IT IS MY PLEASURE TO INTRODUCE LORI
ISOM AND HEATHER MEF FORD. LORI
IS THE TREASURER OF THE
DEPARTMENT OF PHARMACOLOGY. I
ALMOST SAID PHARMACY
I KNEW THAT WASN'T RIGHT AT THE
UNIVERSITY OF MICHIGAN AND AT
HEATHER IS AT ST. JUDE'S
HOSPITAL AND SO I WILL TURN IT
OVER TO YOU TWO TO MODERATE.
>> GREAT, VICKY AND I WILL ECHO
THAT SENT SENTIMENT. YESTERDAY
WE RERPED A LOT FROM PEOPLE IN
ADJACENT TO EPILEPSY FIELDS.
AND I THINK WE WILL HAVE A
LITTLE MORE EPILEPSY FOCUS TODAY
TO ROUND OUT THE ENTIRE MEETING
AND REALLY LEARN ABOUT
STRATEGIES FOR TREATING THESE
DIFFICULT TO TREAT DISEASES. SO
LORI AND I PUT THIS SESSION
TOGETHER THINKING ABOUT WHAT IS
IT THAT WE NEED TO THINK ABOUT
AS WE DESIGN THESE THERAPIES
SPECIFICALLY FOR EPILEPSIES AND
AS WE THINK ABOUT HOW DO WE
DESIGN TARGETED THERAPIES FOR
THESE GENETIC CONDITIONS THERE
ARE MANY, MANY CONSIDERATIONS
AND MOST OF THESE WERE TOUCHED
ON YESTERDAY IF NOT IN DETAIL AT
LEAST AT A HIGH LEVEL. AS THING
TO THINK ABOUT AS WE DEVELOP
THERAPIES AND I THINK THE WAY I
THINK ABOUT IT WE NEED TO THINK
ABOUT WHAT IS THE INHERENT
PATTERN FOR THE DISEASE IS IT DE
NOVO DOMINANT. THAT'S WHEN WE
DIAGNOSE PATIENTS BECAUSE WE
HAVE NO IDEA UNTIL THEY
REPRESENT WITH
INSUFFICIENCY WE HAD HEARD. WE
HEARD YESTERDAY FOR SOME OF
THESE FUNCTION YOU NEED TO GET
RID OF THAT RATHER THAN REPLACE
FOR HAPPEN LOIN SUFFICIENCY AND
THE DISORDERS WE HEARD ABOUT
THAT YESTERDAY. THE GENE
REPLACEMENT STRATEGY BUT IF YOU
HAVE THE PARTIALLY FUNCTIONAL
ALLELE THAT'S STILL THERE YOU
CAN THINK ABOUT STRATEGY. IT'S
JUST TO UPREGULATE THAT FOR
PARTIALLY FUNCTIONAL ALLELE.
AND SO THESE ARE SOME OF THE
APPROACHES, RIGHT, UPREGULATION,
GENE REPLACEMENT, IF YOU GAIN A
FUNCTION OR KNOCK IT DOWN. IF
WE'RE UPREGULATING OR WANT MORE
GENE PRODUCT WE CAN TARGET AT
THE DNA LEVEL. TARGET AN AT RNA
LEVEL OR USE ENZYME REPLACEMENT
WHICH IS SOMETHING WITH PROTEIN.
BUT WE HAVE TO TAKE ALL OF THESE
INTO ACCOUNT AND THIS IS
THINKING ABOUT HOW DO WE TARGET
THE -- THERE'S AN ECHO, YEAH?
