
CHIMERIC FOR THE DONOR MARROW.
SO NOW WE'RE NOT GOING TO DO
BRAIN TRANSPLANTS, I'M SORRY,
BUT -- NOT TO -- BUT IN BRASS
TAX TERTACKS TERMS, TO ME, IT IS
AMAZING TO HAVE SOME BIOMARKER
OF TARGET ENGAGEMENT.
I DON'T KNOW WHETHER YOU HAVE
SUCH A BIOMARKER IN EPILEPSIES.
SO IN OTHER WORDS, IF YOU CAN
DOSE A SUBJECT, TYPICALLY YOU GO
IN WITH A LOW DOSE.
IF YOU CAN EVALUATE THE
PERCENTAGE ON TARGET ENGAGEMENT
RELATIVE TO AFFECT ON SYMPTOMS,
THIS IS PURE GOLD, BECAUSE YOU
CAN THEN DERIVE A
RELATIONSHIP -- THE ANSWER TO
YOUR QUESTION, AND YES, THAT'S
CLINICAL RESEARCH, SO YES, YOU
SORT OF HOLD -- YOU SORT OF
CLOSE YOUR EYES IN AN EMOTIONAL
WAY, BUT I DON'T KNOW OF IT ANY
OTHER WAY.
>> JUST TO COMMENT ALSO, WE
DON'T HAVE THE BIOMARKER YET.
AS FAR AS I KNOW.
BUT YOUR QUESTION I REALLY GETST
THE COMPLEXITY OF THE SYSTEMS
THAT WE'RE WORKING ON IN THE
EPILEPSIES BECAUSE I DON'T THINK
WE KNOW THE ANSWER.
I MEAN, EVERY HUMAN BRAIN IS
QUITE CAPABLE OF HAVING A FULL
BLOWN GENERALIZED TAXIC TONIC KC
SEIZURE.
EACH EPILEPSY TYPE HAS ITS OWN
BALANCE POINT.
EVEN IF WE KNEW -- WELL, IF WE
KNEW THE BALANCE POINT, WE'D
HAVE A BETTER SENSE OF JUST
EXACTLY HOW MUCH OF IT NEEDS TO
BE IMPACTED, WHETHER IT'S
DECREASING ECK EYE TAI EXCITATIR
INCREASING INHIBITION.
>> CATHY IS GOING TO BE HERE IN
A BIT, I CERTAINLY PLAN TO FALL
DOWN ON THOSE KNEES WHEN SHE
GETS HERE.
SHE GOT THE FIRST AAV THERAPY
FOR GENETIC DISEASE APPROVED AND
PFIZER JUST GOT APPROVAL FOR HER
HEMOPHILIA DRUG.
I DON'T KNOW OF ANYBODY ELSE.
BUT SO THE REASON I BROUGHT HER
UP, SHE CAN SPEAK AT GREAT
LENGTH ABOUT THE UTILITY OF
LARGER ANIMAL MODELS.
THERE ARE THESE KING CHARLES
SPANIELS WITH THIS OR THIS OTHER
KIND OF DOG WITH THAT, AND YOU
CAN DO DOSE-RESPONSES.
BUT IS THERE A DOG --
>> THERE IS.
DOGS ARE PROBABLY ONE OF THE
BEST MAMMALIAN SPECIES TO STUDY
WHEN IT COMES TO EPILEPSY.
ABSOLUTELY.
>> POODLES.
>> WE CAN DISCUSS OVER LUNCH
JUST HOW MUCH PRE-CLINICAL
OPPORTUNITY WE HAVE HERE, BUT
YEAH, YEP.
>> I'LL JUST ECHO THAT.
I DON'T KNOW ANYONE ELSE THAT'S
DEVELOPED TWO OUT OF SIX
APPROVED DRUGS IN THE WORLD
OTHER THAN KATHY.
>> KATHY WAS MEANT TO BE THE
FOURTH SPEAKER OF THIS SESSION
BUT BECAUSE SHE'S TRAVELING, SHE
WILL BE HERE THIS AFTERNOON AND
ANN WILL BE DOING THE
INTRODUCTION.
WITH THAT, WE ARE AT THE TOP OF
THE HOUR, IT'S TIME FOR LUNCH
AND POSTER SESSION.
AND THANK YOU TO OUR THREE OF
FOUR SPEAKERS WHO YOU REALLY
HAVE ACCOMPLISHED WHAT WE HOPED
FOR, WHICH IS THE OUTSIDE
PERSPECTIVE AND THE INTERSECTION
WITH THE EPILEPSY, SO A HAND FOR
OUR SPEAKERS, PLEASE.
[APPLAUSE]
>> IT'S MY PLEASURE TO INTRODUCE
THE MODERATOR OF OUR NEXT
SESSION, DR. ANN -- EXCUSE ME,
CAN I GET EVERYONE'S ATTENTION.
THANK YOU.
IT'S MY PLEASURE TO INTRODUCE
THE MODERATOR FOR THE NEXT
SESSION, DR. ANN PODURI A
PROFESSOR AT BOSTON CHILDREN'S
HOSPITAL AND HARVARD AND WE
CHAIRED A COMMITTEE TOGETHER AND
I HAVE KNOWN ANN FOR QUITE SOME
TIME.
TAKE IT AWAY, ANN.
>> ABOUT AFTERNOON, EVERYONE.
THANKS FOR BEING HERE AND THANKS
EVERYONE ONLINE.
WE HAD A GOOD FIRST SESSION TO
SET THE STAGE FOR THIS ONE.
BEFORE I START TO INTRODUCE THIS
ONE I WANT TO THANK VICKY FOR
BRINGING US TOGETHER AND HELPING
US THINK WHAT WOULD BE NOT JUST
HELPFUL BUT FORWARD LOOKING
EFFORTS TO HAVE THE
CONVERSATION.
I'M EXCITED TO BRING A WONDERFUL
LINE UP OF SPEAKERS ON THE PATH
PROGRESS, PITFALLS AND LESSONS
FROM NEUROLOGICAL AND
NON-NEUROLOGICAL TRAILS AND
TREATMENTS AND WE KNOW WHAT
GENES AND CELLS WE WANT TO
TARGET AND STARTING TO LEARN
NATURAL HISTORY AND WE HEARD
FLOUED AND -- LOUD AND CLEAR
THE TOOLBOX THERE AND IT'S A
GREAT CALL TO ACTION FOR ALL OFS
TO THINK ABOUT THAT AND WE HAVE
WORK THAT GOES IN BETWEEN THE
IDEAS AND TOOLBOXES AND GETTING
DRUGS AND S TO PATIENTS AND
WE'RE DELIGHTED TO HAVE SEVERAL
EXAMPLES NOW WHERE THAT HAS
HAPPENED ALL THE WAY TO TRIALS.
AS WITH SESSION 1, SESSION 2 WE
WANTED TO BRING YOU SOME
EXAMPLES THAT AREN'T IN THE
SPACE AND THINK WE CAN LEARN
FROM THE OTHER EXAMPLES AND THE
BASIC FOUNDATIONS FOR PLATFORMS
IN EPILEPSIES AND DELIGHTED WE
HAVE SOME NEUROLOGICAL AND SOME
NON-NEUROLOGICAL AND SOME
EPILEPSY AND EPILEPSY ADJACENT
DISORDERS WE'LL HEAR ABOUT.
THE OTHER ASPECT IS LOOKING AT
OUR FIELD AND BEYOND HOW ARE WE
GOING TO NOT JUST GET THE TRIALS
TO HAPPEN BUT HOW ARE WE GOING
TO GET THE TRIALS TO HAPPEN FOR
EVERY PATIENT.
YOU'LL HEAR SOME EXAMPLES AND
IDEAS LOOKING TO THE FUTURE.
HOPEFULLY NOT TOO DISTANT WHERE
WE CAN DIAGNOSE EVERYBODY WITH
THE DISORDER.
SO THEY'RE NOT HIDING IN THE
SHADOWS AS MENTIONED THIS
MORNING BUT REALLY KNOWN AND
PRESENTING AND PREVENTING EARLY
MAYBE PRENATAL APPROACH CAN BE
USED.
WITH THAT I'LL GIVE A QUICK RUN
DOWN OF OUR SPEAKERS.
ALL RIGHT.
WE'LL START WITH CARSTEN
BONNEMAN AND I'VE KNOWN HIM
SINCE HE WAS RUNNING A MUSCULAR
CLINIC AT CHOC AND IN ADDITION
TO THE FANTASTIC THINGS YOU'LL
HEAR ABOUT GENE THERAPY AS A
PLATFORM, HE'S BEEN INVOLVED
FROM PATIENT DESCRIPTION TO GENE
AND NOW THERAPIES.
A LOVELY ARC HE'LL TELL US ABOUT
AND LIZ BERRY KRAVITZ AND WILL
TALK TO US ABOUT ANGEL SYNDROME
AND THERAPIES AND BROUGHT MANY
PEOPLE TOGETHER WITH HER HARD
WORK AND LOOKING TO THE
REGULATORY ENVIRONMENT AND
FLORIAN EICHLER TALKING ABOUT
RISK AND TREATMENT CHOICES AND
NEUROLOGICAL DISEASES AND IS A
PROFESSOR IN THE MUSCULAR
DYSTROPHY PROGRAM AND HAS DONE
EXCITING WORK AND WE HAVE KATHY
HIGH TO TALK ABOUT THE NEW PATHS
OF WATERFALL LETTONS LEARN FROM
AAV AND FROM ROCKEFELLER AND
HE'S TALKED ABOUT FOUNDATIONAL
WORK ALREADY AND HAS DONE
FOUNDATIONAL WORK WITH
TREATMENTS YOU'LL NOW HEAR ABOUT
AND WENDY CHUNG FROM BOSTON
CHILDREN'S HOSPITAL AND TALK
ABOUT FROM N OF 1 TO POPULATION
HEALTH TO TREAT GENETIC
EPILEPSIES AND IS PASSIONATE
ABOUT EARLY DIAGNOSIS IN
PATIENTS AND HOW CAN WE REALLY
THINK ABOUT NOT JUST DISORDERS
BUT THE BROAD POPULATION OF
CHILDREN WITH NEUROLOGICAL
DISORDERS AND ALL THE STRATEGIES
CAN APPLY TO THEM IN THE FUTURE.
WITH THAT I'LL TURN IT OVER TO
CARSTEN WHO IS HERE.
>> THANK YOU VERY MUCH.
CAN YOU HEAR ME OR SHOULD I SIT
CLOSER TO THE MICROPHONE?
YEAH?
OKAY.
THANK YOU FOR HAVING ME.
MY LAB IS UPSTAIRS IN THIS
BUILDING SO IT'S HOMETOWN FOR
ME.
I'M GOING TO TRY TO DO AND IN
THE NEXT HALF HOUR IS GET YOU
REAL WORLD EXPERIENCE OF GENE
THERAPY INTO PATIENTS WITH A
NEURODEGENERATIVE DISEASE AND
THOUGHTS AND WHAT THAT ACTUALLY
IS AND WHAT WE SHOULD THINK
ABOUT.
THIS IS NO NEWS TO YOU OR IN THE
ROOM WHETHER COLLECTIVELY WE'RE
AWARE THEY'RE MOSTLY GENETIC AND
MOSTLY AFFECT CHILDREN AND WHEN
THEY AFFECT CHILDREN THERE'S A
LARGE UNMET NEED THAT RARE
DISEASES COLLECTIVELY GET
DISORDERS IN THE RARE DISEASE
SPACE.
AND WITH MANY GENETIC DISEASES
THAT MAKE UP RARE DISEASE AND
PREPARED BY NEXT GENERATION
SEQUENCING WE'RE DISCOVERING
MORE AND MORE DISEASE CHANGE
THAN JUST ONE FAMILY OR A FEW
PATIENTS AND HALF THE DISEASES
HAVE A RARE GENETIC TARGET AND
THINK ABOUT THE TREATMENT AND IN
FRONT OF YOU IS SOMETHING YOU
UNDERSTAND GENETICALLY AND THE
WORK -- ROOT TO GOT THERE AND
THEY ENCOMPASS ANYTHING WITH THE
GENETIC THERAPIES AND THEY'RE
ATTRACTIVE BECAUSE THEY'RE ROOT
CAUSAL AND GENETIC DISORDERS THE
ROOT IS THE GENETIC MUTATION AND
THE CLOSER WE GET THE HIGHER WE
CAN EXPECT THE IMPACT TO BE.
AND SO IT'S A NEED AND OFTEN
OPPORTUNITY TO DEVELOP PLATFORM
GENETIC THERAPIES AND THERAPIES
A TOOL BOX THAT ALLOWS US TO
APPLY LEARNING FROM ONE DISEASE
TO A SIMILAR DISEASE WITH A MUCH
SHORTER DEVELOPMENTAL PIPELINE
TO GET THERE.
THAT'S WHERE MOST IN THE ROOM
TRIED TO LEARN THIS.
BUT YOU HAVE TO START WITH
DISEASES AND IN MY TALK I'LL BE
TALKING ABOUT THE WORKHORSE OF
GENE THERAPY AND GENE
REPLACEMENT THERAPY.
YOU HEARD ABOUT THERAPEUTIC
APPROACHES THIS MORNING AND THIS
IS HAPPENING AT THE SIMPLISTIC
GENE REPLACEMENT AND YOU'LL SEE
THE APPROACH THAT WILL INFORM
ALL OTHER APPROACH AT THE SAME
TIME SO AAV AS YOU HEARD THIS
MORNING IS A SMALL VIRUS THAT
COMES ALONG FOR THE RIDE FOR
LARGER ADENOVIRUSES AND COMES
ALONG BECAUSE IT HAS AN
INCOMPLETE GENE AND IT'S
PROBABLY NOT PATHOGENIC AT ALL
MAYBE SOME HEPATITIS THAT COULD
HAVE BEEN CAUGHT IT'S A
NON-PATHOGENIC VIRUS SIMPLE IN
ITS GENOME YOU CAN SEE AND
THAT'S NOT A COMPLETE GENOME.
IT NEEDS VIRUSES TO HELP IT
ALONG.
IT'S A SINGLE-STRANDED DNA
VIRUS.
IT PACKAGES A SINGLE STRAND OF
DNA IN THE CAPSID AND THE
INCOMPLETE GENOME HAS THE
CAPACITY FOR 4.6KB AND MANY
NATURALLY OCCURRING PHENOTYPES
WHETHER IT'S OUT IN NATURAL AND
ANIMAL SPECIES AND THOSE ARE THE
ONES THAT HAVE BEEN USED IN GENE
THERAPIES TO DATE BUT AS YOU
HEARD THIS MORNING THERE'S NEW
TYPE DEVELOPING ALL THE TIME AND
VERY IMPORTANT BECAUSE THEY CAN
IMPROVE THE TARGET INTO CELL
MUTATION AND YOU WANT TO GO BY
NOT GOING AT THE SAME TIME AND
DO NOT WANT TO GO AND THAT
ENHANCED TARGET BEING TROPISM
AND THE FUTURE IS HAPPENING IN
SOME TRIALS BUT WHAT I TELL YOU
ABOUT TODAY ARE TRADITIONAL
PHENOTYPES.
WHAT YOU PACKAGE INTO AN AAV IS
THE GENE OF THE AAV ARE REPLACED
WITH WHAT YOU WANT TO DELIVER IN
BETWEEN THE TWO LEFT OVER AND
IT'S DRIVEN BY A PROMOTER OR
ANOTHER GOOD MORNING ELEMENT
THAT IS VERY IMPORTANT AND YOU
CAN PUT ANYTHING THAT FITS IN
THE MUTATION YOU CAN FIT IN
THERE AND EDITING TOOLS AND
ANYTHING THAT FITS CAN BE
DELIVERED.
THE DELIVERY AND TROPISM IS
DEPENDENT ON THE CAPSID.
THERE'S THINGS YOU CAN DO IN THE
TRANS GENE AVAILABLE IF YOU WANT
TO DELIVER DOUBLE STRANDED DNA
RIGHT AWAY FOR THE EXPRESSION OF
THE VIRUS YOU CAN DO THAT AS
COMPLIMENTARY CONSTRUCT AND
THEY'RE DOUBLE STRANDED AND WHAT
WE HAVE HERE IN A TRIAL I'LL
TELL YOU ABOUT.
BUT A SINGLE STRANDED AAV IS
IMPORTANT TO AAV AND FOR THE
MOST PART DOES NOT INTEGRATE
INTO THE GENE AND THE NUCLEAR
DELIVERS THE MESSAGE THERE WHICH
IS GOOD FOR POST MITOTIC CELLS
AND HIGH TURNOVER AND CAN BE A
PROBLEM WHEN THE CELLS TURN OVER
BECAUSE IT'S NOT INHERITED WITH
THE CHROMOSOMES.
AND THIS IS JUST A VERY BRIEFLY
HOW YOU PUT THIS TOGETHER.
I JUST WANT TO SHOW YOU THAT
WHAT WE HAVE PUT TOGETHER WITH
THE HELP OF THE VIRUSES AND THE
HELPER GENES TOGETHER IN A DISH
AND MAKE AAV.
THAT IS TRUE BUT IN REAL LIFE
IT'S MUCH MORE COMPLICATED
PROCESS THAT REQUIRES MANY STEPS
OF PURIFICATION AND ANALYTICS.
AND THAT'S WHAT MAKES AAV
EXPENSIVE IN THE PROCESS.
WHAT COUNTS AS QUANTITATIVE AND
POTENCY AND TECHNICAL TERMS WITH
REAL MEANING YOU NEED TO HAVE
FULL VIRUS PARTICLES THAT
DELIVER THE GOODS TO BE
EFFICACIOUS.
AND THIS IS TO SHOW THAT THIS IS
ALREADY MANY MANY CLINICAL
TRIALS HAPPENING IN PEDIATRIC
NEUROLOGICAL DISEASES.
WE HAVE FDA APPROVED MEDIATED
GENES AND THEY LEAD THE PACK
HERE AND THE OTHER TWO ARE IN
DISEASES AND NEUROLOGICAL
DISEASES AND NEUROMUSCULAR
DISEASE AROUND AND DUCHENNE'S
MUSCULAR DYSTROPHY AND THESE ARE
APPROVED FOR THESE DISORDERS
COMMON AMONG THESE STEEZS --
DISEASES AND I HAVE TO SAY WE
WOULD HAVE IT APPRESSED FOR
CERTAIN DISEASE AND NOW YOU GET
CHILDREN WALKING WITH THE
DISEASE WITH THE CAVEAT YOU HAVE
TO DO IT EARLY.
YOU HAVE A NARROW WINDOW OF
OPPORTUNITIES AND WE'LL COME
BACK.
THAT'S AN IMPORTANT TOPIC TO
DISCUSS.
REALLY THIS HAS OPENED THE DOORS
AND GENE THERAPY WITH THE CAVEAT
THAT NOT EVERYTHING IS AS GOOD
TO BE EXPECTED AS GOOD AS THE
OUTCOMES.
WE THINK HOW CAN WE MAKE THIS
APPROACH OF AAV GENE THERAPY
PARTICULARLY TO
NEURODEGENERATIVE DISORDER AND
IT STARTED WITH PATIENT ADVOCACY
AND MADE A VECTOR THAT WAS
CAPABLE OF THE GENE AND THEY
CAME TO US AND SAID CAN YOU MAKE
A CLINICAL TRIAL.
HOW DO WE DO THIS AND PUT THIS
INTO PATIENTS?
IT WAS DESIGN TO BE PUT
INTRAFECALLY INTO THE FLUID OF
THE CHILDREN.
THAT LED TO THE FIRST IN HUMAN
INTRAFECAL GENE THERAPY TRIAL
AND THE FIRST TIME IT WAS PUT IN
THIS SPACE FOR GENE --
INTRATHECAL SPACE FOR CHILDREN 5
YEARS AND OLDER.
AND GIANT AX OM YOU WILL
NEUROPATHY AND IF YOU UBIQUINATE
WITH THE TISSUES AND NEURONS YOU
SEE FILL AMOUNT THAT RESPONDS
THE AXONS FROM THE DISEASE.
AND IT'S ALSO IN THE HAIR
CHILDREN WITH CURLY HAIR BECAUSE
OF KERATIN IN THE DISEASE.
BUT IT STARTS AT THE ATRAVELIA
ATRAXIA AND AFFECTS MORE AND
AFFECTS THE OPTIC NERVE.
IT'S ONE OF THE MORE PROGRESSIVE
DISORDERS I KNOW IN CHILDHOOD.
BUT IT'S A SMALL GENE AND
RECESSIVE AND WE THINK OF GENE
REPLACEMENT.
PUT THE MISSING GENE IN WITH THE
GENE DELIVERY AND HOW DO YOU GET
TO THE CNS?
YOU CAN GO INTRAVENOUS.