HOW DO WE TARGET THE MUTATION OR
THE GENE BUT THERE ARE OTHER
MORE COMPLICATED THINGS WE HAVE
TO THINK ABOUT AS WELL. SO WHEN
CAN WE TREAT AND THEN HOW DO WE
TREAT? WE HEARD ABOUT SOME
GREAT STRATEGIES YESTERDAY EVEN
TREATING, YOU KNOW, PRENATALLY
WHICH I THINK IS AMAZING. BUT
CAN WE TREAT -- HOW EARLY CAN WE
TREAT AND HOW EARLY DO WE NEED
TO TREAT? HOW FREQUENTLY DO WE
NEED TO TREAT IF IT'S NOT A
PERMANENT TREATMENT LIKE A GENE
REPLACEMENT? HOW DO WE REACH
THOSE IMPORTANT LEVELS IN THE
BRAIN THAT WE NEED TO GET TO TO
REALLY HAVE AN EFFECTIVE THERAPY
FOR EPILEPSY? AND SO HOW DO YOU
DELIVER IT. CAN WE DO THIS
SYSTEMICALLY AND I THINK
YESTERDAY WAS REALLY INFORMATIVE
FOR ME IN THINKING ABOUT SOME OF
THESE THINGS AND THEN THE
SESSION THIS MORNING WE'RE GOING
TO TRY TO I THINK TOUCH ON ALL
OF THESE IN DIFFERENT WAYS. SO
WE HAVE THREE GREAT SPEAKERS
THIS MORNING. OUR FIRST SPEAKER
WILL BE GEMMA CARVILL WHO IS AN
ASSISTANT PROFESSOR AT
NORTHWESTERN UNIVERSITY WHO IS
GOING TO TOUCH ON HOW DO WE
THINK ABOUT THOSE MUTATIONAL
MECHANISMS? HOW DO WE IDENTIFY
WHAT MUTATIONS ARE ACTUALLY
PATHOGENIC VERSUS BENIGN. THIS
IS OFTEN A FRUSTRATION FOR US IN
GENETICS ESPECIALLY AS WE GET TO
THIS. CAN WE GET PAST THAT AND
TEST ALL THE MUTATIONS AND
PREDICT WHEN THE PATIENT HAS A
TEST WHETHER IT'S BENIGN OR
PATHOGENIC AND THINKING ABOUT
THOSE BEING A FUNCTION OR NOT
AND THEN WE'RE GOING TO HEAR
FROM ISABEL AZNAREZ WHO LORI
WILL INTRODUCE LATER ABOUT
SPECIFIC STRATEGY FOR TREATING
EPILEPSIES AND WILL TALK ABOUT
THE STORY. AND THEN GAIA COLA
SAN TODAY WHO WILL DIVE INTO
TIMING OF TREATMENT AND
DELIVERY. OF GENETIC THERAPIES
FOR EPILEPSY SO I AM GOING TO
START BY BRINGING GEMMA CARVILL
WHO IS NOT HERE IN PERSON BUT
WHO IS HERE ONLINE AND GIVE US
OUR FIRST TALK THIS MORNING. SO
GEMMA, I THINK I WILL GET YOU
TAKE IT AWAY. THERE SHE IS,
GREAT.
>> GEMMA: GOOD MORNING,
EVERYBODY, I CAN SEE YOU ALL.
CAN YOU GIVE ME A WAVE IF YOU
HEAR ME? HOPEFULLY SEE YOU ALL
IN-PERSON SOON BUT IT'S GREAT TO
SEE YOU YOU FROM FAR IN THE
LITTLE CORNER HERE I'M HERE TO
SET THE STAGE OF WHERE WE'RE AT
IN TERMS OF THE GENETIC
LANDSCAPE OF THE EPILEPSIES.
AND SO TO KICK OFF. I SKIPPED
THE SLIDE THAT I LOVE THAT SHOWS
THE PROGRESS THAT WE'VE MADE IN
TERMS OF THE GENE DISCOVERY AND
THE GENES IDENTIFIED FOR
EPILEPSY BUT IN THE INTEREST OF
TIME WHAT I AM REALLY GOING TO
JUMP INTO TODAY IS THINKING
ABOUT THE DIFFERENT PATHOGENIC
MECHANISMS THAT ALL OF THE
EPILEPSY RELATED GENES CONFER.
I LIKE TO GET EVERYBODY ON THE
SAME PAGE BY INTRUSION THE TYPES
OF MECHANISMS AND I AM FOCUSING
ON THE ATE SOEMS BUT THIS APPLY
TO THE X CHROMOSOME AS WELL AND
THERE ARE MANY X LINKED EPILEPSY
GENES AND THERE CAN BE LOSS OF
FUNCTION SO RECESSIVE IN WHICH
CASE THERE'S NO FUNCTIONAL
PROTEIN MARRIED FROM EARLY
ALLELE AND THERE ARE A NUMBER OF
RECESSIVE EPILEPSY RELATED
GENES. I WILL NAME JUST TWO
HERE AND THERE ARE MANY HAPPEN
LOW INSUFFICIENT GENE Z ALE W.