THAT DELIVERS BECAUSE OF THE
BLOOD BRAIN BARRIER AND IT'S
QUITE PERMEABLE AND HOPEFULLY
WE'LL HAVE NEWER TYPES LATER TO
OVERCOME THAT.
YOU CAN'T GO DIRECTORY TO THE
SPACE AND WE HAVE CHOSEN THE
INTRATHECAL WAY TO GET THERE BUT
THERE ARE OTHER WAYS IN WHICH WE
CAN DISCUSS LATER IF YOU THINK
OF BRAIN OCCUPATION OF AAV.
YOU DON'T HAVE TO GO AND READ
THIS BUT TO SAY AT THIS POINT
THERE'S 14 PATIENTS 6 TO 14 AT
FOUR DIFFERENT DOSE LEVELS.
THIS IS THE CONSTRUCT AND A
COMPLEMENTARY CONSTRUCT AND A
RELATIVELY WEEK PROMOTER AND THE
WEAK PROMOTER IS AN IMPORTANT
ACCESS IN THE SPACE OF THE
TRIALS IT'S STRONG ENOUGH BUT
NOT STRONG ENOUGH TO DRIVE
SPECIFICITY FROM THE TRIAL AND
PACKAGED INTO AAV 9.
AND THIS IS THE ESCALATION.
WE STARTED ONE WILL A LOW DOSE
INITIALLY AGAIN THE FIRST
APPLICATION AND CURRENTLY HIGHER
DOSE AND INTRATHECAL DELIVERY
AND THE INTRODUCTION LITERALLY
ROTATED DURING THE TIME TO ALLOW
HOPING TO HIT OUR TARGETS AND
HIGHLIGHTING THE OPTIC NERVE AND
THE BONE.
WE HAVE TO DO THIS PART OF THE
TRIAL.
YOU SEE THE BIOPSY AND INFUSION
OF THE AAV INTO THIS SPACE AND
WE CAN SEE THE TREND AFTER
DELIVERY.
WE SAW ANY OPPORTUNITY OF THE
MODULATION OF THE AAV AND NOT
WAITING FOR THINGS TO HAPPEN.
WE DID THE VIRUS IN THE SPACE
AND YOU KNOW WE SEE THAT IN A
LITTLE BIT AND ALSO TO ALLOW US
TO GET THE TRANS GENE PATIENTS
WHO HAVE FUNCTION WITH NO
PROTEIN PRODUCTION AND HAVE
NEVER SEEN THIS PROTEIN AND WHEN
YOU GIVE THEM THE AAV YOU DO A
LITTLE BIT OF TRANSPLANTATION
AND WANT TO MAKE SURE THEY DON'T
REJECT IT.
AND YOU HAVE TRIALS THAT CAN BE
REJECTED.
WE DID THIS WITH A PROTOCOL
RAPAMYCIN IS NOT LOST IN THE
SPACE AND THIS WAS A CASE OF THE
AFBD AND IT HAD NO EVIDENCE OF
THE AAV RELATED TOXICITY WHICH
IS WHEN WE IDENTIFY TOXICITY OF
THE PATIENT.
THE PROMOTER WAS SUFFICIENTLY
LOW REACTIVE AND DIDN'T
OVERPRODUCE THE GENE INTRODUCING
THE TOXICITY INDEPENDENTLY.
SO WHAT IS SOME AFFIRMATION IN
THE SPACE IN THREE MONTHS
ASYMPTOMATIC AND PROTEIN
INNERVATION AND
REPRESENTATIVESIVE AND THERE WAS
NO INFLAMMATION AND WE SAW
MENINGITIS THAT COULD BE MANAGED
WITH THES REGIMENT.
AND ANOTHER LESSON FROM THIS
TRIAL IS THAT WE DID NOT EXCLUDE
PATIENTS WHO WERE ZERO POSITIVE
AT BASELINE.
MANY SUSPENDED GENE THERAPY
TRIALS YOU HAVE ANTIBODIES YOU
WANT TO GIVE BUT WE IGNORED THAT
IN THIS TRIAL TO SUGGEST THAT
THAT WOULD NOT EXTEND TO THE
SPACE AND AT BASELINE NONE OF
OUR PATIENTS HAVE ANTIBODIES IN
THE CNS SPACE WITH DOSING
HOWEVER, ONCE YOU INTRODUCE
INTRATHECALLY THE SYSTEM WAKES
UP MAKING ANTIBODIES IN THE
PERIPHERY AND PATIENTS RESPOND
YOU CAN SEE HERE WE HAVE
NEUTRALIZING ANTIBODY ACROSS THE
BOARD DOABLE OVER A YEAR AND
PROBABLY MORE.
HOPEFULLY THIS WOULD HELP IN
DOSING.
WHAT ABOUT EFFICACY ANALYSIS
HERE?
THIS WAS A PRIMARY.
BAYESIAN ANALYSIS AND WE
GENERATED INDEPENDENT AND MOST
IMPORTANTLY THE PATIENT'S OWN
HISTORY WITH THE MOTOR FUNCTION
MEASURE WHICH YOU CAN SEE IS
DEEPLY BEFORE WE DOSE WITH IT
AND WE HAVE ABSOLUTE
CONFIRMATION IN OUR INDEPENDENT
NATURAL HISTORY STUDY AND WHAT
YOU CAN SEE IS THE POSSIBILITY
OF SLOWING THE MOTOR FUNCTION.
THIS IS A MAITHE MAIN APPROACH
SO THERE'S AN END POINT AND HAVE
19%.
SIGNIFICANT IN THE ANALYSIS AND
YOU CAN SEE THESE CHILDREN HAVE
A PROGRESSION BUT IT'S A SLOW
PROGRESSION.
IT HAS TO DO WITH WHEN WE
ININ AND
HOW WE INTERVENE AND WHEN YOU
LOOK WHERE THE DISEASE STARTS
YOU CAN SEE THESE ARE ACTION
POTENTIALS AND MEASUREMENT AND
NO CHILD EVER RECORDED THIS
ANYWHERE AND YOU CAN SEE AFTER
DOSES IN PARTICULAR THE NERVES
AT ENTRY IN THE ARM WE HAVE NOT
ONLY IMPROVEMENT IN THE ACTION
BUT AFTER DOSING SOMETIMES 4
YEARS OLD.
IT TAKES PATIENTS TIME FOR A
NERVE TO REPAIR IF THE NERVE IS
STILL VIABLE.
THAT MAY BE AN ADVANTAGE AND
THERE MAY BE MORE CAPABLE OF
GOING TO THAT DISEASE AND WE
ALSO HAVE EVIDENCE OF
REGENERATIVE CAPABILITY IN THE
CENTRAL NERVE AFTER DOSING.
BUT LOOK AT THIS PROBLEM.
THIS IS A PERIPHERAL NERVE AND I
WANT TO CLEAR THIS ENTIRE AXON
FOR PATHOLOGY AND FILAMENT AND
IT'S GOING TO TAKE TIME AND WHEN
YOU START THERAPY.
THIS IS WHAT WE HAVE TO DOSE AND
ENDING THE GENETIC DISEASE AND
WE HAVE A WINDOW OF OPPORTUNITY
AND SOMETIMES SLOWLY.
BUT IN OUR PATIENTS IT CLOSES IN
DIFFERENT TIMES FROM LONG NERVES
TO THE LEGS ARE MORE INFECTED
AND THE SHORT TERM IN THE ARM
ARE SHOWN AFTER ADMINISTRATION
THEREFORE EVIDENCE OF
REGENERATIVE CAPABILITY AND
EVIDENCE OF SLOWING OF THE
DISEASE BUT THE FULL IMPACT I
THINK WILL BE FOR YOUNG CHILDREN
EARLY IN THE DISEASE.
AND THIS IS RELATIONSHIP TO
COMPLICATIONS YOU HAVE THE
DISEASE ONLY 9 MONTHS LATER.
SHE WAS DOSED AT THE LOWEST DOSE
AND THIS CHILD DNA AND THEY SAID
YOU CAN'T DOSE YOUNG CHILDREN
YOU HAVE TO GO TO OLDER PATIENTS
AND THE MEDICAL PEOPLE HAD US GO
TO PATIENTS MORE ADVANCED IN THE
DISEASE AND THEREFORE HAD MORE
MEDICAL COMPLICATIONS AND LO AND
BEHOLD WE LOST TWO PATIENTS TO
THE DISEASE EARLY ON WITH THE
OLDER CHILDREN.
AND I SHOWED YOU AT THE LOWER
DOSE YOU CAN SEE WE LOOKED AT
THE BRAIN AND OPTIC NERVE AND
THAT'S SOMETHING TO CONSIDER AND
THINK ABOUT CHILDREN'S CNS
DISEASE AND MAYBE DIFFERENT
LEVELS WOULD BE A GOOD ENTRY
POINT AND GET GOOD DISTRIBUTION
FROM THE INTRATHECAL
ADMINISTRATION.
THERE'S A HUMAN GENOME BUT
DIFFERENT.
[OFF-MIC]
>> NO, IT DOESN'T.
A LOT OF IT GOES TO THE SPLEEN
AND, YEAH.
A LOT OF IT GOES TO THE SPLEEN.
YOU LOOK AT THE SPLEEN.
THIS PROVIDES INSIGHT.
I THINK A COLLABORATIVE MODEL OF
EFFICACY AND ACADEMIA AND
INTRAMURAL, NIH AND INDUSTRY CAN
COME TOGETHER.
INDUSTRY HAS DROPPED OUT
MEANWHILE WE HAVE THIS IN THE
END AND YOU CAN DISCUSS THIS.
AND THE FIRST INTRATHECAL TRIAL
THAT ESTABLISH THOSE AND SAFETY
AND ESTABLISHED A PLATFORM FOR
THE DISEASE NOT BEING CARRIED
FORWARD.
I'M RUNNING OUT OF TIME BUT WANT
TO GIVE YOU THE LESSONS EMERGING
FROM THIS AND MAYBE I CAN PICK
THE PLATFORM.
AND THESE ARE INTRAFECAL DOSING.
IN NEURAL MODULATION IT'S VERY
IMPORTANT TO REALIZE FROM THE
ASPECT OF GENE THERAPY INHERENT
FROM THE APPROACH AND WHAT YOU
DO AND DELIVER.
AND INTRATHECAL DOSING HAS
EFFECTIVE TARGETING OF THE
CAPSID AND SO WHAT YOU CAN DO TO
IMPROVE THAT WILL BE HELPFUL AND
THE TIME BEING IMPORTANT.
LET ME JUST ACKNOWLEDGE MANY
PEOPLE.
THANK YOU VERY MUCH.
>> THANK YOU.
ANY QUESTIONS?
THAT'S A GOOD PROBLEM THIS IS A
DISEASE SO IN FAMILIES WHERE
THERE'S BEEN ONE CHILD AFFECTED,
FAMILY MEMBERS WILL KNOW BECAUSE
OF THE PHENOTYPE AND SO WE HAD
THE OPPORTUNITY TO EXAMINE 1
YEAR OF AGE AND THERE'S A
NEUROLOGICAL PHENOTYPE.
MOST OF THE TRACING IS NOT EXOME
BASED THE GENE CANDIDATE SO IF
THERE'S NO SUSPICION OF THE
DISEASE AND WE GET THE WHOLE
EXOME SEQUENCING TO FIND IT AND
THE DIAGNOSIS IS MADE WITHOUT
SUSPECT
SUSPECTING IT AND HOPE ANY WITH
PATIENTS EARLY ON AND PHENOTYPES
MAKE MORE LIKE THE NEUROPATHY
AND THOSE SEE PRODUCTION LATER.
THANK YOU.
>> HI, EVERYONE.
I WAS PRIVILEGED AND HAPPY TO BE
INVITED TO SPEAK HERE.
THANKS TO ANN AND THE
ORGANIZERS.
I'M GOING TO TALK ABOUT -- I
HAVE A GENERAL TITLE BUT I'M
GOING TO TALK ABOUT ANGELMAN
SYNDROME BECAUSE I THINK IT'S
GOING FORWARD FOR WHAT WE CAN
EXPECT WHEN WE BRING ALL THESE
GREAT BASIC SCIENCE ADVANCES
WE'VE BEEN TALKING ABOUT INTO
THE CLINIC AND TREAT PATIENTS
AFTER THEY'VE ALREADY UNDER GONE
SOME LEVEL OF DEVELOPMENT.
YOU HAVE A LOT OF DISCLOSURES
AND WORK WITH A LOT OF COMPANIES
WORKING ON REQUIREDS AND THE
USPI FOR THE ANGELMAN SYNDROME
TRIALS THEREFORE I HAVE NO BIAS.
I'M INTERESTED IN ALL OF THEM
WORKING.
SO UNFORTUNATELY THIS MORNING WE
HAD INTRODUCTION TO ANGELMAN
SYNDROME.
I'M GOING TO RUN OVER THIS
QUICKLY.
IT'S A SEVERE DEVELOPMENTAL
DISORDER WITH SEVERELY PROFOUND
INTELLECTUAL DISABILITY AND MOST
PATIENTS DON'T TALK AT ALL.
MOTOR SKILL AND SLEEP AND
SEIZURE AND THEY HAVE A LOT OF
BEHAVIOR PROBLEMS, VERY
IMPULSIVE AND ANXIOUS AND
DIFFICULT AND ATTENTION SEEKING
AND EXCESSIVE SOCIABILITY IN
PUBLIC AND SOME DYSMORPHIC
FEATURES AND SOME HAVE
MICROSELFCEPHALY -- MICROCEPHALY
AND THIS GENE INTRINSIC IN
NEURONS BUT NOT IN ANY OTHER
CELLS AND ALL OF US ARE RUNNING
ON OUR MATERNAL GENE AND THE
PATERNAL GENE IS SHUT DOWN.
THERE'S VARIOUS ASPECTS OF THE
MATERNAL GENE THAT CAUSE
ANGELMAN SYNDROME INCLUDING A
DELETION WHICH IS COMMON AND GET
TWO CHROMOSOMES 15 FROM YOUR
FATHER AND MAKE IT LOOK LIKE A
PATERNAL GENE AND A MUTATION IN
THE MATERNALLY DERIVED GENE AND
THE NON-DELETION FORMS ARE
HIGHER FUNCTIONING MEAN THEY MAY
HAVE A FEW WORDS.
THEY HAVE LESSEE -- LESS
SEIZURES.
THE ANGELMAN SYNDROME COMMUNITY
HAS BEEN VERY PROACTIVE IN HOW
TO GET SET UP FOR CLINICAL
TRIALS.
THEY WATCHED OUT FAIL AND
LEARNED ALL THE LESSONS WE HAD
TO TEACH THEM.
THEY DID A DISEASE CONCEPT
KNOWING THEY'D NEED THAT FOR THE
FDA.
THIS MEANS INTERVIEWING
CAREGIVERS ABOUT WHAT'S MOST
IMPORTANT TO THEM AND GUESS WHAT
COMES UP ON TOP?
I'M NOT SURE WHERE MY POINTER
IS.
OH, THERE IS NO POINTER.
SO COMMUNICATION IS NUMBER ONE.
I THINK IF YOU TOOK ANY
DEVELOPMENTAL DISORDER WITH THE
LEVEL OF ANGELMAN SYNDROME THIS
WOULD COME UP NUMBER ONE AND
SESURES AND COGNITIVE FUNCTION
IS WHAT THEY WANT TREATED
DOCUMENTED FOR THE FDA AND THIS
IS ON THE BAILEY SCALES OF
INFANT DEVELOPMENT AND USE THAT
IN ANGELMAN SYNDROME PATIENTS OF
ALL AGE THOUGH THE MEASURE IS
FROM 0 TO 3 BECAUSE NO ANGELMAN
SYNDROME PATIENT GETS ABOVE 3.
THIS IS THE SCALE AND ONCE THEY
GET TO 4 IT'S FLAT THEY DON'T
MAKE PROGRESS.
THEY MAYBE MAKE SOME IN GROSS
MOTOR SKILLS AND FOR THE
DELETION PATIENTS THEY'RE MORE
IMPAIRED THAN THE NON-DELETION
PATIENTS.
THEY ALSO THOUGHT WE NEED A
BIOMARKER BECAUSE MAYBE WE DON'T
WANT TO DO CLINICAL TRIALS FOR
YEARS AND YEAR AND THERE'S A
NICE BIOMEDICAL OF INCREASED
DELTA POWER IN BLUE AND THAT
CORRELATES NICELY WITH THE
COGNITIVE SCORE ON THE BAY
BAYLEY AND IF YOU PREDICT THE
SCORE YOU GET A NICE CORRELATION
WITH THE ACTUAL BAYLEY COGNITIVE
SCORE SHOWING A NICE CORRELATION
OF A BIOMEDICAL WITH FUNCTIONAL
LEVEL IN ANGELMAN SYNDROME.
AND THEN IT TURNS OUT ANGELMAN
SYNDROME IS ACTUALLY SOMEWHAT
LOW-HANGING FRUIT GENETICALLY IN
TERMS OF A TREATMENT.
THIS IS A NORMAL PERSON MAKING
THE CHROMOSOME AND ALL THE
ASSOCIATED GENES INCLUDING THIS
ANTI-TRANSCRIPT THAT IS SHUT
DOWN AND THE PATERNAL CHROMOSOME
AND IT HIT RUNS INTO UB3A AND
SHUTS IT DOWN.
IN ANGELMAN SYNDROME WE SHUT IT
DOWN IN UB3A AND IF WE THROW INI
SO AND ALLOW IS TO BLOCK THIS
TRANSCRIPT, NOW WE CAN GET
TRANSCRIPTION OF UBE3 OFF THE
PATERNAL WHEEL.
IT TURNS OUT THIS WAS VERY
SUCCESSFUL IN MOUSE AND THIS IS
WORK IN A PAPER WHERE THE
TRANSCRIPT COULD BE SHOWN TO
COME DOWN AND THE UBE3A GOES UP
AND SEE IN THE WESTERN BLOT AND
NEURONS WE'RE MAKING UBE3A WHEN
EXPOSED TO THE ASO.
SO AS A RESULT OF THAT WORK
THREE CLINICAL DEVELOPMENT
EFFORTS WERE CITED.
ONE WAS GENETICS A COMPANY SET
UP BY THE ANGELMAN SYNDROME
SYNDROME AND THERAPEUTICS WHICH
THEY FELT THEY WERE MOVING
SLOWLY AND WANTED TO SPEED THEM
UP AND ULTIMATELY PARTNERED WITH
ULTRA INFORM GENYX AND A -- SOME
COULD BE A PLATFORM TRIAL BUT
WEREN'T BECAUSE THEY WERE WITH
DIFFERENT COMPANIES.
SIMILAR OBJECTIVES, SAFETY,
PHARMACO KINETICS OF THE DRUG
AND ANY OF THE DRUGS AND
CLINICAL ACTIVITY AND USING THE
OUTCOMES MEASURES THE BAYLEY 3
AND THE MOTOR MONITOR AND THIS
WAS THE VIDEOS OTHERWISE THEY'RE
ALL USING THE SAME GROUP OF
OUTCOME MEASURES BECAUSE THEY'RE
OUGHT MATCHED IN ANGELMAN
SYNDROME.
I'LL SHOW YOU WHAT'S GONE ON
WITH ALL THREE OF THE TRIALS.
THIS IS A ROCHE TRIAL.
THEY HAD DIFFERENT COHORTS AND
THE STARTED WITH OLDER PATIENTS
DOWN TO 1 TO 4-YEAR-OLDS AND HAD
A PAUSE AND HAD TWO TO THREE
DOSES AND THEN A PAUSE AND THEN
A LONG-TERM EXTENSION AND THIS
IS PROBLEMATIC BECAUSE THE
PATIENTS WERE UNDER DOSED AND
THE DOSING WAS TOO LONG AND
PEOPLE STARTED COMING OFF THE
DRUGS BEFORE THE NEXT DOSE.
THE SIDE EFFECTS WERE LIMITING
AND COULDN'T GO TO THE PLANS
HALF DOSE AND LAST SUMMER THEY
OBSERVED THE LEVEL OF EFFICACY
WAS NOT SUFFICIENT TO MEET THE
INTERNAL CRITERIA TO MOVE
FORWARD.
IT TURNED OUT ROCHE HAD A CHANGE
AND WASN'T TOO INTERESTED IN
RARE DISEASES AND THEY DID ADMIT
THEY HAD AN EFFECT ON THE EEG
ENCOURAGING AND HAD TO FIND A
PARTNER TO SALVAGE IT EVERY
SINCE.
THAT'S WHAT WE KNOW ABOUT ROCHE.
THEY'LL PRESENT MORE DATA IN
ABOUT A BOTH.
THIS IS ANOTHER TRIAL AND THEY
INCREASED THE TRIAL BETWEEN
COHORTS AND LOW, MEDIUM AND
HIGHEST AND YOUNG KIDS 2-5 AND
TREATED ADULTS.