THESE ARE DE NOVO AND RESULT IN
ABOUT 50% OF PROTEIN LEVELS AS
COMPARED TO THE WILD TYPE. ALSO
PRETTY COMMON PARTICULARLY IN
CHANNELS OF THE EPILEPSIES ARE
GAIN OF FUNCTION. THE LEVEL OF
PROTEIN IS THE SAME AS WE
CALL "WILD TYPE" BUT THERE ARE
THOSE MISSING VARIANTS ALTER
PROTEINS. SO THEY ACT IN A GAIN
OF FUNCTION MANNER. AND LASTLY
THE PROBABLY THE MOST DIFFICULT
TO THINK ABOUT FROM A
THERAPEUTIC STANDPOINT ARE THE
DOMINANT NEGATIVE AND SO AGAIN
THESE TEND TO BE DE NOVO
VARIANTS THAT OCCUR IN THE TWO
ALLELES AND THE INHERENT
PROPERTY OF DOMINANT NEGATIVE
MECHANISMS IS THAT VARIANT TENDS
TO INTERFERE WITH THE FUNCTION
OF THE WILD TYPE SUCH THAT THE
AMOUNT OF PROTEIN IS 30% AS COME
FIRE DEPARTMENT -- COMPARED TO
THE WILD TYPE.
THINKING ABOUT THE MECHANISM IS
REALLY, REALLY KEY WHEN WE'RE
SELECTING THE TYPE OF
THERAPEUTIC APPROACH AND WE
HEARD NICE STORIES ABOUT THIS
YESTERDAY AND OTHER NEUROLOGICAL
DISORDERS AND OF COURSE IT'S
TRUE IN EPILEPSY AS WELL AND SO
FOR THE LOSS OF FUNCTION
ESSENTIALLY ALL WE HAVE TO DO IS
INCREASE THE AMOUNT OF PROTEIN
LEVELS AND RECESSIVE. WE NEED
TO GET TO ABOUT 50% BECAUSE WE
KNOW THAT CARE OWE ROTES IN
GENERAL ARE NOT AFFECTED. AND
IN THE DOMINANT NEGATIVE IDEALLY
WHAT WE WANT TO DO IS HAVE A
DISEASE ALLELE SPECIFIC
KNOCKDOWN AND/OR IDEALLY A
CORRECTION. AND SO I LIKE TO
USE THE SODIUM CHANNELS AS A
REALLY NICE EXAMPLE OF HOW
INCREASING AND DECREASING THE
AMOUNT OF PROTEIN IS REALLY
IMPORTANT DEPENDENT ON THE
PATHOGENIC MECHANISM. AND SO I
AM SHOWING YOU TWO EPILEPSY
RELATED GENES HERE. SCN 21A AND
2A. BUT THESE DO SO IN A LOSS
OF FUNCTION MANNER. SO WITH
THIS LOSS OF FUNCTION, THIS
MEANS THAT ESSENTIALLY THERE IS
A DECREASE IN THE AMOUNT OF
SODIUM THAT IS ENTERING THE
INTRACELLULAR SPACE AND SO THIS
IS PROBABLY WHY WHEN WE USE
SODIUM CHANNEL BLOCKERS THIS CAN
ACTUALLY EXACERBATE THE
SEIZURES, CONVERSELY WE THINK
ABOUT GAIN OF FUNCTION VARIANTS
IN SCN 2A. IN THIS INSTANCE
THERE'S ACTUALLY AN INCREASE
INFLUX OF THE SODIUM. SO THIS
IS PROBABLY WHY WE USE SODIUM
CHANNEL BLOCKERS. THERE'S AT
LEAST SOME EFFICACY IN TERMS OF
TREATING THE SEIZURES FOR
INDIVIDUALS WITH GAIN OF
FUNCTION VARIANTS AND SO THIS IS
IN IMPLICATIONS WHEN THINKING
ABOUT WHAT TO USE AND IN GENE
TARGETING THERAPIES THIS MEANS
THE INSTANCE OF SCN 1A WHAT WE
WANT TO DO IS INCREASE THE
AMOUNT OF NAV 1.1 WHEREAS
IDEALLY WE WANT TO DECREASE THE
AMOUNT OF NAV 1.2 IN THE SECOND
ONE. ONE OF THE MAJOR
CHALLENGES THAT WE HAVE IN THE
EPILEPSIES IS THAT MANY GENES
CAN CONFER MORE THAN ONE
PATHOGENIC MECHANISM AND THAT
THEY REALLY ARE VARIANT SPECIFIC
EFFECTS. I THINK 2A WHICH I
HIGHLIGHTED IS A REALLY NICE
EXAMPLE OF THIS. WHERE GAIN OF
FUNCTION THROUGHOUT THE GENE
CONFER A DEE TYPE OF PHENOTYPE.