THEY'RE THE ONLY ONES TO DO THAT
SO FAR.
THE FIRST COUPLE COHORTS HAD A
LONG WEIGHTING FOR LONG-TERM
EXTENSION AND THEN THOSE
PATIENTS ALL WENT TO AN EXTENDED
LONG-TERM EXTENSION.
THIS WAS ALSO SAFE AND WELL
TOLERATED.
THEY DID SEEM TO SHOW
IMPROVEMENT ACROSS MULTIPLE OF
THESE MEASURES SO AT SIX MONTHS
AND THESE ARE OFFICIAL
STATEMENTS.
TWO-THIRDS ACHIEVED IMPROVEMENT
IN COGNITION AND LANGUAGE AND
GROSS MOTOR SKILLS SAID TO BE
BETTER THAN WHAT YOU WOULD SEE
IN NATURAL HISTORY.
THE MAJORITY ALSO SHOWED IN
IMPROVEMENT IN EEG ACTIVITY
CORRELATING WITH POSITIVE
CHANGES IN THE DEVELOPMENTAL
SKILL.
THEY HAVEN'T PRESENTED PUBLIC
DATA.
ULT
ULTRAGENYX HAS A DIFFERENT
DISCLOSURE AND IT'S THERE BUT
NOT IN THE PUBLIC DOMAIN HAVING
SEEN A LOT OF THE PATIENTS.
SO THE STUDY INCREASED AS YOU
WENT FROM DOSE 1 TO DOSE 4.
THEY HAD FOUR MONTHLY DOSES AND
THEN WENT INTO MAINTENANCE
DOSING EVERY THREE MONTHS AND
HAD VARIOUS CIRCUITOUS ROUTE
ACTUALLY.
SO THE FIRST FIVE PARTICIPANTS
WHO WERE ALL DOSED AT OUR SITE
DURING THE PANDEMIC IT TURNS OUT
ALL DEVELOPED A SEVERE ADVERSE
EVENT WHICH WAS LEG WEAKNESS.
OTHERWISE THERE WERE MINOR
THINGS BUT ESSENTIALLY IT WAS A
SHOW STOPPER.
THE PATIENTS GOT INFLAMMATION,
YOU SEE THE INCREASED SIGNAL
AROUND THE NERVES AND HAD THIS
WAS CLEARLY AN ISSUE THAT WAS
TOXICITY.
THEY THOUGHT IT MAY BE AN AUTO
IMMUNE REACTION BUT SPENT TIME
PROVING THAT WASN'T TRUE AND THE
PATIENTS RESOLVED WITHIN A FEW
MONTHS AND THE CORTICAL
IMPROVEMENTS LASTED LONGER THAN
THE ADVERSE EVENTS.
THESE PATIENTS SHOWED
IMPROVEMENT IN THE CGI AND EEG.
THIS IS A LIST OF SOME OF THE
KINDS OF IMPROVEMENTS THAT WE'RE
SEEING.
THE FDA HAS PUT THE STUDY ON
HOLD FOR A LONG TIME AND GENETIC
AND ULTRAGENYX WENT TO LOWER
DOSES AND MOVED TO CANADA AND
U.K. AND SOME PATIENTS HAD LOST
GAINS AND ONE GOT AN EXTENDED
ACCESS FOR BECAUSE HE WAS HAVING
FREQUENT EPISODES AND FINALLY
THE FDA ALLOWED THE STUDY TO
RESTART AFTER THEY PRESENTED
THEIR U.S. DATA AFTER TWO YEARS
AND NOW THE STUDY IS GOING AGAIN
IN THE USA AT THE DOSES BEING
USED OUTSIDE THE USA.
TO GIVE YOU A FLAVOR FOR WHAT WE
FOUND IN THE FIRST FIVE PATIENTS
AND ONE OF THE FAMILIES SAID I'D
RATHER HAVE HIM IN A WHEELCHAIR
WITH THE GAINS HE'S MADE THAN
COME OFF THIS ASO.
THIS IS THE AMOUNT OF CHANGE IN
A YEAR THAT A PATIENT WITH
ANGELMAN SYNDROME MAKES AFTER
AGE 4.
THE DOTS ARE THE AMOUNT OF
CHANGE THE PATIENTS MADE IN LESS
THAN A YEAR.
SO THE CHANGE WAS VERY DIFFERENT
FROM WHAT WE SEE IN NATURAL
HISTORY.
SO WHEN THEY RE-YERE-NEAINITIAT
TRIAL AND HAD COHORTS 4-7 TO
PROVE SAFETY AND GOT 34 IN
COHORT A OUTSIDE THE USA AND
HAVEN'T BEEN GOING ALONG ENOUGH
IN THE USA TO HAVE THE DATA CUT.
WHAT HAVE THEY SEEN?
THE KIND OF STANDARDS THINGS YOU
MIGHT SEE.
THERE HAVEN'T BEEN EXTENSIVE
SIDE EFFECTS.
A COUPLE FAMILIES DISCONTINUED
BECAUSE OF TRAVEL AND EFFORT.
THREE PARTICIPANTS DID DEVELOP
MILD SYMPTOMS AND THEY ALL
RESOLVED AND GETTING DOSE AGAIN
AFTER RADICULOPATHY AND WE HAVE
SHARING THE NATURAL HISTORY DATA
WITH ALL INDUSTRY PARTNERS.
THERE'S TWO BATCHES.
ONE IS 2006 TO 2014 DOING THE
BAYLEY 3 AND THE VALUES AND THE
VALUES WERE CONVERTED AND
THERE'S A WAY TO DO THAT IN THE
MANUAL AND THE RECENT HISTORY OF
THE BAYLEY 4 WAS TESTED AND QUE
HAVE GSBs FROM THEM.
THE SECOND DOTTED LINE WOULD BE
STATISTICALLY SIGNIFICANT YOU
WOULDN'T SEE JUST FROM TEST
ADMINISTRATION AND SO AS YOU CAN
SEE COGNITION IS DOING MUCH
BETTER THAN NATURAL HISTORY OVER
THE COURSE OF THE TIME AND MOST
OF THIS IS COHORT 4-7 BUT
THEY'RE FOLLOWING THE SAME PATH
IN ALL THESE GRAPHS AND THIS IS
RECEPTIVE COMMUNICATION, SAME
RESULT.
THIS IS GROSS MOTOR SKILLS AND
NATURAL HISTORY AND ON THE ASO
AND WHEN THEY ONLY HAD DATA FROM
4-7 AND THIS IS THE ASA THE
ANGELMAN SYNDROME SYNDROME SO
YOU GET CONSISTENCY ACROSS SITES
AND SLEEP SEVERITY IMPROVED AND
BEHAVIORAL SEVERITY IMPROVED A
GREAT DEAL.
WHETHER YOU LOOK AT IT AS MEANS
OR IN A RESPONDER ANALYSIS IN
OTHER WORDS PATIENTS THAT HAD
IMPROVEMENTS VERSUS THOSE THAT
DIDN'T.
AND THIS IS WHAT ULTRA GENICS
HAD TO DO TO LOOK ACROSS THE
DOMAINS IN ANGELMAN SYNDROME
BECAUSE DIFFERENT THINGS AND YOU
CAN SEE FROM THE CHART IMPROVE
IN DIFFERENT PATIENTS AND
THEY'RE MORE SEVERE IN DIFFERENT
AREAS.
THE GREEN IS SOMETHING THAT
IMPROVED MORE THAN WOULD BE AND
IN THE CASE OF BEHAVIOR AND
SLEEP IN A CLINICAL AND
MEANINGFUL AMOUNT AND IN THE
CASE OF THE OTHER DOMAINS IS THE
BAYLEY AMOUNT MORE THAN WHAT
WOULD BE STATISTICALLY PREDICTED
OF VARIATION FROM ONE
ADMINISTRATION TO THE OTHER.
YOU CAN SEE MOST HAVE IMPROVED
IN ONE DOMAIN AND SOME HAVE
IMPROVED IN MANY DOMAINS AND
THIS IS EARLIER.
THESE ARE PATIENTS AT DAY 170
AND COHORT A AND B AND MANY
IMPROVED ALSO.
SO THIS IS THE KIND OF MEASURE
ONE COULD USE TO LOOK ACROSS THE
DISEASE.
THIS LOOKS ACROSS DISEASE AS THE
OVER ALL ANGELMAN SYNDROME
SEVERITY SCALE THE LOWER THE
BETTER.
THAT IS SHOWS IMPROVEMENT.
AND THIS GOES WITH THE COGNITIVE
AND LANGUAGE IMPROVEMENTS AND
THE SLEEP SYNDROME WHICH ARE
IMPROVING TO GO WITH THOSE
IMPROVEMENTS.
AND THESE IS TREATMENT AND THE
GREEN ARE THINGS THEY GAINED
DURING THE FIRST PART OF THE
TRIAL WHEN THEY WERE ON THE ASO
EARLY ON BEFORE THEY GOT THE
POLY RAH -- ROO --
RADICULOPATHY AND THIS WAS GARND
AND LOST IN ASSOCIATION WITH THE
TREATMENT OF THE DRUG.
AND THEN A VIDEO WAS ALWAYS
WORTH A THOUSAND PLOTS.
SO I'M GOING TO SEE IF THESE
WORK.
THIS IS OUR ANGELMAN PATIENT
SITTING ON THE TRAMPOLINE AND
HAS TROUBLE GETTING ON HER FEET
TO JUMP WITH HER SISTERS AND
JUST SITS ON THE TRAMPOLINE TO
BE TOGETHER WITH THEM AND CAN
STAND UP.
SHE'S ACTUALLY PRETTY WELL
COORDINATED FOR ANGELMAN BUT
CAN'T REALLY JUMP AND HAS
TROUBLE MAINTAINING HER BALANCE.
THIS IS HER CHILD AFTER FIVE
DOSES OF AN ASO.
THESE WERE MAYBE SIX MONTHS
AFTER GOING ON THE ASO.
AND THERE SHE IS HAVING NO
TROUBLE JUMPING ON THE
TRAMPOLINE WITH HER SISTERS.
REMEMBER AFTER AGE 4 THESE KIDS
MAKE BASICALLY NO PROGRESS AND
SHE CAN JUMP ON TO HER AND SIT
AND JUMP BACK AND JUMP.
SO THAT'S REALLY A SUBSTANTIAL
CHANGE IN MOTOR FUNCTIONING.
HERE IS ONE OF OUR YOUNGEST
PATIENTS WHO IS GOING TO BE OVER
HERE.
AND HER MOTHER'S TRYING TO GET
HER TO WALK.
SO WHEN SHE CAME IN THE TRIAL
SHE WAS NOT AMBULATORY.
SHE COULD TAKE A FEW STEPS
BEFORE FALLING.
GETS UP AND THEN FALLS DOWN AND
HIS IS HER STATUS AT THE TRIAL
THEN AFTER ABOUT SIX TREATMENTS
THIS IS HER ON AN ANGELMAN
SYNDROME WALK WHERE SHE JUST
WALKED ALMOST A MILE AND HERE
SHE COMES RIGHT THROUGH THE
GATE.
SHE HAS HER ARMS UP AS IS
TYPICAL OF ANGELMAN SYNDROME BUT
THEY'LL COME DOWN WITH TIME.
THE PATIENTS GET MORE STABLE AND
THEY STOP HOLDING THEIR ARMS UP.
SO IN CONCLUSION, THE ASO IS IN
ALL STUDIES THAT HAVE SHOWN
BENEFITS.
I HAVE A PHONE FULL OF VIDEO
THAT COULD KNOCK YOU OFF YOUR
SOCKS BUT WE HAVE TO COLLECT
DATA IN A STANDARD FASHION.
SO SAFETY HAS BEEN ACCESSIBLE
FOR ALL THREE DRUGS.
UNDER DOSING HAS BEEN A PROBLEM
IN ALL THE TRIALS.
EVEN WITH 3 MONTHS THE DOSE
WEARS OFF AND THEN THEY HAVE
BEHAVIOR AND SLEEP REGRESSION
WHICH ARE THE MOST COMMON
SYMPTOMS AND THE DATA IS ALL
COLLECTED WHEN THEY COME BACK
FOR THE NEXT INFUSION AND SO
IT'S PROBABLY AN UNDER ESTIMATE
OF WHAT THEY'RE DOING AT PEAK.
THESE ARE EXTREMELY EXCITING
LIFE CHANGING THERAPIES AND THE
DATA IS GOING IN FOR PHASE III
AND WE'LL GO INTO THE PHASE III
BY THE END OF THE YEAR WITH TWO
COMPANIES AND THESE ARE
QUESTIONS FOR THE WORKSHOP THERE
ARE STILL ALL THESE QUESTIONS.
AT WHAT AGE DO WE NEED TO
CORRECT?
SO FAR WE'VE SEEN CHANGES BUT
ARE WE GOING TO A LOW ENOUGH
AGE.
WE HAVE FEW UNDER 4 WHO HAVE
BEEN TREATED.
HOW MUCH CORRECTION IS POSSIBLE
AT DIFFERENT AGES?
WHAT IF WE GOT IN AT NEWBORN
TIME?
COULD WE FIX LANGUAGE AND SOME
PATIENT HAVE DEVELOPED WORDS AND
TWO-WORD STATEMENTS BUT MANY
HAVEN'T DEVELOPED EXCESSIVE
LANGUAGE.
WHAT ARE THE TIME RANGES FOR
CLINICAL CHANGES?
THIS IS NOT A BABY WE'RE
TREATING.
BABIES HAVE A BRAIN WIRED TO
HAVE RAPID EXPANSION OF
DEVELOPMENT.
WE DON'T HAVE THAT ANYMORE IN
THESE KIDS.
SO THEY'RE GOING TO DEVELOP BUT
THERE'S NO SIGN IN OUR
PATIENTS --
[NO AUDIO]
-- HOW WE MEASURE ONE DOMAIN AND
THE FDA STILL WANTS US TO PICK
THE ONE DOMAIN IN A GENETIC WAY
WITH MANY MANIFESTATIONS BUT IT
DIDN'T MAKE SENSE TO US BUT
THAT'S WHERE WE ARE WITH THE
FDA.
WITH THAT I'M GOING TO THANK MY
ANGELMAN TEAM AND OUR FUNDING
FROM THE ANGELMAN FOUNDATIONS
AND THE COMPANIES AND FROM THE
FDA AND NATURAL HISTORY STUDY
RECENTLY DOVE DEF
AND OUR FAMILIES WHO ARE OUR
PARTNERS IN MAKING THIS HAPPEN.
[APPLAUSE]
>> DO I HAVE ANY IDEA WHAT THE
PHASE III TRIAL STRUCTURE WILL
LOOK LIKE?
ACCORDING TO THE FDA, YES, IT'S
GOING TO BE A RANDOMIZED PLACEBO
CONTROL AND TRYING TO GET AWAY
FROM SHAM CONTROLS BECAUSE IT
WILL BE VERY DIFFICULT TO BLIND
THOSE BECAUSE IT'S A BIG RISK
WITH THE ANESTHESIA FOR THE LP.
WE HAVE GREAT NATURAL HISTORY,
NOT GOOD ENOUGH.
WE'LL BE DOING A CONTROL TRIAL.
WE WANT TO DO PLACEBO CONTROLLED
BECAUSE WE CAN GET CSS FOR
BIOMARKERS IN THE UNTREATED
GROUP AND WE HAVE TO DO
ANESTHESIA FOR THE SHAM OR
EVERYONE WILL BE UNBLINDED AND I
THINK IT WILL BE RANDOMIZED 2-1
AND THAT'S WHAT HAS BEEN BANDIED
ABOUT THOUGH NONE OF THIS IS
FINAL AND MAYBE FOR A YEAR AND
EVERYBODY WHO GETS A PLACEBO
WILL GO ON DRUG AT THE END.
>> I'M SURPRISED THE FDA WITH
THE ON, OFF, ON EFFECT.
BUT IN THE PHASE III TRIAL WILL
YOU REDUCE THE TIME SPAN OR STAY
GIVEN WHAT YOU SAID?
>> AND WHAT THE INTERVAL WILL BE
AFTER THAT IS STILL UP IN THE
AIR.
I MEAN, IF I HAD MY WAY IT WOULD
BE EVERY TWO MONTHS.
WHY?
IF THEY DON'T HAVE A TWO-MONTH
OPTION WE'LL NEVER GET INSURANCE
TO COVER IT EVERY TWO MONTHS AND
WILL HAVE PATIENTS ON THIS
ROLLER COSTAR OF IT'S WEARING
OFF AND WE'RE NOT SLEEPING
ANYMORE AT NIGHT AGAIN.
I'M A STRONG VOICE AT THE
INDUSTRY MEETINGS AND TRYING TO
CONVINCE THEM TO AT LEAST HAVE A
TWO-MONTH OPTION.
>> THIS EXTRAORDINARY.
THANK YOU.
I KNOW THERE'S ONLY SO MUCH YOU
CAN SAY SINCE YOU'RE AN
INVESTIGATOR IN ALL THREE TRIALS
BUT I'M CURIOUS ABOUT THE METCAM
OF THE ALLEGEDLY FAILED ROCHE
DRUG.
IS ANY COMPONENT ATTRIBUTABLE TO
THE CHEMISTRY TO THIS TARGET OR
YOU CAN'T SAY?
>> OKAY, WHAT WOULD ROCHE LET ME
SAY?
IT HAS NOTHING TO DO WITH THE
CHEMISTRY.
IT HAS NOTHING TO DO WITH
ANYTHING WRONG WITH THE
MOLECULE.
WHAT I WOULD SAY IS THAT IT HAS
FAR MORE TO DO WITH THE CHANGE
IN ROCHE'S PRIORITIES ABOUT WHAT
THEY'RE GOING TO DEVELOP.
WE KNOW IT'S ALSO BECAUSE THEY
STOPPED IT IN THE MIDDLE OF THE
TRIAL FOR NO GOOD REASON.
THAT WAS NO PROBLEMATIC SAFETY
DATA OR EFFICACY TRIAL AND SAID
WE'RE NOT INTERESTED ANYMORE AND
NOT GOING TO RUN THE TRIAL.
THAT'S A BIG PART OF THE REASON
FOR THE ANGELMAN SYNDROME
PROGRAM BEING DROPPED AS WELL.
>> EXCELLENT.
I'M DELIGHTED TO BE HERE AND IN
ILLUSTRIOUS COMPANY AND FORWARD
THINKING AGENDA ON THERAPY FOR
EPILEPSY.
YOU HEARD A LOT THIS MORNING
THAT WILL MAKE MYS WORK AND
CHALLENGES IN THE GENE THERAPY
TRIALS ARE HERE TO STAY AND I
HOPE THERE'LL BE LESSONS
LEARNED.
I WILL FOCUS MOSTLY ON
PROGRESSIVE DISORDERS THE WHITE
MATTER OF THE BRAIN AND MY
MESSAGE IN SHORT IS DISEASE
CONTEXT MATTERS AND DISEASE
COURSE AND VULNERABILITY OF
PATIENTS AND THAT IS REALLY WHAT
DRIVES TRIALS AS WE THINK ABOUT
VULNERABILITY IN RELATIONSHIP TO
DISEASE AND THE PLATFORM THAT
WILL BE WITH INVESTIGATORS AND
NAVIGATE.
BRIEFLY MY DISCLOSURES.
YOU'VE HEARD A LOT ABOUT AAV
GENE THERAPY AND EX VIVO THERAPY
AND I'LL PRESENT THE IN VIVO
APPROACHES USING AAV AND EX VIVO
GENE THERAPY AND SHOW HOW WE
APPLIED THIS IN VARIOUS
DYSTROPHIES DISORDERS AFFECTING
THE WHITE MATTER OF THE BRAIN I
CAN SEE THE BIOMARKER FOR THE
PATHOLOGY AND IMAGE WHAT IS
HAPPENING IN THE BRAIN AND SEE
THE RESOLUTION THERE.
SO IN VIVO GENE DELIVERY IS
DIRECT TO THE ORGAN AND WITH THE
EX VIVO IT DELIVERS THE
CORRECTED GENE.
FIRST I'LL PRESENT CANAVAN
DISEASE DISORDER AND THIS LEADS
TO THE ACCUMULATION OF A
PLEASURE OF URINE AS WELL AS IN
LEADING TO THE DISORDER WHERE
CHILDREN HAVE A HEAD SIZE AND
NEVER SIT UP ON THEIR OWN.
SOME CAN REACH SEIZURES AND THE
MRI IS WHITE MATTER EFFECTED AND
THE BRAIN STEM THAT IS USUALLY
MYELINATED EARLY NEVER MYELI
MYELINMYELIN
MYELINATES AND EVEN WITH A LIVER
DIRECTED DISORDER WAS SHOWN
IMPROVEMENT IN THE MICE SHOWING
SYSTEMIC CORRECTION WITH AN
ADDITION.
HERE THE FIRST PATIENT BEING
TREATED WAS AAV 9 AN OPEN LABEL
TRIAL FOR CHILDREN UP TO 30
MONTHS OF AGE.
AS MENTIONED OFTEN TODAY WE WANT
TO GET TO CHILDREN AS QUICKLY
AND AS EARLY AS AND POSSIBLE AND
FINISHED THE LOW DOSE COHORT AND
THEY'VE TREATED NOW TWO PATIENTS
AND THE HIGHER DOSE AS WELL.
SO ONE OF THE FIRST THINGS WE
NOTICED IS IMMUNE RESPONSES
AFTER THE ADMINISTRATION WAS
SOMETHING FOUND AND WE SEE DROPS
IN PLATELETS IN THE FIRST FEW
DAYS THAT USUALLY RESPONDS
SPONTANEOUSLY AFTER THE FIRST
WEEK BUT THEN ALSO ARISES IN AST
AND ALT AND TO THE LIVER
FUNCTIONS THAT NEED TO BE
MANAGED WITH GLUCCOCORTICOID
DOSE ADJUSTMENT.
THIS REQUIRED LEARNING IN THE
BEGINNING AND WE HAD TO LEARN
HOW TO DO THIS.
NEVERTHELESS WE SEE DRAMATIC
REDUCTIONS HERE IN URINE FROM
THE CLASSIC HIGH LEVELS THAT YOU
FIND IN THE DISEASE STATE DOWN
TO THE OTHER RANGE ASSOCIATED
WITH MILD DISEASE AND THIS
HAPPENS NOT ONLY HERE BUT IN CSF
AND SPECTROSCOPY IN THE BRAIN
AND WE DID NOT EXPECT TOGETHER
WE SAW SHRINKAGE OF THE BRAIN
SWELLING THAT USUALLY OCCURS AND
WE SAW.
WE LOOKED AT THE FIRST TWO AND
THOUGHT LUMBER PUNCTURES WERE
DOING AT 3 MONTHS BUT SINCE HAVE
NOT SEEN THAT AND IT SHOWS YOU
HERE THE AFFECT HERE OF THE GENE
THERAPY ON THE UNEXPECTED TURN.
AND NEVERTHELESS WE SAW
IMPROVEMENT IN MYELINATION WITH
EVER PATIENT TREATED AND YOU SEE
NICE MYELINATION OCCURRING ON T2
AND EVERY TIME YOU SEE MYELIN
BEING PUT DOWN IN THE WEIGHTED
IMAGE AND SOMETHING WE NEVER SEE
IN THE UNTREATED CONDITION.
MORE IMPORTANTLY WE SAW THESE
CHILDREN THAT NEVER LEARNED TO
SIT UP ON THEIR OWN AND NOW
BRINGING HAND TO MOUTH AND STILL
QUITE UNSTABLE HERE AFTER
TREATMENT BUT THEN STARTING TO
TAKE STEPS ON THEIR OWN AND THIS
LITTLE GIRL NOW ENTERING
KINDERGARTEN AND ABLE TO
AMBULATE INDEPENDENTLY.
SOMETHING THAT GIVES MUCH
SATISFACTION.
SO TO SUMMARIZE HERE, SPONGIFORM
EN ENCEPHALOPATHY AND WE TALK
ABOUT PERMISSIVE BLOOD BRAIN
BARRIER IN YOUNG CHILDREN ALLOWS
FOR SYSTEMIC AAV 9 AND GENE
DELIVER DELIVERY AND WE STEPPED
BACK AND HAVE BEEN ABLE TO
MANAGE AND AVOID EARLY
ADDITIONAL TURNING TURE.
TO HIGHLIGHT ANOTHER DISEASE WE
MADE PROGRESS IN IN INFANTILE
TAY SACHS AND SANDHOFF DISEASE
LEADS TO DEVASTATING COURSE WITH
HALF THESE CHILDREN IN THE FIRST
YEARS OF LIFE AND HALF THE
CHILDREN LEARN TO SIT UP ON
THEIR OWN TOGETHER AND NEVER DO
LEARN TO SIT UP ON THEIR OWN AND
YOU SEE THE PATHOLOGY HERE.
THE SOLUTION AROUND THE NEURONS
IS VERY WIDESPREAD IN THE BRAIN
AND THE RATIONALE HERE FOR GENE
THERAPY SHOWED THALAMIC
INJECTION OF AAV GM2 COULD LEAD
TO WIDESPREAD DELIVERY ACROSS
THE BRAIN BASED ON THE THALAMUS
AND THE FUNCTIONAL HUB FOR THE
TRANSPORTER AS WELL AS NOW YOU
HAVE NEIGHBORING CELLS AND SO WE
EMBARKED ON A WORLDWIDE TRIAL
RECRUITING PATIENTS AROUND THE
WORLD AND WORKING WITH A
NEUROSURGEON YOU CAN SEE THE
DELIVERY TO THE THALAMUS WE SEE
THE INJECTION HERE AND WE'VE
JUST COMPLETED THE DOSE
ESCALATION HERE.
THIS IS BILATERAL INTRATHALAMUS
AND AS WELL AS INTRATHECAL
DELIVERY AND WE THOUGHT WE COULD
HAVE LESS OF AN IMMUNE RESPONSE
AND WE DO SEE SYSTEMIC LEAKAGE
AND TOGETHER WE HAVE SEEN
ELEVATIONS IN LIVER ENZYMES AND
CORRESPONDS TO SEEING SOME T
CELL REACTIVITY.
NEVERTHELESS WE SEE INCREASES IN
CSF HEX AENZYME ACTIVITY AND
MEASURE THIS IN PATIENTS WITH
DETAILS I WON'T GO INTO HERE BUT
THIS ALSO CORRESPONDS TO THE
DROP WE HAVE SEEN REDUCING THE
SUBSTRATE THAT IS USUALLY
BUILDING UP AND CAUSING THOSE
INTRUSIONS THAT ARE A PROBLEM.
SO THIS WAS INITIALLY HOPEFUL
BUT WE DID SEE SETBACKS IN THE
JUVENILE COHORT OF OUR TRIAL.
WE WERE TREATING JUVENILE
PATIENTS AND THEY OFTEN PRESENT
WITH MOVEMENT DISORDERS AND THEN
DYSTONIA AND SEVERAL PATIENTS WE
SAW WORSENING THEREOF AFTER AAV
DELIVERY LEADING TO GENERALIZED
DISTONIA IN -- DYSTONIA AND
WONDERED WHETHER IT WAS DUE TO
INJECTION OR SAFETY WAS IMPACT
AND IN ANALYZING THE MRIs WE
FOUND THEY ALL HAD SOME EDEMA
RESOLVED WITH NO LASTING
REACTION.
AND WE SEE THE POOR MYELINATION
AND SEE IT'S INCOMPLETE NOW
IMPROVED OVER TIME.
SO STILL EARLY DAYS AND CLINICAL
READOUTS OF THE TRIAL.
WE'VE SEEN FROM PATIENTS THAT
HAVE CONTROL AND EVEN PULLING TO
STAND IT'S PRESERVED AND THAT IS
SOMETHING THAT WE WOULD NOT HAVE
EXPECTED IN THE NATURAL HISTORY
OF DISEASE.
SO JUST TO SUMMARIZE HERE WE'VE
SEEN THAT WE HAVE PROOF OF
CONCEPT OF ENZYME ACTIVITY
INCREASED WITHIN THE PATIENTS
MRI SHOWED EARLY SIGNALS
IMPROVED MYELINATION AND MADE
GAINS AND SOME JUVENILE
EXPERIENCED DYSTONIA AND IS NOT
THE RIGHT TREATMENT FOR THEM AND
THE LAST DISORDER I'LL TOUCH ON
IS X ALD ADRENOLEUKODYSTROPHY
AND THE SAME GENE, TWO
APPROACHES I'LL OUTLINE.
THIS IS A DEVASTATING DISORDER.
A YOUNG BOY COMES TO ME AND IS
SIX MONTHS BEFORE HE SEES ME IN
KARATE CLASS.
VERY PRECOCIOUS BOY AND THEN
ONCE AFFECTED HE COULD HARDLY
WALK AND HAS LOST HIS VISUAL
CHARACTERISTICS AND DEVASTATING
DISORDER THAT STRIKES BOYS IN
THEIR PRIME.
WE BUILT ON TWO DECADES OF
EXPERIENCE IN PATIENTS KNOWING
TREATED EARLY THESE BOYS COULD
BENEFIT FROM A WELL MATCHED BONE
MARROW TRANSPLANTATION.
WE THINK BECAUSE THE MICROGLIAL
CHANGES AROUND THE END AND WHEN
YOU BRING IN BONE MARROW DERIVED
MONOCYTES THEY DIFFERENTIATE TO
MICROGLIA AND CELLS EXPRESSING
PROTEIN.
WE EXPANDED THIS BECAUSE OF THE
ENGRAFTMENT PROBLEMS AND DECIDED
TO EMBARK ON THE APPROACH WHERE
WE HARVESTED BETWEEN THE BOYS
THEMSELVES AND TRANSVECTED THEM
AND DELIVERED TRANSITIONING AND
WATCHED THESE BOYS FOR A
TWO-YEAR PERIOD.
JUST TO KEEP IN MIND IT'S
IDENTICAL TO CONVENTIONAL BONE
MARROW TRANSPLANTATION AND CELLS
FROM THE BOYS THEMSELVES BUT NOT
FROM ALLOGENEIC DONOR.
I'LL CUT A LONG STORY SHORT HERE
TO SAY WE DROPPED ALL THE WAY TO
AN APPROVED FIRST GENE THERAPY
BY FDA.
LOTS OF UPS AROUND DOWNS OVER
THE YEARS.
SETBACKS THAT OCCURRED BOTH IN
TERMS OF THE COMMERCIAL PROCESS
AND THEN ALSO RECENT CASES OF
THE SYNDROME THAT NEVERTHELESS
WE GOT UNANIMOUS ADVISORY
APPROVAL AND STILL IN FAVOR OF
OUR GENE THERAPY APPROACH FOR
THESE BOYS.
I WANT TO HIGHLIGHT MOST OF OUR
CASES OF MYELODYSPLASTIC THERAPY
WE ARE WORKING ON HOW TO FIGURE
THIS OUT IN THE COMMERCIAL
SPACE.
WE'RE GOING BACK TO THE REGIMENT
WE HAD AND THERE MAY BE OTHER
COMPONENTS WE HAVE TO UNDERSTAND
AROUND MUTAGENESIS.
JUST TO HIGHLIGHT HERE
MICROGLIAL CELL LOSS AND OPEN
BLOOD BRAIN BARRIER ALLOW GENE
DELIVERY THROUGH HEMATOPOIETIC
STEM CELLS AND 94% ACHIEVED
STABLE NEUROLOGIC FUNCTION BUT
THERE'S STILL CHALLENGES IN THE
SYNDROME WE NEED TO FIGURE OUT.
SO GIST TO BRIEFLY HIGHLIGHT WE
ARE ALSO TREATING THE SPINAL
CORD DISEASE.
I WANT TO JUST EMPHASIZE THIS
WORK WOULD NOT HAVE BEEN
POSSIBLE WITHOUT BUILDING ON
EVERYTHING THAT WAS ACCOMPLISHED
BY BRIAN KASPAR AND JERRY
MENDELL AND WE LOOKED AT THE
ADRENOMYELOPATHY AND PACKAGED IT
TO A PROMOTER AND I WILL NOT GO
INTO DETAILS BECAUSE YOU HEARD
SIMILAR STORIES.
WE USED INTRATHECAL SOURCES TO
SLOW DELIVERY TO AVOID AS MUCH
SYSTEMIC LEAKAGE AS POSSIBLE AND
SHOW PROOF OF CONCEPT IN OUR ALD
MOUSE MODEL AND THIS IS
CURRENTLY IN TRIAL AT U MASS AND
AMSTERDAM WHERE WE NOW TREAT FOR
PATIENTS.
TO SUMMARIZE BRIEFLY, THE
MESSAGE I'M TRYING TO -- THE
PICTURE I'M TRYING TO PAINT IS
EVERY DISEASE MAY REQUIRE
DIFFERENT GENE THERAPY DEPENDS
ON WHAT CELL TYPES ARE AFFECTED
AND WHAT STAGE YOU ARE IN.
COULD USE AN AAV IN VIVO
APPROACH TO DIRECTLY TARGET
CERTAIN CELLS IN THE BRAIN IF
YOU DON'T WANT TO GO THROUGH
CONDITIONING AND THE CHE
CHEMOTHERAPY MAY NOT BE
TOLERATED IN A MORE FRAGILE
PATIENT POPULATION.
ON THE OTHER HAND YOU WANT TO
GET TO THE MICROGLIA AND
HEMATOPOINTETIC APPROACH AND
WE'RE MANAGING TREATMENT
COMPLICATIONS IS KEY.
I THINK WE HAVE SEEN TOXICITY
BUT WE'VE ALSO SEEN TOXICITY AT
THE SITE OF ENGAGEMENT OF THE
GENE THERAPY SO I DON'T TAKE
THIS ALL NEGATIVE.
I ACTUALLY TAKE THIS AS A SIGN
THAT WE ARE REACHING THERAPEUTIC
LEVELS AT THE SAME TIME WE
MANAGE WHERE KNOWING HOW TO
MONITOR AND FOLLOW MUTAGENESIS
AND YOU SEE THE SYNDROME AND
MIC
MICROANGIOPATHY AND LIVER
INFLAMMATION AND WE HAVE A
FELLOWSHIP AND THIS REQUIRES
BROAD TRAINING AND NEED A WHOLE
GENERATION OF INVESTIGATORS
FAMILIAR WITH THIS.
NEW GENETIC MEDICINES TO ALLOW
PRECISE TARGETING OF GENES AND
ADVERSE EVENTS CAN RESULT FROM
UNIQUE INTERPLAY OF TECHNOLOGY
AND DISEASE BIOLOGY.
I PERSONALLY THINK WE HAVE TO
MOVE AWAY FROM THINKING ABOUT
TECHNOLOGY PLATFORMS ALONE AND
CONSIDER SPECIFIC BIOLOGY IN THE
CONTEXT OF TECHNOLOGY BEING USED
WITH EVERY DISEASE DIFFERS AND
THE DISEASE STAGE IS CRITICAL IN
DIFFERENT DISEASE STAGES YOU
MIGHT SEE REALLY A CHANGE IN
TARGET CELLS AND THE EXPRESSION
AND THE VULNERABILITY OF THE
PATIENTS WITH STRATIFICATION.
WITH THAT I WANT TO ACKNOWLEDGE
FIRST AND FOREMOST ALL THE
PATIENTS THAT HAVE BEEN
COURAGEOUS AND PARTICIPATE IN
THE EXPERIMENTAL TRIALS WITH
WHOM WE COULDN'T HAVE DONE THIS.
THANK YOU AND I'M HAPPY TO
ANSWER QUESTIONS.
>> I CAN REPEAT THE QUESTION.
[OFF-MIC]
SO JUST TO BE CLEAR THE
QUESTION WAS TIMING FOR THOSE
THAT COULDN'T HEAR DO WE WAIT
UNTIL PATIENTS DEVELOP SYMPTOMS.
WE HAVE NEVER TREATED BEFORE
WE'VE SEEN CLEAR EVIDENCE OF
DISEASE.
THE ADVANTAGE WE HAVE WITH MRI
IS THAT WE HAVE THE SURROGATE
MARKER HERE AND WE KNOW WHEN A
LESION IS OCCURRING AND WHEN
THERE IS CONTRAST ENHANCEMENT
AND A FIRE BURNING.
SO WE CAN GET TO PATIENTS BEFORE
THEY HAVE SYMPTOMS BUT KNOWING
WELL THAT THERE IS ALREADY
PATHOLOGY EMERGING.
WE ARE STILL DOING THAT BUT WE
ARE BEING MORE CAUTIOUS AND
LOOKING FOR MATCH SIBLING DONORS
AND WILL BE GOING FOR
CONVENTIONAL BONE MARROW
TRANSPLANTATION KNOWING THAT
THEY MIGHT DO JUST AS WELL WITH
A
AN ALGENEIC TRANSPLANT AND
MAKING SMALL CHANGES AROUND THE
CONDITIONING REGIMENT.
WE'RE HOPING IT WILL IMPROVE
MOVING INTO THE FIRST TRIAL
ACROSS THE COUNTRY ALL PATIENTS
GETS MONITORED WITH MRI AND DO
WE SEE A LESION EMERGE, THAT IS
THEN THE TRIGGER.
SO IT'S NOT DIRECTLY FOR NEWBORN
SCREENING.
>> THAT'S INTERESTING.
THE QUESTION I HAD WAS ABOUT
YOUR CONDITIONING REGIMENT AND
IS IT DIFFERENT THAN WHAT'S
BEING USED FROM OTHER GROUPS FOR
THE MLD PATIENTS.
ARE YOU SEEING MORE OR LESS
DYSPLASIA?
>> SO WE'RE ENVIOUS OF THE MLD
BECAUSE THEY'VE NOT SEEN
INSERTIONAL MUTE MO-- MUTAGENE
AND WHAT WAS TAKEN OVER DECADES
WILL CHANGE ONLY ONE THING AT A
TIME KNOWING WE HAVE TO BUILD ON
THE SAFETY DATA OF THE PAST.
SO WE TOOK OVER FROM THE FIRST
EXPERIMENT IN PARIS AND WHERE
WE'VE SEEN MOST CASES EMERGE.
WE'RE HOPING THAT WILL BE IT.
>> HI, HOW ARE YOU.
I'M FROM CURE EPILEPSY.
A QUESTION ON YOUR ALG AND AS
YOU LOOK AT THE SERUM LEVELS FOR
CSF14 AND DOES THAT HAVE
CORRELATION WITH YOUR ALD?
>> SORRY, YOU WERE ASKING ABOUT?
>> THE MICROGLIAL MYOPATHY.
>> WE DON'T LOOK AT CSF1R
SPECIFICALLY.
I THINK IT'S VERY RELEVANT FOR
AXONAL STEROIDS.
I THINK IT WILL BE AN IMPORTANT
MARKER WE MIGHT LOOK AT THOSE AS
WELL.
[APPLAUSE]
>> WE'LL HAVE A PANEL DISCUSSION
AT THE END BUT WE HAVE A BREAK
NOW FOR ALMOST 20 MINUTES SO
PLEASE COME BACK BY 3:45 AND
CERTAINLY ENGAGE WITH THE
SPEAKERS ON THE BREAK AND AFTER THE PANEL DISCUSSION IT'D BE
GREAT TO HAVE A GROUP DISCUSSION AT THE END.
>> ALL RIGHT.
WE'RE GOING TO GET STARTED AGAIN.
WE'RE PLEASED SESSION 2 WAS ABLE
TO ATTRACT THIS SESSION AND NEW
PATHS TO WATERFALL AND LESSONS
FROM AAV PRODUCT DEVELOPMENT AND
GENETIC BLINDNESS AND HEMOPHILIA
AND THANK YOU FOR BEING HERE.
>> I'M ONLY SORRY ANOTHER
OBLIGATION KEPT ME FROM BEING
THIS MORNING BECAUSE I WOULD
HAVE LEARNED A LOT OF ABOUT
GENETIC EPILEPSY SUCH AN
IMPORTANT PROBLEM.
I'M GOING TO TALK WITH TWO AAV
PRODUCTS ONE FOR THE CONGENITAL
FORM OF BLINDNESS AND HEMOPLOID
B AND FIRST THESE ARE MY
DISCLOSURES.
THESE EXEMPLIFY TWO PROBLEMS AND
MAY BE OF INTEREST TO THE GROUP.
IN HEMOPHILIA WE HAD A
SIGNIFICANT ADVERSE EVENT NOT
PREDICTED BY STUDIES IN MICE,
RATS, RABBITS, HEMOPHILIC
ANIMALS AND THE OTHER FOR
CONGENITAL BLINDNESS THE MAJOR
HURDLE TURNED OUT TO BE NO
PHARMACOLOGIC PRODUCTS FOR
INHERITED RETINAL DISEASE AND NO
CONSENSUS FOR A PRIMARY END
POINT AND WE HAD TO DEVELOP ONE
AND THEN VALIDATE IT AND ADDS
YOU MAY KNOW IT CAN BE DIFFICULT
TO GET THE REGULATORY DEVELOPERS
AND COMPARE THEM AS GENE DRUG
DELIVERY PROBLEMS AND SHARE
PROBLEMS I ALWAYS THINK IT'S
IMPORTANT FOR THE DRUG DEVELOP
TO CONSULT.
LET ME START BY TALKING ABOUT
HEMOPHILIA B.
I'M A HEMATOLOGIST.