WHEREAS LOSS OF FUNCTION
VARIANCE ALSO DE NOVO TEND TO
CAUSE AUTISM SPECTRUM DISORDERS
AND INTELLECTUAL DISABILITY AND
SO THIS IS AN EXAMPLE OF 2A
ANOTHER GOOD EXAMPLE IS Q2 WHERE
LOSS OF FUNCTION VARIANTS ARE
ASSOCIATED WITH THE SELF
LIMITING EPILEPSIES AND DOMINANT
NEGATIVE VARIANTS ARE ASSOCIATED
WITH THE DEES. AND SO THIS IS
TRUE FOR MANY OTHER CHANNELS AND
OTHERS TOO WE'RE STARTING TO
FIND MORE AND MORE THAT THERE
ARE DIFFERENT PATHOGENIC
MECHANISMS THAT ARE BASED ON THE
SPECIFIC VARIANT. AND SO ONE OF
THE CHALLENGES THAT WE HAVE IN
THE FIELD IS HOW DO WE DETERMINE
THE PATHOGENIC EFFECT OF A
SPECIFIC VARIANT. SO GAIN
VERSUS LOSS OR DOMINANT
NEGATIVE. AND REALLY
IMPORTANTLY A HUGE CHALLENGE FOR
OUR FIELD IS AND GENETICS IN
GENERAL I'D SAY IS HOW DO WE
RESOLVE THOSE VARIANTS OF
UNCERTAIN SIGNIFICANCE. THOSE
WHERE WE DON'T HAVE ENOUGH
INFORMATION TO CALL IT AS
PATHOGENIC OR BENIGN ONE WAY OR
THE OTHER AND THESE VARIANTS
OVERWHELMINGLY ARE MISSING
VARIANTS IN THESE GENES AND THE
FOCUS OF MY GROUP AND MANY
GROUPS ARE TO RESOLVE THOSE AND
DETERMINE THE PATHOGENIC
EFFECTS. BUT BEFORE I JUMP INTO
THE WORK THAT WE'VE BEEN DOING I
WANT TO THINK CONCEPTUALLY ABOUT
WHAT ARE THE DIFFERENT TOOLS
THAT WE HAVE TO BE ABLE TO DO
THIS? AND THE FIRST IS GENOTYPE
PHENOTYPE CORRELATIONS. I
SHOWED YOU ON THE PRECEDING
SLIDE HOW THERE ARE LOSS OF
FUNCTION THAT GIVES US TWO VERY
DISTINCT CLINICAL FEATURES AND
THIS WORKS REALLY WELL WHEN WE
HAVE LARGE GROUPS OF PATIENTS
FOR A SPECIFIC GENE. THAT,
HOWEVER, TAKES TIME AND OF
COURSE IS NOT ALWAYS CLEARCUT
FROM THE OUTSET. WE'VE KNOWN
ABOUT SEN 2A FOR A LONG TIME AND
NOW ARE WE ONLY STARTING TO
TEASE APART THOSE EFFECTS. ONE
OF THE WAYS IN WHICH WE THINK
ABOUT DETERMINING VARIANT EFFECT
IS THROUGH FUNCTIONAL
CHARACTERIZATION AND I WOULD SAY
TRADITIONALLY IN THE FIELD KIND
OF HOW WE THOUGHT ABOUT
MODELLING IS REALLY LOW
THROUGHPUT MODELING. MODELING
OF SPECIFIC VARIETIES IN PRIMARY
CELL LINES OR IPSCS, SO INHERENT
PROTEIN STEM CELLS AS WELL AS
ANIMAL MODELS AND THESE MODELS
ARE GREAT FOR MODELING LARGE