YOU'LL REMEMBER A KEY REACTION
IS THE ACTIVATION OF FACTOR 10
AND THAT TAKES PLACE UNDER THE
ACTION OF THE ENZYME AND THE
CO-FACTOR 8.
BOTH ARE INCLUDED IN THE X
CHROMOSOME AND SO HEMOPHILIA A
AND B OR FACTOR 9 DEFICIENCIES
IN MALES AND THOSE BORN WITH
THESE LEVELS OF FACTOR A OR 9
AND WE HAVE DEVELOPED TREATMENTS
AND FIRST A CLOTTING
CONCENTRATION AND CLOTTING
FACTOR CONCENTRATE WHICH INFUSED
INTRAVENOUSLY AND CAN PREVENT
AND IN THE LAST FIVE YEARS OR SO
FOR FACTOR 8 DEFICIENCY AN
ANTIBODY WAS DEVELOPED BY ROCHE
AND HOLDS FACTOR 9 AND 10 AND
SUBINJECTION IS A POSSIBILITY
WITH PEOPLE WITH HEMOPHILIA A.
THE WORK WE DID WAS BASED ON THE
GENE IN THE 1990s AND BEGAN WITH
A VARIETY OF VECTORS AND THE ONE
THAT WORKED BEST WAS AAB AND
STARTED WITH THE HEMOPHILIA B
MODEL BECAUSE THERE'S SHORTER
THAN THE FACTOR A GENE AND
EASILY FIT INTO AN AAV VECTOR.
WE SHOULD WE COULD INTRODUCE
THEM BY DIRECT INTRAMUSCULAR
INJECTION INTO THE MUSCLES OF A
DOG OR IN TO THE LIVER AND GET
LONG-TERM EXPRESSION IN THE DOG
OF CLOTTING FACTOR LEVELS AS YOU
CAN SEE IN THE BOTTOM FOR
INTRAMUSCULAR INJECTION WERE
BARELY ABOVE THE BASELINE WHICH
WAS NUL BUT STILL
DISTINGUISHABLE FROM THAT OR
GOING TO THE LIVER WITH A TEN
FOLD LOWER DOSE YOU CAN DELIVER.
WHEN WE GOT READY TO BEGIN THE
CLINICAL TRIALS THERE WAS NO
EXPERIENCE GIVING AAV INTRAM
INTRAMUSCULARLY OR LIVER IN
HUMANS AND BEGAN WITH THE
INTRAMUSCULAR INJECTION
REASONING IF SOMETHING TERRIBLE
WENT WRONG AND WE INJECTED THE
VECTOR INTO THE QUADRICEP IF WE
HAD TO RESECT IT AND REVERSIBLE
IN THE SENSE GOING TO THE LIVER
WOULD NOT BE.
THIS IS OUR WORK AT CHILDREN'S
HOSPITAL IN PHILADELPHIA WITH
THE INTRAMUSCULAR INJECTIONS AND
WHAT YOU SEE IN THE SECOND PANEL
IS AN IMMUNOHISTO CHEMISTRY FROM
THE BIOPSY AND IT SHOWS HE'S
MAKING FACTOR 9 AND TWITCH FIBE
ARE BETTER THAN FAST TWITCH
FIBERS AND WHAT YOU SEE IN THE
PATTERN THERE.
THE CIRCULATING LEVELS IN HUMANS
WERE NOT GOOD ENOUGH TO
AMELIORATE THE DISEASE AND
THOUGHT WE COULD DO PREFERENTIAL
ADMINISTRATION IN A PERSON AND
LETS MOVE ON TO THE LIVER.
WE DID THE INITIAL INFUSIONS IN
THE LIVER IN THE INTERVENTIONAL
RADIOLOGY SUITE THROUGH THE
HEPATIC ARTERY AND NOW AS YOU
HEARD FROM SEVERAL SPEAKERS WE
KNOW IF YOU GIVE IT
INTRAVENOUSLY MOST WILL GO TO
THE LIVER.
WE DIDN'T KNOW THAT THEN.
BUT ANYWAY, WHEN WE DID THIS WE
HAD TO START AT A LOW DOSE AND
NO PREVIOUS EXPERIENCE WITH
TRANSDUCING TO THE HUMAN LIVER
WITH AAV BUT BY THE TIME WE GOT
TO THE DOSE PREDICTED TO BE
THERAPEUTIC FROM THE STUDY AND
ANIMAL MODEL WE SAW FACTOR 9
EXPRESSION AND YOU CAN SEE FOR
THE FIRST FOUR WEEKS WE WERE
GETTING LEVELS OF 10 TO 12%.
HOWEVER, THE LEVELS STARTED TO
SLOWLY DECLINE AT THE SAME TIME
HE DELIVERED A RISE IN HIS LIVER
ENZYM
ENZYMES SO THE TRIAL WAS PLACED
ON HOLD AND WERE NOT EAGER TO DO
THIS IN OTHERS AND THIS IS AFTER
ONE PATIENT HAD DIED FROM
INTRODUCTION INTO THE ADENO
VECTOR AND WANTED TO UNDERSTAND
BEFORE WE WENT FORWARD.
THE TIME COURSE DID SUGGEST TO
US THIS WAS NOT DIRECT TOXICITY
FROM OUR VECTOR.
IT TOOK FOUR WEEKS TO DEVELOP
AND WE THOUGHT THIS MIGHT VERY
WELL BE IMMUNE RESPONSE TO A
CAPSID OR A TRANS VECTOR WHICH
MAY LOOK LIKE A FOREIGN VECTOR
FOR A PERSON WITH HEMOPHILIA AND
HAD NO TRANSIENT CAUSE FOR
RISING LIVER ENZYMES AND AFTER A
NUMBER OF STUDIES I DONT HAVE
TIME TO TELL YOU ABOUT WE SPENT
YEARS WORKING ON THIS THANKS TO
OUR FUNDING FROM HOWARD HUGHES
AND THE NIH AND TOOK YEARS AND
35 PUBLICATIONS AND THE MODEL WE
CAME UP WITH AND RED CIRCLES ARE
AAV AND HEPATOCYTES AND SOME OF
THE VECTOR GOES TO THE NUCLEUS
AND STARTS MAKING VECTOR 9.
A LOT REMAINS AND WE KNOW CAPSID
UNDER GOES PROTEASOMAL
PROCESSING AND EVENTUALLY GETS
TRANSMITTED TO THE ENDOPLASMIC
RETICULUM AND PLACED ON THE
TRANSDUCED CELL WHERE IT THEN
MAKES THE HEPATOCYTE TARGET FOR
CIRCULATING THE CD 8 T CELLS
BECAUSE IT THINKS IT'S VIRALLY
INFECTED.
WE DID A NUMBER OF THINGS.
WE IDENTIFIED THE PEPTIDE
COMPLEX WE DOING TYPING ON A
PATIENT AND THEN USING
INFORMATICS PROGRAMS TO PREDICT
WHICH PEPTIDES FROM THE CAPSID
WERE THE PREFERRED BINDERS TO
THOSE.
AND THEN WE USED THAT PENTAMER
OF THE PEPTIDE AND MOLECULE TO
ISOLATE A POPULATION OF CAPSID
SPECIFIC CD 8 T CELLS AND CLONED
THE T CELL RECEPTOR AND WERE
ABLE TO SET UP AN IN VITRO
SYSTEM AND WHAT IT CONVINCED US
OF WAS THIS WAS A DOSE DEPENDENT
PHENOMENON.
WE DIDN'T SEE IT IN THE DOSE
ESCALATION AND WOULD SOLVE
PROBLEMS.
AND SO WE WERE SPENDING A LOT OF
TIME TRYING TO WORK ON MORE
LIVER TROPIC CAPSIDS, A STRONGER
PROMOTER AND SO FORTH BUT THE
REAL ANSWER FOR US FOR
HEMOPHILIA CAME FROM WORK DONE
BY A COLLEGIATE CHILDREN'S
HOSPITAL HEMATOLOGY AND
COLLABORATED WITH A GROUP IN
ITALY TO DESCRIBE A HIGH
SPECIFIC ACTIVITY FACTOR 9
VARIANT IN A KINDRED THAT
PRESENTED WITH COAGULATABILITY
AND INCREASED THE ENZYME
TENFOLD.
WE REMADE OUR VECTORS WITH THIS
MORE SPECIFIC FACTOR 9.
WE USED THE BETTER HEPATOTROPIC
CAPSID AND WERE ABLE TO DROP OUR
DOSE FOURFOLD FROM THE DOSE
WHERE WE SAW THE IMMUNE
RESPONSES BEFORE AND LO AND
BEHOLD WE GOT A 3-FOLD HIGHER
CIRCULATING LEVEL OF FACTOR 9
AND NO PROBLEMS WITH IMMUNE
RESPONSES.
IS THAT PATIENT WENT FROM AND
WERE ABLE TO REPEAT THAT FOR
MOST OF THE REMAINING 10
PATIENTS.
TWO DEVELOPED THE IMMUNE
RESPONSES BUT THEY WERE EASILY
AND QUICKLY CONTROLLED WITH THE
COURSE OF STEROIDS AND YOU HEARD
THEM TALKING ABOUT FEATURES
STILL USED TO CONTROL THOSE
IMMUNE RESPONSES IN THE LIVER.
SO THE LEVELS OF CIRCULATING
FACTOR 9 THOSE PEOPLE HAD WERE
SUFFICIENT TO MARKEDLY REDUCE
THE FREQUENCY OF BLEEDING ON THE
LEFT SIDE OF THE CHART YOU SEE
THE NUMBER OF BLEEDS EACH OF THE
10 PEOPLE HAD IN THE YEAR BEFORE
VECTOR INFUSION AND THEN IN A
YEAR AFTER VECTOR INFUSION ON
THE RIGHT.
SO A MARK REDUCTION IN THE USE
OF FACTOR AS WELL AS REDUCTION
IN BLEEDING.
SO 30% LEVELS ARE GREAT AND
THEIR ADEQUATE TO PREVENT THE
BLEEDING EVEN IN PEOPLE WHO HAVE
HAD HEMOPHILIA MANY YEARS.
THESE PATIENTS WERE ALL ADULTS.
AS A GENE THERAPY DRUG
DEVELOPMENT PROBLEM IT STARTED
WITH A CLEAR PROOF OF CONCEPT IN
AN ANIMAL MODEL.
THAT'S IMPORTANT.
BUT THERE WAS NO CLINICAL
EXPERIENCE WITH EITHER ROUTES OF
ADMINISTRATION WE USED EITHER IN
THE MUSCLE OR LIVER.
THE CHOICE OF ENDS POINTS WAS
CLEAR BASED ON 50 YEARS OF DRUG
DEVELOPMENT FOR HEMOPHILIA AND
THE TEST ADVANTAGE CLEAR
QUANTITATIVE END POINTS.
THE BLEEDING FREQUENCY AND
CIRCULATING LEVEL OF CLOTTING
FACTOR.
HOWEVER, ALL THESE ISSUES
RELATED TO THE IMMUNE RESPONSE
TO INTRAVENOUSLY INFUSE AAV HAD
NOT BEEN PREDICTED BY ANIMAL
MODELS.
I THINK THE REASON IS WE'RE ONE
OF THE FEW SPECIES THAT ARE
NATURAL HOSTS FOR AAV AND A LOT
HAS NO DO WITH MEMORY T CELLS.
WE HAD TO WORK THAT OUT BECAUSE
THERE WERE NO GOOD ANIMAL MODELS
FOR IT.
I'LL MOVE ON TO THE PROBLEMS WE
HAD WITH LUXTERNA.
THIS IS AN ULTRA RARE RETINAL
DYSTROPHY CAUSED BY MUTATIONS BY
A PROTEIN RPE65 AND NIGHT
BLINDNESS IS ONE OF THE EARLIEST
SYMPTOMS.
SOME CHILDREN ARE BORN WITH
LITTLE VISION AND THE PARENT
MAKE THE DIAGNOSIS BECAUSE THEY
SEE THE CHILD IS NOT TRACKING
VISUALLY AND THEY ALL HAVE
SEVERE VISUAL IMPAIRMENT THAT
CONTINUES TO PROGRESS.
AND THERE'S NO RETINAL DYSTROPHY
BEFORE THE GENE WAS DEVELOPED
BUT THERE WAS AN NATIONALLY
OCCURRING DOG MODEL.
AND A COLLEAGUE RESTORED VISION
IN THE DOG.
IN YOU SEE THE RETINA WITH THE
RODS AND CONES INTERMIXED AND
THIS IS BASICALLY A ROD BASED
DISEASE BUT UP IN THE TOP THE
GRAY CELLS ARE THE RETINAL
PIGMENT EPITHELIAL CELLS.
THE PHOTO RECEPTORS DO NOT
COMPLETE ALL THEIR OWN
METABOLISM.
THEY'RE SOME OF THE MOST
METABOLICALLY ACTIVE CELLS IN
THE BODY.
INNING BLUE ARE ACTIVITIES IN
THE PHOTO RECEPTORS AND IN GREEN
THE ONES THAT TAKE PLACE IN THE
RETINAL PIGMENT EPITHELIAL
CELLS.
THE POINT IS EVENTUALLY WHEN
LIGHT STARTS YOU CHANGE TO A
TRANSFORM BUT THEN THE TRANS RET
NOL HAS TO BE TRANSPORTED BACK
TO THE RPE CELLS WHERE UNDER THE
ACTIVITY OF RPE65 THE RETINAL IS
REGENERATED AND WITHOUT THIS THE
CYCLE IS BROKEN AND THE ANATOMY
IS PRESERVED FOR A RELATIVELY
LONG TIME THOUGH THE BIO
CHEMISTRY IS BROKEN FROM THE
OUTSET AND WHAT GIVES US THE
OPPORTUNITY TO CORRECT THE
GENETIC DEFECT BECAUSE THE
ANATOMY IS STILL THERE AND IN
FACT.
THIS IS THE TOTAL PROGRAM TO GO
THROUGH IT QUICKLY.
THE FIRST WITH A STUDY IN THE
WORSE OF THE TWO EYES OF
AFFECTED INDIVIDUALS.
THE ORANGE BLOCK.
ALL DOSES WERE SAFE AND IT HIT
COVERS MORE OF THE RETINA.
IT HAD A LARGER VOLUME AND
DECIDED WE'D TAKE THAT FORWARD
INTO PHASE III.
HOWEVER, BEFORE WE STARTED PHASE
III WE HAD TO DO A SECOND PHASE
I STUDY WHERE WE INJECT WILL THE
CONTRALATERAL EYE WITH THE DOSE
INTENDED FOR PHASE III TO SHOW
IT WOULD BE SAFE AND WON'T HAVE
AN IMMUNE RESPONSE AND HAVE ONE
EYE INJECTED AND THEN THE OTHER
EYE INJECTED.
IT WAS ALL SAFE AND WE WERE ABLE
TO START PHASE III.
I'LL SAY A LITTLE BIT ABOUT THE
PHASE 3 TRIAL DESIGN AND ENDED
UP USING RANDOMIZED CONTROL
CROSSOVER DESIGN, OPEN LABEL.
WE ENROLLED CHILDREN AS WELL AS
ADULTS IN ALL OF THESE STUDIES,
PHASE I AND PHASE III.
I MENTIONED BEFORE BECAUSE THERE
WAS NO TREATMENT FOR THIS
DISEASE, WE HAD TO DEVELOP AND
VALIDATE A NOVEL END POINT.
THAT'S ON THE RIGHT THERE.
THE MULTI-LUMINOUS MOBILITY TEST
VALIDATION STUDY DONE IN OTHER
INDIVIDUALS WITH NORMAL VISION
OR WITHIN INHERITED RETINAL
DYSTROPHY AND I'LL SAY A LITTLE
BIT ABOUT THAT AND THE NATURAL
HISTORY DATA IN THE DISEASE WERE
SCANT.
THEY WERE MOSTLY SINGLE
INSTITUTION CASE REPORTS AND SO
AS PART OF THE CLINICAL
DEVELOPMENT PROGRAM WE CARRIED
OUT THE LARGEST NATURAL HISTORY
STUDY ON THIS THOUGH WE DID NOT
HAVE THE DATA WHEN WE STARTED
PHASE 3.
-- PHASE III.
WE WERE CARRYING IT OUT
SIMULTANEOUSLY AND I WON'T TALK
ABOUT THE MOST DIFFICULT PART OF
ALL THIS.
ANYWAY THE PRIMARY END POINT WAS
A MOBILITY TEST.
ALL THE REGULATORS ONLY BOTH
SIDES OF THE ATLANTIC WERE
NEE
NEEDED FOR THE PRIMARY END POINT
NOT A MEASURE OF VISUAL FUNCTION
BUT FUNCTIONAL VISION.
WHAT IS A VISUALLY DEPENDENT
ACTIVITY OF DAILY LIVING THE
PERSON COULDN'T DO BEFORE THIS
AND WAS ABLE TO DO AFTER THE
TREATMENT.
THAT WAS THE END POINT THEY WERE
LOOKING FOR.
AND IF YOU TAKE ABOUT VISUALLY
DEPENDENT ACTIVITIES OF DAILY
LIVING THAT WOULD BE RESTORED IN
THIS SITUATION IT COULD BE THE
ABILITY TO READ, IT COULD BE THE
ABILITY TO NAVIGATE.
BECAUSE WE WERE ENROLLING
CHILDREN TOO WE WANTED TO USE
SOMETHING THAT YOU COULD DO EVEN
IF YOU COULDN'T READ AND SO WE
DID FALL BACK ON A MOBILITY TEST
AND THE STRUCTURE OF THIS TEST
IS SHOWN HERE BASICALLY THE
MOBILITY TEST THAT WE USE IS A
SERIES OF ARROWS SILK SCREENED
ON TO A MAT AND INTRASPERSED
AMONG THOSE ARE OPTICAL THE
PATIENT IS INSTRUCTED TO AVOID.
WE CARRIED THIS OUT AT SEVEN
DIFFERENT LIGHT LEVELS RANGING
FROM THE VERY BRIGHT LEVEL OF AN
OFFICE TO THE VERY DIM LEVEL OF
A NIGHT LIGHT AND THERE WERE
STEPS IN BETWEEN THOSE.
THE WAY IT WAS USED AT THE
BASELINE IT WAS DETERMINED THE
LOWEST LIGHT FOR THE PATIENT AND
EXECUTE THE COURSE WITHIN THE
DEFINED TIME PERIOD AND WITHIN
MAKING ONLY A CERTAIN NUMBER OF
ERRORS AND I CAN'T MAKE MORE
ERRORS THAN THAT BY COLLIDING
WITH OBSTACLES BECAUSE THEY'LL
FAIL.
AND THEN YOU DO THE
INTERVENTION, WHICH IN THIS CASE
WAS BOTH EYES BEING INJECTED AND
THEN AT THE END OF ONE YEAR YOU
COMPARE THE PEOPLE WHO GOT THE
INTERVENTION TO A CONTROL GROUP
WHO MET ALL THE ELIGIBLE
CRITERIA BUT DID NOT GET
INJECTIONS AND THEN THAT'S THE
PRIMARY END POINT.
THE DIFFERENCE AND THE ABILITY
AT THE BASELINE VERSUS THE
INTERVENTION AT ONE YEAR.
SO WE DEVELOPED THE END POINT IN
DIALOGUE WITH THE FDA AND THEY
MADE A NUMBER OF SUGGESTIONS
THAT MADE IT MORE DIFFICULT TO
DO BUT MORE RIGOROUS AND
CONVINCING AND FOR THAT I THANK
THEM.
SO ONE OF THESE WAS WE HAD 12
COURSES IN RANDOM ORDER.
AND WE WERE ALREADY TESTING EACH
INDIVIDUALLY AND THE BILATERAL
TESTING CONDITION.
EVERYWHERE ONE OF THE COURSE WAS
VIDEO TAPED AND THE VIDEOTAPES
WERE SENT UP SHUFFLED ORDER TO
AN INDEPENDENT READING CENTER
WHO GRADED FOR TIME AND ERRORS
BASED ON A DETAILED RUBRIC WE
HAD GIVEN THEM.
THE PHASE III TRIAL DESIGN WAS
AS FOLLOWS.
WE COULDN'T USE NATURAL HISTORY
DATA.
IT WASN'T ENOUGH.
IT WASN'T ROBUST ENOUGH SO WE
COULDN'T DO THAT.
THE PERFECT SCIENTIFIC CONTROL
IS TO INJECT ONE EYE, LEAVE THE
OTHER ONE UNINJECTED AND COMPARE
THE TWO PERFORMSANCE AND HAS TH
SAME MUTATION AND DETERIORATION
BUT THE FDA POINTED OUT NO ONE
WOULD USE THE PRODUCT THAT WAY
AND WOULDN'T LET US DO IT THAT
WAY AND INSTEAD ENDED UP IN A
RANDOMIZED COSOVER DESIGN.
IT WAS OPEN LABEL SO PEOPLE WHO
MET THE ELIGIBILITY CRITERIA
WERE RANDOMIZED 2-1 TO EITHER
THE INTERVENTION GROUP TO GET
ONE EYE INJECTED AND A WEEK
LATER THE OTHER EYE INJECTED OR
TO THE CONTROL GROUP AND AFTER
TESTING AT BASELINE ASSESSED AT
30 DAYS, 90 DAYS, 165 DAYS AND
OTHER VISUAL FUNCTION 2E69S.
THE TEST WE HAD TO DO WAS
OUTLINED HERE.
PEOPLE CAME IN AND HAD THEIR
VISUAL ACUITY AND FUNCTION
MEASURED AND EXECUTED THE COURSE
TWICE ONE MONTH APART AND GAVE
US THE RELIABILITY DATA AND DID
THEY HAVE REPRODUCIBLE SCORES
AND THEN DID IT ONE YEAR LATER.
WE LEARNED SOMETHING VERY
IMPORTANT.
WE WERE DOING THIS ACTUALLY
WHILE WE WERE DOING PHASE III OF
THE INHERITED RETINAL DISEASE
SUBJECTS 28% GOT WORSE OVER THE
COURSE OF ONE YEAR.
WHY IS THAT IMPORTANT?
WHEN WE PROPOSED OUR TRIAL
DESIGN TO THE FDA AND WE ASKED
TO DO THE CROSSOVER AND SAID WE
NEEDED A YEAR IF WE WERE ABLE TO
SHOW THE CHANGE LEVELS IN NORMAL
PEOPLE WERE ZERO AND THEY COULD
PAST AT THE LOWEST LEVEL AND
THEN A YEAR LATER COULD PASS AT
THE SAME AND THOSE IN BLUE FIVE
GOT WORSE IN ONE YEAR AND TWO
GOT WORSE AND IF WE HAD THE DATA
IT WOULD HELP US CROSS OVER MORE
QUICKLY BUT DID SHOW THE TEST
COULD TRACK PERFORMANCE IN
PEOPLE WITH AN INHERITED RETINAL
DYSTROPHY OVER TIME.
AS I SAID THE GROUPS WERE
STRATIFIED FOR PERFORMANCE AT
THE BASELINE AND THE PEOPLE
WOULD GOT THE INTERVENTION
IMPROVED BY SEVERAL HEIGHT LEVEL
WHEREAS THE PEOPLE IN THE
CONTROL GROUP MAY BE APPROVED A
LITTLE BIT MAYBE HAD LEARNING
EFFECT BUT DIDN'T IMPROVE MY
MUCH AND MOST WERE ABLE TO
CROSSOVER AT THE END OF THE YEAR
AND RECAPITULATED THE DATA FROM
THE ORIGINAL INTERVENTION GROUP
AND ALL IMPROVED.
I'LL JUST SAY -- I'M OVER TIME.
WE DID HAVE OVER 4,000 VID
VIDEOTAPES BY THE TIME THE
PROGRAM WAS DONE THOUGH THERE
WERE ONLY 43 PATIENTS IN THE
PHASE III STUDY.
THE FDA CONTINUOUSLY EMPHASIZED
WE NEEDED TO EXPLAIN THE
MEANINGFULNESS ON IMPROVING ON
THE NOVEL END POINT.
WE CONTENDED THAT IF YOU
IMPROVED BY ONE LIGHT LEVEL IT
WOULD MAKE A DIFFERENCE.
THE FDA WANTED TO SEE AT LEAST
TWO LIGHT LEVELS AND AS I SHOWED
YOU FORTUNATELY THE AVERAGE
IMPROVEMENT WAS TO LIGHT LEVELS.
NOTE THIS TEST HAS A CEILING
EFFECT.
YOU CAN'T GET BETTER THAN ONE
LOOK AND IF YOU ANSWER AS MANY
AS THE CHILDREN DID ABLE TO PASS
AT 10 AND 4 IF THEY ENTERED AT 4
LUX WE'D ONLY SEE ONE LIGHT
LEVEL IMPROVEMENT.
OKAY IF WE COMPARE THEM THE
UNDERLYING PATHOPHYSIOLOGY WAS
EXQUISITELY WELL UNDERSTOOD.
WE HAD PROOF OF CONCEPT IN A
LARGE ANIMAL MODEL AND I THINK
THAT'S IMPORTANT.
THESE ARE OUTBRED STRENGTHS OF
ANIMALS NOT INBRED MICE.
FOR BOTH THERE WAS EITHER ZERO
EXPERIENCE WITH THAT ROUTE OF
ADMINISTRATION OF AAV OR IN THE
CASE OF SUBRETINAL
ADMINISTRATION ONE ADULT IN THE
U.K. WHEN WE STARTED THIS WORK.
AFTER THAT THEY DIVERGED
PROBLEMS FOR THE CHOICE OF END
POINTS WAS CLEAR FOR HEMOPHILIA
AND HAD TO BE IN THE
IMMUNOTHERAPY AND RESPONSES WERE
NOT PREDICTED WITH SYSTEMIC
ADMINISTRATION OF AAV BUT WITH
INHERITED RETINAL DYSTROPHY AND
GO IN WITH A SMALL DOSE IN A
PRIVILEGED SITE YOU GET A FREE
PASS AS LONG AS YOU DON'T GO TOO
HIGH ON THE DOSE.
OKAY.
I THINK I'M GOING TO HAVE TO
CONCLUDE HERE BY ACKNOWLEDGING
THE MANY PEOPLE BECAUSE I'M OVER
TIME.
THE MANY PEOPLE WHO WERE
INVOLVED BOTH IN THE HEMOPHILIA
B STUDY DONE AT CHOP AND THEN
PFIZER AND IN THE TRIAL STUDIES
DONE AT CHOC AND UNIVERSITY OF
IOWA AND SPARTAN.
THANK YOU FOR YOUR ATTENTION.
I'M SORRY FOR GOING OVER TIME.
>> THAT WAS A LOT OF WORK.
MY QUESTION IS IN TERMS OF WHAT
YOU KNOW ABOUT THE IMMUNE
RESPONSE IN AAV AND WHAT YOU
LEARNED DO YOU THINK IT'S FEW
TILE TO THINK ABOUT REDOSING?
>> NO, I DON'T THINK IT'S FUTILE
TO THINK RE-DOSING.
WE HAVE SUCCESSFULLY RE-DOSED
UNNON-HUMAN PRIMATES.
THAT'S A POSSIBILITY.
FOR SYSTEMIC ADMINISTRATION YOU
DO HAVE THESE HIGH TIDER
ANTIBODIES BUT THERE'S PROMISING
DATA TO TRY TO GET RID OF THAT
AND THEN YOU'LL HAVE TO QUELL
THE T CELL RESPONSE WHICH IS
GOING TO BE BRISKER THAN WHAT
WE'VE SEEN FROM NATURAL EXPOSURE
TO AAV.
>> KATHY, I WONDER IF YOU CAN
STEP BACK AND THINK OF YOUR
INTERACTIONS WITH THE FDA.
AND WHAT THEY'D BE TODAY IF YOU
BROUGHT THE TWO PROGRAMS
FORWARD.
DO YOU THINK THERE WOULD BE THE
SAME NUMBERS OF GROUPS IN
CONCERNS GIVEN SAY SOMEBODY ELSE
ALREADY DEVELOPED TWO DRUGS.
>> NO.
THE EARLY BIRD GETS THE WORM AND
THE SECOND MOUSE GETS THE
CHEESE.
WE WERE THE FIRST MOUSE AND OUR
NECK KEPT GETTING SNAPPED IN THE
TRAP AND YOU UNCOVER THE PROBLEM
AND YOU'RE ON HOLD UNTIL IT'S
SOLVED.
THANKS FOR ASKING THE QUESTION.
OF COURSE THERE WERE NO GUIDANCE
DOCUMENTS WHEN WE WERE DOING
THIS WORK.
NOW, THERE'S GUIDANCE DOCUMENTS
SOMETIMES EVERY MISTAKE TRICK TO
DEVELOP THE PROGRAM.
AS ALL OF US GAIN EXPERIENCE
EVERYTHING BECOMES MORE
RESOURCEFUL.
>> NOW FOR OUR FINAL SPEAKER
DR. WENDY CHUNG JOINING US
ONLINE.
WE CAN SEE YOU NOW.
WE'LL HEAR ABOUT ADVANCES IN
GENOMIC MEDICINE.
>> I'LL THINK ABOUT THIS WITH
EPILEPSY IN MIND AND START WITH
AUTISM THOUGH IT WAS FREQUENTLY
ASSOCIATED WITH EPILEPSY AND
SAME IS TRUE WHEN I THINK OF
AUTISM BE AN UMBRELLA DIAGNOSIS
WITH FEATURES DEPENDING ON THE
UNDERLYING ETIOLOGY.
MANY KNOW ME AS SOMEONE WHO'S
THOUGHT ABOUT THIS FOR A WHILE
AND WITHIN AUTISM THERE'S
EXTREME HETEROGENEITY AND HARD
TO UNDERSTAND THAT PROGNOSIS
SUPPORT WHAT CAN BE TAILORED FOR
THE INDIVIDUAL REQUIRED
STRATIFICATION ESPECIALLY FOR
YOUNG CHILDREN WHERE THE
PROGNOSIS IS NOT CLEAR.
IN DOING THAT, I WILL TALK ABOUT
STARK A NATIONAL AUTISM RESEARCH
COHORT AND THIS HAS INDIVIDUALS
WITH AUTISM AND OFFERED BUT NOT
REQUIRED TO PARTICIPATE IN THE
GENOMIC STUDIES NOW INCLUDING
WHOLE GENOME SEQUENCES WITH DATA
FREELY AVAILABLE FOR ANY WHO
WOULD LIKE TO USE IT WITH THE
STRATIFICATION BY UNDERLYING
GENETIC ETIOLOGY.
WITH THAT WE'RE STUDYING THE
PHENOTYPES AND WHAT'S IMPORTANT
IT TO RETURN GOOD MORNING
RESULTS WHEN WE IDENTIFY A
MONOGENIC ETIOLOGY WITH 10% OF
THE COHORTS AND HAVE A
CONTINUATION ON THE JOURNEY FOR
INDIVIDUALS WITH A SISTER STUDY
CALLED SIMON SEARCH LIGHT.
I SHOULD SAY SPARK IS DEFINED BY
THE PHENOTYPE DRIVEN WITH A
PROFESSION DIAGNOSIS OF AUTISM
WE CONFIRMED BY RECORD REVIEW TO
BE VALIDATED IN TERMS OF WHAT IS
SELF-REPORTED.
SIMON SEARCH LIGHT IS DEFINED BY
GENE OR COPY NUMBER VARIANT.
AS WE INCLUDED THIS FOR SPARK
IT'S A U.S.-BASED COHORT
ANCHORED ACROSS 31 CLINICAL
SITES MANY OF WHICH MAY
REPRESENT YOUR SITES.
THE DATA IS FREELY ABLE AND USE
PARTICIPANTS IN THEIR RESEARCH
STUDIES.
AS WE'VE BEEN RETURNING THE
INFORMATION THESE ARE GENETIC
RESULTS BY MONTH WE'VE BEEN
RETURNING OVER TIME.
SEE A LARGE NUMBER OF
INDIVIDUALS ESPECIALLY RECENTLY
GETTING GENETIC DIAGNOSES WITH
THIS AND STARTED TO AS A
COMMUNITY UNDERSTAND BETTER THE
GENES INVOLVED AND I'LL
HIGHLIGHT THERE ARE PARTICULAR
GENES PROBABLY BOTH MORE RELATED
TO EPILEPSY SPECIFICALLY THOSE
INVOLVED IN NEUROTRANSMISSION,
CHANNELOPATHIIES I'LL COME BACK
TO IN A SECOND AND SOME EASIER
THAN OTHERS TO THINK ABOUT
THERAPEUTIC TREATMENT.
MANY OF THESE WE RECOGNIZE RIGHT
NOW DUE TO MUTATIONS IN SOME
CASES AND I SAY THIS BASED ON
THE THERAPY IN SOME CASES LOSS
OF FUNCTIONAL ALLELES WITH
INSUFFICIENCY AND OTHERS WITH
MISSENT ALLELES WHY MAY
REPRESENT MISFUNCTION BUT NOT
LOSS OF FUNCTION AND THE WINDOW
OF OPPORTUNITY FOR TREATMENT
BECOMES NOT ONLY GENE SPECIFIC
BUT IN SOME CASES SUB GENE
SPECIFIC WITH DIFFERENT
MOLECULAR MECHANISMS BASED ON
THE UNDERLYING ALLELE.
AS I ALLUDED TO, INDIVIDUALS
GENETICALLY DIAGNOSED ARE
INVITED TO SIMONS SEARCH LIGHT
AND SOME BASED ON GENETIC
DIAGNOSIS LARGELY FROM CLINICAL
TESTING AND IT'S AN
INTERNATIONAL ONLINE REGISTRY TO
ANY QUALIFIED INVESTIGATOR.
FOR THOSE IN SIMONS SEARCH LIGHT
THERE'S APPROXIMATELY 170
CONDITIONS MORE NOW AND FOR
THOSE I KNOW THIS IS SMALL BUT
YOU MAY RECOGNIZE YOUR FAVORITE
GENE WITHIN THIS AND MANY OF
THESE GENES ARE GENES THAT
REPRESENT EPILEPSY CONDITIONS AS
WELL SO QUITE A BIT OF OVERLAP.
WE TRADE TO MAKE THIS AS
ACCESSIBLE AS POSSIBLE BY
INCLUDING MULTIPLE LANGUAGES AND
HAVE THE ABILITY TO SPEAK WITH A
GENETIC COUNSELORS AND
COLLECTION INFORMATION AND WHEN
POSSIBLE BIO SPECIMENS IN SOME
CASES IPS LINES FREELY ABLE TO
RESEARCHERS TO POWER SOME
PRECLINICAL STUDIES.
I'LL SHIFT NOW TO THIS CONDITION
I'VE STUDIED A WHILE IT'S LIKE
OTHERS ALSO ASSOCIATED WITH
EPILEPSY IN ABOUT 42%
DEVELOPMENT AND DELAY AND AUTISM
AND IN A QUARTER AND MORE
COMPLICATED IN THAT IT'S
NEURODEGENERATIVE.
WITH THAT WE ALSO HAVE VISUAL
IMPAIRMENT AND ADDITIONAL
FACTORS INCLUDE STRABISMUS AND
CATARACT.
THIS IS ALSO ASSOCIATED WITH
PERIPHERAL NEUROPATHY AND
SPASTICITY AND AMBULATION AND AS
THE CHALLENGING BECAUSE IT CAN
BE LETHAL BEFORE 5 YEARS OF AGE
IN SEVERELY IMPAIRED
INDIVIDUALS.
IT'S NEURODEGENERATIVE AND IF
YOU FOCUS ON THE CEREBELLUM
THOUGH WE CAN SEE THIS FOR
MULTIPLE PARTS OF THE BRAIN THE
REMARKABLE ATROPHY OVER A 2 YEAR
PERIOD IN THE CEREBELLUM AND
WE'VE DONE AUTOPSIES IN A FEW
INDIVIDU
INDIVIDUALS BEING ABLE TO SEE
NEURONAL CELL TYPES AND THE
CEREBELLUM MOST SEVERELY
IMPAIRED.
THE GENE IS A MOLECULAR
MECHANISM AND IT'S A MOLECULAR
MOTOR A HOMODIMER AND THE FEET
ARE THE MOTOR DOMAIN.
THIS IS THE END TERMINUS AND
IT'S TRANSPORTING CARGO ALONG
THE MICROTUBULE.
THIS HOMO DIMER IS IMPORTANT IN
THE SENSE THAT MOST MUTATION
HETEROZYGOUS AND ACT THROUGH A
DOMINANT NEGATIVE EFFECT.
THAT IS MUTATIONS LARGELY MISSED
SENSED MUTATIONS LARGELY IN THE
FEET OR THE MOTOR DOMAIN EITHER
MAKING CONTACT WITH THE MICROAND
THEY ACT TO POISON THE TOTALITY
OF THAT PROTEIN.
IN THEORY THERE'S AGAIN A SENSE
OF URGENCY MORE SO FOR ME FOR
THIS CONDITION THAN OTHERS I
WORK ON DUE TO THE DEGENERATIVE
NATURE AND FATALITIES ASSOCIATED
WITH THIS.
SO THIS WAS A CONDITION WE
DECIDED TO BE SLIGHTLY MORE
AGGRESSIVE WITH IN TERMS OF THE
HANDOFF TREATMENT.
HERE'S ONE OF THE CHALLENGES.
AND THIS IS A MUTATION IN THE
GENE AND STICK ON THE TOP WITH
THE LEFT PART THE GRAY NOW BLOWN
UP HERE OF THE MOTOR DOMAIN AND
EACH OF THE CIRCLES REPRESENTS A
DIFFERENT PATIENT.
AND HAVE RECURRENT MUTATIONS AND
CERTAIN POSITIONS.
THESE ARE UNRELATED INDIVIDUALS
AND THESE ARE MOSTLY DE NOVO
MUTATIONS AND YOU CAN SEE THE
LAUNCH NUMBER OF INDIVIDUALS SO
FAR ARE SINGLE INDIVIDUALS WITH
THE INDIVIDUAL ALLELES.
I'VE ALSO SHOWN THOUGH I HAVEN'T
TALKED ABOUT IT THERE'S FEW
RECESSIVE CASES AND I'M NOT
GOING TO SPEAK ABOUT IN A FEW
HETEROZYGOUS CASES ASSOCIATED
WITH A MILDER PHENOTYPE.
THE CHALLENGE AS WE WERE
THINKING ABOUT BOTH PROGNOSIS
FOR FAMILIES WHO GET THE NEW
DIAGNOSIS AS WELL AS HOW
AGGRESSIVE TO BE WITH TREATMENT
IS THAT THERE'S SUCH
HETEROGENEITY AND IN PARTICULAR
FOR A PEDIATRIC CONDITION
ASSOCIATED BOTH WITH A
DEVELOPMENT ASPECT ON THE UP
SLOPE AND DEGENERATIVE ASPECT ON
THE DOWN SLOPE AND THE EARLY
DAYS WHEN YOU'RE LARGELY GETTING
ACROSS SECTIONAL DATA UNTIL YOU
HAVE ENOUGH TIME TO GET
LONGITUDINAL DATA IT'S VERY
CHALLENGING TO UNDERSTAND THE
SEVERITY OF EACH OF THE ALLELES
AND WITH THE HETEROGENEITY TO
THINK ABOUT PROGNOSIS.
IT'S BEEN QUITE CHALLENGING IN
THAT WAY.
WE HAVE BEEN ABLE TO HAVE AN IN
VITRO MOLECULAR PHENOTYPE TO
BEING ABLE TO LOOK AT THE BIO
PHYSICAL PROPERTIES OF THE
MOTOR.
WHEN IT GETS STALLED AND FALLS
OFF THE MICROTUBULE AND HOW MUCH
IT CAN CARRY IN THE AXON AND
BEING ABLE TO USE THIS AS A
QUANTITATIVE PHENOTYPE WHERE WE
CAN MAKE A CORRELATION BETWEEN
MOLECULAR PHENOTYPE AND CLINICAL
PHENOTYPE.
THOUGH IT'S AGAIN NOT PERFECT
FOR ALL THE REASONS I SAID WITH
THE CLINICAL PHENOTYPE, THAT HAS
HELPED US IN TERMS OF SEVERITY
ESPECIALLY WITH THE EXTREMES WE
SEE.
WITH THAT WE'VE BEEN ABLE TO
DEVELOP HEURISTIC SEVERITY SCORE
AND NOW THAT WE HAVE IN SOME
INDIVIDUALS NOW THREE YEARS OF
LONGITUDINAL DATA STILL LIMITED
BUT ABLE TO MAKE THE
CORRELATIONS.
IN DOING SO TRYING TO THINK
ABOUT TARGETS FOR A TREATMENT
AND THIS WORK IS NOW IN
COLLABORATION WITH STAN COOK AND
THE TEAM AND THE STRATEGY IN
THIS CASE IS TO USE AN ALLELE
SPECIFIC ASO FOR RNA H1
DEGRADATION AND TRYING TO LEAVE
A SITUATION OF A PROTEIN THAT IS
FUNCTIONAL.
THE STRATEGY IN THIS CASE IS NOT
TO TARGET THE MUTANTS ALLELE PER
SE IN THE SENSE OF THE ACTUAL
MUTATION OR THE NUCLEOTIDE THAT
IS PROBLEMATIC BUT INSTEAD TO
TAKE UP POLYMORPHISM THAT IS
STILL WITHIN THE GENE AND INSIST
ON THE SAME STRAND AS THE
TRANSCRIPT BUT USE IT, I CALL A
HANDLE, BUT USE IT TO GRAB THE
GENE AND LEAD TO ALLELE SPECIFIC
DEGRADATION.
SO FAR WE'VE TREATED -- I'VE
TREATED ONE PATIENT.
THE STARTED AT 9 -- 8 YEARS OLD
AND WHILE THE TREATMENT HAS HAD
SUCCESS IT'S HAD SOME
LIMITATIONS AS WELL.
THIS IS SHOWING HER LONGITUDINAL
DATA OVER TIME AND THIS IS
INTRATHECAL INJECTION OF THE
ASO.
WE'VE HAD SEVERAL OUTCOME
MEASURES AND KNOWING THIS WAS
ASSOCIATED WITH EPILEPSY IN HER
CASE WE'VE LOOKED AT THE SEIZURE
DIARY FROM HER PARENTS AND
THERE'S BEEN EEGs BEING ABLE TO
LOOK AT THE NUMBER OF REPORTED
SEIZURES, THE LENGTH AND NUMBER
OF SEIZURES AND BECAUSE OF THE
SPASTICITY CAN BE ASSOCIATED
WITH FALLS AND BONE FRACTURES.
SO LOOKING AT THIS AND WITH THE
DIARIES HER PARENTS AND
CAREGIVERS LOOK LOOKING AT THE
BASELINE DATA WITH THE RUN IN
AND WITH INCREASING DOSE
ADMINISTRATION BEING ABLE TO SEE
THE ADDITIONAL TIME POINTS THEN
YOU CAN SEE A DECREASE IN THE
NUMBER OF SEIZURES.
THE LONGEST SEIZURES AND
PROGRESS INCREASED HER MOBILITY.
I WON'T GO IN MORE DETAIL BUT
ALSO LEARNING AND THIS WAS AN N
OF 1 TREATMENT.
ALSO THIS WERE MANY THINGS WE
LEARNED THAT DIDN'T NECESSARY
MOVE.
WE HAD INCLUDED A SIX-MINUTE
WALK TEST WHICH DESPITE
INCREASED AMBULATION DIDN'T
SIGNIFICANTLY CHANGE BUT THERE
WERE OTHER THINGS I DIDN'T KNOW
WOULD CHANGE LIKE COMPLEXITY OF
SPEECH, FINE MOTOR SKILLS AND
OTHER FACTORS BY VIDEO REVIEW
CLEARLY HAVE IMPROVED OVER TIME.
AND WITH THIS NOW A SECOND
PATIENT IS ACTUALLY BEING DOSED
WITH THE SAME ASO.
SO WITH THIS AND THIS IS THE
FINAL CHAPTER, KNOWING WHAT WE
KNOW ABOUT THESE RARE CONDITIONS
AND THAT AS THE A WINDOW OF
TREATABILITY IN THAT WINDOW IS
PROBABLY BEST IF EARLY BUT
IMPORTANT TO DISTINGUISH WHO
DOES AND DOESN'T NEED TREATMENT
WE STARTED IN NEW YORK CITY A
GENOMIC NEWBORN SCREENING
PROGRAM CALLED GUARDIAN GENOMIC
SCREENING AGAINST ALL DISEASES
AND FROM THE EXPERIENCE IN
SPINAL MUSCULAR ATROPHY AND A
PILOT STUDY IN NEW YORK WITH
NEWBORN SCREENING QUITE
SUCCESSFUL AND HAS NOW BEEN THE
BASIS FOR WHICH WE ADDED THAT TO
THE UNIVERSAL SCREENING PANEL.
SINCE THEN, WE'VE DONE PILOT
STUDIES WITH DUCHENNE MUSCULAR
DYSTROPHY AND SOME ARGUE THE
MOST AMBITIOUS AND DOING WHOLE
GENOME SEQUENCING ON THE NEWBORN
BLOOD SPOT IN COLLABORATION WITH
THE NEW YORK STATE DEPARTMENT OF
HEALTH.
WHILE WE DO SEQUENCING ON THE
WHOLE GENOME WE ONLY LOOK AT A
TARGETED SET OF GENES THIS IS
ALL A RESEARCH INCENTED STUDY IN
THE NEW YORK PRESBYTERIAN SYSTEM
FOCUSSED ON 238 GENES.
MOST OF WHICH ARE EITHER
OVERLAPPING FOR A QUALITY
CONTROL POINT OF VIEW WITH
TRADITIONAL NEWBORN SCREENING
GENES OR WITH GENES THERE'S
IMMEDIATELY FDA APPROVED
TREATMENT.
WITHIN THIS I WON'T GO TOO MUCH
IN THE DETAIL BUT FOCUS ON THE
GROUP 2 CONDITION.
I DESCRIBED THE CORE CONDITIONS
AND EVERYBODY WHO AGREES THE
STUDY DOES THAT AND AT THE GROUP
2 WERE AT THE REQUEST OF PARENTS
SAYING WE'RE ALSO INTERESTED IN
CONDITIONS RELATED TO EPILEPSY
OR SEIZURES BECAUSE THERE'S
SOMETHING WE MIGHT BE ABLE TO DO
WITH EARLY RECOGNITION AND
TREATMENT OF THE SEIZURES AND
THOSE CONDITIONS MAY STILL HAVE
RESIDUAL NEURAL DEVELOPMENT OR
COGNITIVE ISSUES AND THERE WAS
NOT 100% ANONYMITY IN THE
INTEREST IN WANTING THAT
INFORMATION SO WE THAT AN
OPTIO
OPTIONAL MODULE IN THE STUDY AND
WHEN APPROACHED APPROXIMATELY
75% OF PARENTS DESIRE AND
CONSENT TO DOING THE STUDY AND
IMPORTANTLY FOR THE GROUP 2
CONDITIONS OPTIONAL OVER ALL 92%
OF PARENTS OF THE VAST MAJORITY
OPT FOR CONDITIONS THOUGH THE
PERCENTAGE IS SLIGHTLY LESS FOR
THOSE WHO SPEAK SPANISH AND
CONSENT TO THE STUDY IN SPANISH.
THE STUDY IS INCREDIBLY HET
HETEROGENOUS FROM AN ETHNICITY
POINT OF VIEW AND WE DON'T HAVE
MUCH BIAS IN THE ENROLLMENT.
THESE ARE THE RESULTS OF WHAT
WAS RETURNED.
I POINT OUT THE GROUP 2 ARE LESS
FREQUENT THAN THE GROUP 1.
THERE ARE FALSE POSITIVES I'LL
HIGHLIGHT ON THE NEXT SLIDE AND
TRUE POSITIVES AND SOME
PRESUMPTIVE POSITIVES BECAUSE
THE CHILDREN HAVE NOT YET HAD
SYMPTOMS SO STILL RELATIVELY
EARLY DAYS.
FOR THIS GROUP I'LL POINT OUT
THIS ASCERTAINMENT IS
POPULATION-BASED ASCERTAINMENT
AND WHAT IS INTERESTING IN
NEWBORN SCREENING WHEN WE DO
THIS IS REALIZE THE FREQUENCY OF
THE CONDITIONS MAY NOT BE WHAT
WE CLINICALLY ASCERTAIN.
THE TOP ROW IS THE MOST COMMON
WE SEE WITHIN GROUP 2 FOR SCN1A
AND ONLY SEQUENCE THE BABY TO
START AND WHEN WE SEQUENCE THE
PARENTS IN THE CONNATE TRY WE
FIND THEY'RE OFTEN INHERITED
FROM ASYMPTOMATIC PARENTS AND
MANY OF WHAT I CALL FALSE
POSITIVES ARE INHERITED WITH
ASYMPTOMATIC PARENTS WITH NO
FAMILY HISTORY OF EPILEPSY.
AND SCN1A IS ASSOCIATED WITH A
BROAD PHENOTYPE AND THAT COULD
EXPLAIN WHY IT IS BUT DOES GET
COMPLICATED.
YOU CAN IMAGINE WHEN TRYING TO
EXPLAIN THIS TO PARENTS.
ALSO NOTABLY IN TERMS OF
TREATMENT, THIS IS MORE COMMON
AND FOR THIS GROUP I'LL POINT
OUT WE NOW IDENTIFIED EVEN TO
GROUP UPDATE THREE LITTLE GIRLS
WHAT ARE EXPECTED TO BE RETT
SYNDROME AND PRE OR ASYMPTOMATIC
AT THIS STAGE THOUGH BY
FOLLOWING CLOSELY WE CAN ALREADY
START TO SEE DECLINES OVER TIME.
SO WITH THIS WE IDENTIFIED
INDIVIDU
INDIVIDUALS AND THIS IS CDKL5
DIAGNOSED THROUGH GUARDIAN AND
USING THE INFORMATION FOR
TREATMENT.
AND THE REASON I EMPHASIZE ALL
THIS IS THIS COULD AND WAS
INTENDED TO OPEN UP THE
POSSIBILITY OF EARLY DIAGNOSIS
AND POTENTIALLY THERAPIES WE'RE
TALKING ABOUT AT THE CONFERENCE.
WITH THIS WE'RE TRYING TO BUILD
THE WHOLE INFRASTRUCTURE.
I WON'T GO INTO THIS GIVEN THE
INTEREST OF TIME AND SIMPLY TO
SAY WE HOPE WE'RE IMPROVING
EQUITY IN A POPULATION BASED WAY
IMPROVING ACCESS TO THE
DIAGNOSIS WHICH HOPEFULLY OPENS
OPPORTUNITIES FOR TREATMENT AND
THANK EVERYONE WHO HAS BEEN A
PART OF THIS AND LEAVE TIME FOR
QUESTIONS IN THE PANEL.
>> THANKS, SO MUCH, WENDY.
DOES ANYBODY HAVE QUESTIONS TO
START FOR WENDY IF YOU CAN USE
THE MIC THAT WOULD BE GREAT.
LIZ AND FLORIAN AND KATHY,
THAT'D BE GREAT.
>> HI, WENDY.
CAN YOU HEAR ME?
>> I CAN.
>> GREAT.
I WAS CURIOUS ABOUT YOUR
APPROACH FOR KIP 1A USING A
COMMON SNIP OR A SNAP RATHER
THAN THE ACTUAL MUTANT ALLELE
WHICH WHICH I THINK IS A GREAT
APPROACH.
I'M CURIOUS HOW COMMON IS THAT
SNIP AND WHAT PROPORTION OF
PATIENTS COULD YOU USE IT FOR DO
YOU THINK WITH KIP 1A WITHOUT
DEVELOP THERAPY FOR EVERY
PATIENT?
>> THE BOTTOM LINE IS ABOUT 10%.
IN TERMS OF LOOKING AT THE
VARIATION WITH THE GENE ASSUMING
ENOUGH VARIANCE COULD BE
TARGETED A LIBRARY BETWEEN 5 AND
10ASOs BUT DON'T THINK IT WILL
BE LESS THAN FIVE BUT COULD BE
SLIGHTLY MORE THAN 10.
I'M NOT SURE HOW TARGETABLE THE
COMMON ASOs WILL BE AND WE HAVE
SOME EVIDENCE THE ONES WE'D LIKE
TO TAR GET WON'T BE ENOUGH.
>> WAS THE STRATEGY TO TREAT A
GREATER NUMBER OF PATIENTS?
>> A LITTLE BIT OF BOTH.
THE PROCESS FROM THE SCREENING
WHICH ONES ARE MOST SELECTIVE
AND THIS IS THE CLEAR WINNER IN
HER PARTICULAR CASE AND AS A
DEMONSTRATION WITH FIRST IN WE
DIDN'T WORRY NEARLY AS MUCH
ABOUT THE ABILITY TO TARGET
EVERYONE.
WE WERE FIRST TRYING TO FIGURE
OUT COULD WE GET THIS TO WORK
AND DID IT BASED ON ALLELE
SPECIFICITY.
>> AS WE KICK OFF OUR PANEL
DISCUSSION WITH OUR SPEAKERS I
WANTED TO THANK OUR SPEAKERS FOR
THEIR WONDERFUL ILLUSTRATIVE
EXAMPLE AND FOR HIGHLIGHTING HOW
MUCH IS THERE TO SHARE AND HOW
MUCH YOU HAVE SHARED BOTH IN
TERMS OF POTENTIAL RISKS OF
THERAPIES WHICH CAN BE SHARED
WITHIN PLATFORMS BUT EVEN ACROSS
PLATFORMS AND ALSO POTENTIAL
BENEFITS IN HOW WE MEASURE THEM
AND TO GET TO THE CRUX OF ALL
YOUR TALKS, EVERYTHING IS A RISK
WHETHER FOR A TRIAL YOU'VE ALL
OUTLINED HOW TO LOOK FORWARD AND
DEAL WITH THE RISKS AS THEY
UNFOLD UNEXPECTEDLY AND ALSO HOW
TO THINK ABOUT POTENTIAL
BENEFITS AND WHAT OUTCOMES ARE
MOST IMPORTANT.
SO, I WON'T TAKE MORE TIME AND
LEAVE IT FOR MORE QUESTIONS BUT
I WANT TO ACKNOWLEDGE HOW
POWERFUL IT WAS TO HEAR EXAMPLES
AND THE BASIC POINTS WERE SO
WELL COVERED.
>> LET ME ECHO TO THE ORGANIZERS
WHAT AN AVENGER LEVEL OF
ACHIEVEMENT.
I'M GOING TO FOLLOW UP ON WHAT
YOU SAID YOU SPOKE ABOUT THE
ANTICIPATED IMMUNE RESPONSE.
THE CONDITION REGIMENT DEPENDENT
AND YOU MENTIONED LEG WEAKNESS
THAT ULTIMATELY CREATED A
TWO-YEAR CLINICAL HOLD.
AS ONE THINK ABOUT CHILDHOOD
EPILEPSIES AN BENEFIT RISK, A
HOW DO WE DEAL WITH THE FACT AS
BEST I CAN TELL THEY WERE NOT
PREDICTIVE OF LONG LEVEL
EXPERIMENT.
WHAT ADVISE WOULD YOU GIVE TO
THE GENETICISTS OR THOSE WRITING
THE PROFILE, HOW SHOULD WE DEAL
WITH THE FACT THERE MAY BE AN
ASE BUT WE DON'T KNOW WHAT
THEY'RE GOING TO BE?
>> WELL, I THINK EVERYONE IN THE
ROOM UNDERSTANDS THE FDA DOESN'T
LICENSE DRUGS BASED ON ANIMAL
STUDY ALONE BECAUSE IN CLINICAL
INVESTIGATION YOU FIND ASSAYS
THAT WERE NOT PREDICTED BY
ANIMAL STUDY AND I THINK THE
NUMBER IS SOMETHING LIKE ANIMAL
STUDIES ACCURATELY PREDICT ABOUT
70% OF ADVERSE EVENTS SEEN IN
HUMANS.
SO, WHAT CAN YOU DO OTHER THAN
ACKNOWLEDGE THAT IN THE INFORMED
CONSENT AND THEN IT BECOMES A
CHOICE OF THE FAMILIES IF
THEY'RE WILLING TO TAKE THE
RISK.
>> LET ME ADD TO THAT.
I DO THINK IT REQUIRES A LOT OF
COMMUNICATION WITH FAMILIES UP
FRONT.
AND THERE'S A REASON THERE'S
STAGGERED ENROLLMENT AND THIS IS
A HUGE PART OF THAT AND IT'S
VERY HARD FOR FAMILIES TO WRAP
THEIR HEAD AROUND WHY IS IT WE
HAVE TO WAIT UNTIL THE DSMB
MEETS AND IT'S AN INTEGRAL PART
OF OUR LANDSCAPE AND TO BE UP
FRONT COMMUNICATING ABOUT THIS
AND EXPLAIN THIS IS HOW WE LEARN
TOGETHER AND I THINK WE'RE IN A
DIFFERENT STAGE WHERE WE HAVE
MUCH MORE AWARENESS OF THE
IMMUNE RESPONSES COMPARED TO
PIONEERING WORK KATHY DID.
I THINK WE ARE IN A BETTER
POSITION TO REACT AND TRAIN AND
EDUCATE THE NEXT GENERATION OF
PHYSICIANS SO I THINK IT'S QUITE
ENCOURAGING.
>> YEAH, I THINK FOR THE ASOs WE
DON'T KNOW.
THERE ARE SOME THINGS BUT THE
ASO THAT PREDICTED WHAT WAS 10
TIMES THE DOSE IN THE MONKEY AND
THERE WAS NO SIGN OF IT.
IT'S CLEARLY A HUMAN AFFECT AND
YOU'RE NOT GOING TO BE ABLE TO
DO THAT WITHOUT GOING TO CLINIC.
ONE THING WE DID AT THE SITE AT
THE REQUEST OF THE FDA WAS THEY
WANTED TO MAKE SURE EVERYBODY
HAD A CHANCE TO BENEFIT AND SO
THE DOSE ACCELERATION WAS
PROBABLY TOO FAST AND IF THEY
HAD DONE IT AS AN EXTENDING DOSE
IN COHORT OPPOSED TO WITHIN
PATIENTS PROBABLY THEY WOULD
HAVE AVOIDED AND STARTED TO SEE
IT BUT START TO ELEVATE THE
PROTEINS AND WOULD HAVE HAD TO
BACK OFF.
I THINK IT'S A WARNING FOR ASOs
WE SHOULD DO AN ACRENDS -- AS
ASCENDING DOSE PROTOCOL.
ONE HAD IT.
THEY ABOUT BEEN GETTING
INCREASED DOSE AND DIDN'T
UNDERSTAND IT WAS A TIME RELATED
EVENT BUT NOW IN THE END WE
UNDERSTAND IT'S A DOSE RELATED
EVENT.
>> SO WHAT I'M OBSERVING WITH
THE CLINICAL TRIALS AND THERE'S
DATA COLLECTED WHICH IS
UNMATCHED COMPARED TO WHAT IS IN
RESEARCH.
AND THE PROBLEM IS THE DATA IS
NOT ACCESSIBLE BEYOND THE
CLINICAL TRIALS AND MANY WOULD
LOVE TO LEARN MORE ABOUT THE
DISEASE AND AS MENTIONED YOU
LEARN THROUGHOUT THE CLINICAL
TRIALS SOMETHING ABOUT THE
DISEASE.
WE'VE ALSO LOOKED BACK ON THE
TRIAL TO WHICH DEGREE THE DATA
WAS PUB LUCKILY ACCESSIBLE FOR
RESEARCH AND SECONDARILY WHICH
DEGREE WHERE AFTER THE TRIAL
LONG-TERM THERE WAS A
STANDARDIZED WAY FOR MORE
BENEFITS.
>> OKAY.
SO I THINK FOR MOST THE EARLY
GENE THERAPY TRIALS THE
REGULATORY AGENCIES HAVE
RECOMMENDED LONG-TERM FOLLOW-UP.
THERE'S A GUIDANCE FOR AAV
VECTORS IT SHOULD BE FIVE YEARS
FOR INTEGRATING VECTORS IT'S
LONGER THAN THAT.
BUT DESPITE THAT WELL DEFINED
GUIDANCE DOCUMENT THAT WHEN IT'S
APPROVED THEY ASK US TO KEEP A
SAFETY REGISTRY OF THE FIRST 500
PATIENTS WHO GOT THE TREATMENT
TO FOLLOW OUR PHASE III PATIENTS
FOR 10 YEARS.
WE HAVE PERIODICALLY PUBLISHED
THAT OVER TIME.
I THINK THE LAST PUBLICATION WAS
FIVE YEARS AND THERE'S AN
ABSTRACT NOW THAT GIVES DATA OUT
TO EIGHT YEARS BUT I MEAN I
THINK IT'S GOOD FOR THE FIELD TO
THE EXTENT THAT THIS DATA CAN BE
PUBLISHED IN THE MEDICAL
LITERATURE IT'S A GOOD THING
UNTIL THERE'S MORE CONFIDENCE
ABOUT THE SAFETY OF GENE
THERAPY.
I THINK THE RISK BENEFIT RATIO
WILL REMAIN A CHALLENGING TOPIC.
>> AND TO ADD TO THIS I THINK
IT'S RIGHT YOU BROUGHT UP THE
PATIENT'S PERSPECTIVE BECAUSE
IT'S QUITE POWERFUL IN THE RARE
DISEASE FIELD.
COMPANIES, INVESTIGATORS, ALL OF
US ARE ASKED TO MANAGE
RELATIONSHIPS TO MAINTAIN TRUST
AND PART IS BEING AS TRANSPARENT
AS YOU CAN BE ABOUT WHAT YOU
KNOW AND DON'T KNOW WHICH IS
OFTEN MORE PROMINENT THAN
PATIENTS MIGHT RECOGNIZE HOW TO
COME FORWARD WITH THAT AND THEN
SAY WARE NOT WITHHOLDING
ANYTHING WE JUST DON'T KNOW.
THERE'S TENSION IN THE PROCESS.
WE BUILT THINGS LIKE ADVISORY
COUNCILS WHERE WE BRING TOGETHER
MULTIPLE FACES AND COMMUNICATE
TO THE ADVOCACY GROUPS WE'RE
SHARING AS MUCH AS WE CAN
BECAUSE THE BENEFIT OF PATIENTS
IS FIRST AND FOREMOST.
>> YEAH, I THINK YOU RAISED A
COUPLE POINTS.
ONE IS DATA COLLECTION ACROSS
ONE DISEASE BUT ACROSS MULTIPLE
DISEASES AND IN ANGELMAN
SYNDROME THEY HAVE THE DATABASE
AND THERE'S HEAVY PRESSURE ON
COMPANIES THAT HAVE A FAILED
TRIAL AND ARE GETTING OUT OR
HAVE A COMPLETED TRIAL OR ROCHE
IS LEADING THE FIELD WITH THE
BASELINE DATA GOES INTO THE
REGISTRY TO COLLECT ALL OF IT.
I THINK WE'D LIKE TO HAVE ALL
THE TRIAL DATA AND THEY CAN WORK
WITH FDA AND PULL A CONTROL
GROUP OUT IF YOU HAVE DATA
COLLECTED FOR YOUR DISEASE AND
THE GENETIC TREATMENTS ARE
INCREDIBLY IMPORTANT AND ONCE
YOU HAVE ASO APPROVED WE'RE
GOING TO GET THAT APPROVED AND
HAVE A DIFFERENCE IN TREATED
VERSUS UNTREATED PATIENTS IN ONE
YEAR.
WE HAVE NO IDEA WHAT THE
LONG-TERM OUTCOME WILL BE UNLESS
WE HAVE A COLLECTION AND SAME
TRUE OF OTHERS APPROVED BUT THE
FDA REQUIRED A STUDY BE
CONDUCTED BUT THE TRUE QUESTIONS
WERE HOW LONG DID THE PATIENT
STABILIZE AND WHAT GOT WORSE?
NONE OF THAT DATA WAS COLLECTED
AND IT'S A GREAT OPPORTUNITY
LOST.
SAFETY DATA IS YES, IMPORTANT,
BUT FOR SOME LONG-TERM OUTCOMES
COLLECTING EFFICACY DATA IS
TREMENDOUSLY IMPORTANT BECAUSE
OTHERWISE WHEN WE TRY TO ADD THE
NEXT THERAPY HOW WILL WE KNOW
WHERE WE ARE?
>> WE LOOK FOR LIKE ONE THERAPY
FOR ALL THE PATIENT POPULATION
BUT EVENTUALLY WHEN WE MOVE TO
THE DOMAIN WE'LL HAVE ONE
PATIENT AND SEVERAL DIFFERENT.
IN THAT USING FDA APPROVAL AND
COMPARE WITH THE NATURAL HISTORY
OF CARRIER AND HOW DO THEY
IMPROVE?
THANK YOU.
>> YOU HAVE TO KNOW ENOUGH OF
THE RISK YOU'RE TAKING.
WE KNOW IN RARE DISEASES NATURAL
HISTORY IS SPARSE.
HOW MUCH CAN YOU KNOW AND HOW
CAN YOU STEP IN FRONT OF FDA TO
SAY GIVEN WHAT I KNOW AND WHAT I
DON'T KNOW I THINK THIS
WARRANTED.
SO I THINK THERE'S NO QUESTION
NATURAL HISTORY IS IMPORTANT BUT
IT'S HUGELY CHALLENGING AND RARE
CONDITION AND NOTE THE CHANGES
ON THEIR INTERVENTION AND THE
EFFECT YOU SEE OFTEN ARE IN PART
DUE TO THE PLATFORM AND THE
CONTEXT OF THE DISEASE.
I THINK ONE HAS TO CONTEX
CONTEXTUALIZE.
>> I THINK WHEN YOU DEAL WITH
THE END OF 1 TREATMENT AND
CLEARLY SEE A CLINICAL AFFECT
THAT SEEMS TO BE INCONSISTENT
WITH NATURAL HISTORY.
I DON'T KNOW THAT'S EVER AN
APPROVABLE OUTCOME AND HAVE A
SPECIFIC TARGET THAT MAY BE A
POLYMORPHISM BUT MAYBE A NUMBER
OF PATIENTS OR ONE PATIENT IS
THAT EVER AN APPROVABLE THING AT
FDA AND I THINK WE'LL SEE MORE
AND MORE WHEN WE EDIT SPECIFIC
MUTATIONS.
I DON'T KNOW WHERE THAT LEADS US
AND I THOUGHT ABOUT THAT A LOT
BECAUSE THE FDA COULD HAVE A
POLITICAL ONAPPLICATIONS AND
WHAT WILL WE DO AND WHAT IS THE
PLATFORM AND THEIR ROLE?
IF THE FAMILY UNDERSTAND THE
RISK AND THE CLINICIAN EXPLAINED
THEM WELL AND THE ETHICS BOARD
HAS INCREASED THERAPY AND YOU'LL
TREAT ONE PATIENT, I AM CONFUSED
WHERE THE FDA ROLE IS IN THAT
PROCESS AND WHETHER THEY CAN
KEEP UP WITH IT AND THINK THEY
CAN'T KEEP UP IN THE FUTURE.
>> ONE WAY TO MADE AVAILABLE IF
ANOTHER PATIENT IS FOUND THROUGH
PERPETUAL IMB AND THE
INVESTIGATIONAL PRODUCT IS
AVAILABLE AND OVER TIME MAYBE
ENOUGH PATIENTS ARE ACCUMULATED
AND IT COULD BE FOUND AS AN
APPROVALABLE PRODUCT BUT IT
DOESN'T HAVE TO HAPPEN.
>> DON'T THINK IT'S A FORMAL
APPROVAL WITH ONE PATIENT.
>> I HAD A DIFFERENT QUESTION
ALL ABOUT THE OPEN IND AND WE
HAD DISCUSSIONS AT MY
INSTITUTION ABOUT SPENDING
MILLIONS TO MAKE TO THE DRUG WHY
NOT JUST KEEP THE OPEN IND AND
THE COMMENT FROM PHYSICIANS IS
WHO WILL PAY FOR THEIR CLINICAL
CARE AND HOW WILL WE BUILD THIS
CARE FOR NON-APPROVED PRODUCTS?
THAT'S ONE THING TO PUT ON THE
SHELF.
THE OTHER QUESTION I ORIGINALLY
HAD BECAUSE I THINK IT'S A
POWERFUL DISCUSSION WAS I THINK
ALL OF YOU IN THE PANEL IN YOUR
PRESENTATIONS TODAY AND IT'S
AROUND THE EARLIER QUESTION
ABOUT THINKING CRITICALLY ABOUT
PROSPECTIVE STUDIES AND CREATING
BIO BANKS TO GO BACK TO LATER 10
YEARS LATER AFTER INDIVIDUALS
HAVE RECEIVED LIFE-CHANGING
THERAPIES AND THEN DEVELOP
SOMETHING WEIRD OR HAVE A
CLINICAL COURSE NEVER EXPECTED.
SO ENCOURAGING THE NIH OR OTHERS
TO THINK ABOUT HOW WE THINK OF
GOING BACK AND THEN ADDRESS
CLINICALLY RELEVANT QUESTIONS OF
PATIENTS THAT RECEIVE THESE.
>> YEAH, WE SHOULD DO EVERYTHING
WE CAN.
I THINK THE VALUE OF
PRETREATMENT NATURAL HISTORY OF
THE END OF 1 OR A FEW PATIENTS
CAN'T BE UNDERESTIMATED AND IT'S
IMPORTANT TO FOLLOW THEM AND
LOOK AT THE MEASURES AFTER THE
TREATMENT STARTS.
>> I THINK THIS IS THE LIFE
CYCLE.
YOU'RE CONSTANTLY TRYING TO
IMPROVE BECAUSE YOU DON'T HAVE
ENOUGH SHOULDN'T STOP YOU FROM
MOVING BUT YOU ACCUMULATE OVER
TIME IN PARALLEL AND BUILD.
SO
[OFF-MIC]
>> WELL, WE CONVINCE THEM THIS
IS WHAT THEY SHOULD PAY FOR.
SO FAR IT'S WORKED.
I THINK IT CREATES A DOUBLE
STANDARD BECAUSE IT'S HARD TO
GET PUBLIC INSURANCE I.E.,
MEDICAID TO PAY FOR THAT KIND OF
THING SO IT CREATES A DIVIDE
BETWEEN HAVES AND HAVE-NOTES --
HAVE-NOTS.
>> THE CLASS OF THERAPY MATTERS
HERE.
AND THERE'S EARLY DIRECT ACCESS
AND HARDER TO DO THAT FOR AN
EXTRA BASE MODALITY UNLESS
YOU'VE TAKEN IT ALL THE WAY TO
COMMERCIAL APPROVAL.
>> DID YOU HAVE A COMMENT BEFORE
THE NEXT QUESTION?
>> MAINLY ONE OF THE POINTS
DIFFERENCE IN SIMONS SEARCH
LIGHT IS TO AGGREGATE NATURAL
HISTORY DATA ON AS MANY PEOPLE
AS POSSIBLE AND WE'RE ADDING THE
IN-PERSON ASSESSMENTS AS WELL TO
P
PREPARE FOR THE FUTURE STATE AND
UNDERSTAND BEST CLINICAL
PRACTICES AND IF THERE ARE
EITHER TREATMENTS, THERAPIES
THAT MAY BE MORE OR LESS
EFFECTIVE UNTIL WE GET TO
CLINICAL TRIALS.
I THINK THREES WAY TO PREPARE
FOR THE FUTURE STATE NOW.
>> THANKS.
>> I REALIZE IT'S 4:58 IN THE
AFTERNOON SO I'LL SAY SOMETHING
PROVOCATIVE.
TAKE THIS TO SERIOUS PEOPLE AT
CMS AND PEOPLE WHO THINK HARD OF
REIMBURSEMENT.
THE PATH WE GEN EDITORS ARE
TAKING TO GET IN COMMERCIAL
REIMBURSEMENT FOR N OF 1 GUIDE
RNAs IS FIRST, WE HAVE TO BASKET
INDIVIDUALS BIASED ON A
BIOMARKER OR ACCELERATED
APPROVAL.
FOR IMMUNE DEFICIENCIES THIS
WOULD BE CDC COUNT IN SIX MONTHS
AND NORMALIZATION OF SERUM
AMMONIUM.
I DON'T KNOW WHAT THAT IS.
THAT'S IT.
IF THERE'S A HARMONIZABLE
BIOMEDICAL WHATEVER THAT IS, IT
DOESN'T HAVE TO BE FOR ALL OF
THEM JUST SUBSET.
THAT IS HOW WE STRUCTURE THE
CLINICAL DEVELOPMENT.
THAT'S COMPONENT NUMBER ONE.
COMPONENT NUMBER TWO, YOU KEEP
AS MUCH AS THE PROCESS AS YOU
CAN THE SAME.
THE EXCIPIENT AND CROSS OVER IN
WHICH YOU MAKE THE PATIENT
SPECIFIC COMPONENT.
WHAT I HEARD FROM PETER
PERSONALLY THEY THERE ARE 3.3
BILLION BASE PAIRS IN THE HUMAN
GENOME.
I DON'T WANT 3.3 REVIEW CRITERIA
FOR REGULATORS.
SO STRATEGICALLY IN THE NEXT
THREE, FOUR YEARS IS TO GET
PHYSICIANS WHO TREAT SPECIFIC
SYNDROMES TO AGREE AND WE GEN
EDITORS AND THE DELIVERY PEOPLE
HAVE TO AGREE HOW TO BUILD A
PLATFORM UNDER WHICH WE CAN
CHANGE A VERY TINY THING AND
THEN AFTER WE BUILT UP OUR
SUBJECTS THE HOPE IS THE AGENCY
WILL APPROVE THE PROCESS UNDER
WHICH YOU MAY DELIVER.
THAT'S ALL.
>> I THINK YOU CAN GO BEYOND
THAT NOT JUST UP TERMS OF SHARED
BIOMARKERS WHICH OF YET WE DON'T
HAVE AND HOW TO OVERCOME.
DO WE NEED A GENE SPECIFIC
OUTCOME FOR EVERY SINGLE ONE OF
THE HUNDREDS OF GENES WHERE THE
COMMON CORE FEATURES ARE SHARED
OR HAVE A PLATFORM?
>> OR NUMBERS OF SEIZURES OR
DURATION OF SEIZURES.
YOU DON'T HAVE TO USE A
BIOMARKER IN THAT SITUATION IF
YOU HAVE A GOOD CLINICAL END
POINT.
>> DR. BER TTAGNOLLI AND I MET
WITH THE FDA ON RARE DISEASES
AND HOW TO APPROACH THEM AND THE
CONVERSATIONS HERE ARE SIMILAR
TO WHAT OCCURRED THERE.
AND I'LL THROW OUT INFORMATION
THAT WHAT THE FDA SAYS IS THAT
THEY ARE BEING DELUGED WITH 50%
OF THEIR APPLICATIONS WITH RARE
DISEASE, 8,000 APPLICATIONS WENT
A COUPLE YEARS AND THEY'RE
LOOKING FOR GUIDANCE.
THEY SAID WHAT STYMIED THEM MOST
IS THE BIOMARKERS WERE VALIDATED
AND I THINK WHAT YOU SAID HERE
AND THEY CAN USE COMPASSIONATE
USE IS EASY TO DO ON THEIR END
BUT DIDN'T HELP YOU GET PAID.
I THINK WE'RE ALL IN THIS
TOGETHER IN SYSTEMATIZING AND
WITH THAT WE'RE TRYING TO
CONVINCE DR. BERTAGNOLLI TO DO
THAT AT NIH AND HOPEFULLY THINGS
WILL TURN AROUND.
SEEMED INTERESTING.
ANYWAY, I HAVE TO RUN BUT SEE
YOU TOMORROW.
>> THANKS, WALTER.
>> I WANT TO SAY ONE LAST THING
ABOUT GENETIC EPILEPSY AND
MEASURING SEIZURES IS A GREAT
OUTCOME BECAUSE FDA BELIEVES IN
IT AND IT'S MEASURABLE.
FOR OTHERS THEY HAVE EPILEPSY
BUT IT'S NOT THE MAIN AND WIN
ANGELMAN SYNDROME THOUGH
SEIZURES WAS ONE THING AND FOR
MOST THE FAMILIES IN THE TRIALS
COMMUNICATION ARE MORE IMPORTANT
AND WHEN WE WILL HAVE THE
PATIENTS IN TRIAL AND SAY OH,
THEY HAVEN'T HAD SEIZURES IN A
YEAR AND THEY ONLY HAD SEIZURES
EVERY PUBLIC HEALTH OR
SOMETHING.
I THINK WE'RE CHANGING THE
SEIZURES BUT GOES TO ILLUSTRATE
FOR A LOT OF THE GENETIC
EPILEPSIES, THE EPILEPSY IS NOT
THE BIGGEST PROBLEM.
IN THINKING ABOUT BIOMARKERS AND
CLINICAL OUTCOMES WE HAVE TO
FIGURE OUT WAYS OF THINKING OF
THE PARTS THAT AREN'T EPILEPSY
AND WE DID TALK ABOUT THAT
PROBLEM.
>> LAST QUICK FROM
DR. SCHREIBER.
>> I'LL BE BRIEF.
AND LOOKING AT BIO BANKING AND
IT STRUCK ME AS THE DISCUSSION
OF FAEs AND THINGS WE DIDN'T
EXPECT.
IS THERE ANYTHING ELSE WE SHOULD
COLLECT AT BASELINE THAT WE'RE
NOT GETTING NOW THAT WE MIGHT
WANT TO KNOW LATER?
I THINK A CASE OF AN MRI THE
PATIENT HAS ENCEPHALOPATHY AND
HADN'T HAD ONE IN 15 YEARS.
IS THERE SOMETHING LIKE THAT
WE'LL WANT TO HAVE AT BASELINE
TO THEN GO BACK AND LOOK IF
SOMETHING CHANGED?
YES OR NO.
>> THE DIFFICULTY IS RECOGNIZING
NOW WHAT YOU WILL NEED IN THE
FUTURE.
I THINK TO ADD TO WHAT WALTER
SAID, FDA WANTING BETTER DATA IS
ALWAYS PERTINENT WHETHER MRI,
BIOMARKERS, OTHER MEASURES.
IT HAS TO BE AROUND THE
CLINICALLY MEANINGFUL UNMET NEED
THAT'S WHAT WE MISS WE DON'T
DEFINE WELL WHAT WE'RE TRYING TO
CHANGE.
WE FOCUS IN ON THAT INSTEAD OF
GATHERING ALL DATA WILLY-NILLY
ACROSS THE DISEASE, THEN WE WILL
BE ABLE TO ACCELERATE FASTER.
I KNOW IT'S NOT A GOOD ANSWER
BUT I THINK PLATFORM SPECIFIC,
YES, THERE ARE NEW THINGS WE
WANT TO KNOW AND UNDERSTAND
WHAT'S HAPPENING IN THE BONE
MARROW OF SOME OF THESE CHILDREN
BEFORE WE START
>> WE'RE ALWAYS TRYING TO
BREAKING NEWS COST WITH
INFORMATION AND CAN'T DO EVERY
COST AND -- BALANCE COST WITH
INFORMATION AND YOU CAN'T DO
EVERY COST AND WE HAD NO REASON
SOME WOULD HAVE AN IMMUNE
RESPONSE BASED ON THE LIMITED
AMOUNT OF PREVIOUS EXPERIENCE.
SO WE HAD TO MODIFY THE TRIAL
AFTER WE SAW IT TO ADD THE
COLLECTION OF LYMPHOCYTES TO
STUDY IT MORE CAREFULLY.
I THINK ALREADY A NUMBER OF
THESE TRIALS ARE EXHAUSTING FOR
THE PATIENT AND THE FAMILY IN
TERMS OF THE NUMBER OF END
POINTS COLLECTED.
AND SO I THINK TO ADD THINGS IN
ADVANCE WHEN YOU DON'T
ANTICIPATE THEM IS PROBABLY NOT
PRACTICAL.
>> IT'S HARD TO PREDICT.
WE REALIZED THERE WAS A PREVIOUS
HISTORY NOT JUST OUR PATIENTS.
SO WE NOW KNOW WHAT IT'S LIKE
WITH THE ANGELMAN SYNDROME ONLY
BECAUSE IT OCCURRED BUT WE WOULD
NEVER HAVE BEEN ABLE TO PREDICT
WE WOULD NEED THAT SO IT'S HARD
TO COLLECT.
I THINK MRIs ARE OBVIOUS AND
MOST THE PROTOCOL DO COLLECT
MRIs AT THIS BEGINNING OF THE
STUDY.
BUT I MEAN DATA COLLECTION TO
INFORM US IN THE FUTURE WHAT WE
SHOULD COLLECT POOLING THAT IN
THE POT AND THE FUTURE IS
COLLECTING NOW FOR WHAT WE'LL
NEED LATER.
>> ON THAT NOTE I THINK WE'LL
CLOSE OUR SESSION, VICKY.
DID YOU WANT TO SAY A COUPLE
THINGS?
WHILE VICKY'S COMING UP I WANT
TO REFLECT.
WE HAD SUCH A POWERFUL SESSION 1
OF THE PROMISE AND SO MUCH
KNOWLEDGE HAS BEEN INVOLVED OF
THE PLATFORMS AND VECTORS AND
WAYS TO DELIVER.
AND ENERGIZING OUR COMMUNITY
WITH ALL THE GENETICS WE KNOW
AND THE LESSONS WE LEARNED WERE
SOMEWHAT SOBERING BUT I THINK
THEY'RE INSPIRING AND PAVES THE
WAY FORWARD.
WE DON'T NEED TO MAKE THE SAME
MISTAKES BUT CAN LEARN AND
COMPOUND AND ENERGIZED BY BOTH
SESSIONS.
THANK YOU SO MUCH AND THE
MORNING SPEAKERS AS WELL.
I LOOK FORWARD TO TOMORROW.
>> SO THANK YOU TO ALL THE
SPEAKERS TODAY.
IT'S BEEN A FANTASTIC DAY.
IT'S BEEN REALLY VERY
INTERESTING AND AMAZING SO THANK
YOU ALL.
WE'LL START AGAIN TOMORROW
MORNING AT 9:00 a.m.
SO, WE DO HAVE TO GO THROUGH
SECURITY AGAIN FOR THOSE WHO ARE
NOT NIH EMPLOYEES.
SORRY ABOUT THAT BUT THOSE ARE
SECURITY MEASURES AND THERE'S
LOTS OF PLACES TO EAT AND HAVE A
GOOD EVENING AND SEE YOU
TOMORROW.
6:
ABOUT