NUMBER OF VARIANTS, OFTEN
BECAUSE WE CAN MODEL THESE
VARIANTS IN A NEURONAL BRAIN
TYPE CELL SO IT'S A LITTLE BIT
CLOSER TO THE PATHOLOGY IN TERMS
OF WHAT MAY BE CAUSING EPILEPSY
BUT I THINK INCREASINGLY WE NEED
TO START LEVERAGING HIGH
THROUGHPUT MODELING IN ORDER TO
STUDY THE EFFECT OF THE VARIANTS
ON PROTEIN FUNCTION THAT IS
CONSERVED IN A VARIETY OF
DIFFERENT CELL TYPES. IN
ADDITION, I THINK THAT WE NEED
TO START LEVERAGING MACHINE
LEARNING PREDICTORS, WE'RE KIND
OF GETTING TO A STAGE WHERE
THERE'S SO MUCH GENOMIC DATA OUT
THERE AND THAT WE CAN START
HARNESSING IT TO BE ABLE TO USE
MACHINE LEARNING PREDICTORS TO
DETERMINE WHICH VARIETIES ARE
PATHOGENIC OR BENIGN AND WHICH
HAVE DIFFERENT PROPERTIES OR
UNIQUE PROPERTY ON THE EFFECT OF
SPECIFIC PROTEINS. AND SO OF
COURSE THERE ARE GLOBAL
PREDICTORS, LIKE CLINIC PRED,
THESE ARE GENE AGNOSTIC AND AS
OTHERS ARE STARTING TO THINK
ABOUT USING GENE SPECIFIC
PREDICTORS. THESE ARE TO WORK
WITH THAT JEEP AND ARE HIGHLY
SPECIFIC FOR THAT DISEASE GENE
THAT YOU'RE INTERESTED IN. SO I
WILL TAKE YOU THROUGH A COUPLE
EXAMPLES. THE OTHER THING TO
THINK ABOUT IS IS THE IMPORTANCE
OF NOT CONSIDERING THESE IN
SILOS AND THE POWER OF ITERATING
THROUGH THESE DIFFERENT MODEL
SYSTEMS AND COMPUTATIONAL AND
CLINICAL APPROACHES. TO BEST
RESOLVE THE VARIETY AFFECT. AND
SO THE FIRST KIND OF HIGH
THROUGHPUT APPROACH THAT I'M
GOING TO TALK ABOUT ON MAVES,
THESE ARE MULTIPLEX ASSAY OF
VARIANT EFFECT THIS WAS WORK LED
BY JEFF CALHOUN AND KARINA IN MY
LAB AND WHAT THEY DEVELOPED WAS
A VERY HIGH THROUGHPUT ASSAY FOR
ASSESSING THE AFFECT OF THE
VARIANCE IN TSC 2 AND SO WHAT
JEFF AND KARINA DID WAS
INTRODUCED OVER 200 EDITS INTO
HAPLOID CELL. SO ONLY ONE COPY
OF THE HUMAN GENOME WHICH IS
VERY HELPFUL FOR DOING THESE
TYPES OF HIGH THROUGHPUT ASSAYS
AND SO THEY INTRODUCED THESE
VARIANTS INTO THE ENDOGENOUS TSC
2 LOCUS AND CREATED A POOL OF
CELLS THAT HAD A VARIETY OF
DIFFERENT EDITS.
THEY THEN DEVELOPED AN ASSAY
CALLED -- WHICH IS ESSENTIALLY
JUST LOOKING AT LEVELS OF
PHOSPHOR RESSICS WHICH IS A
READOUT FOR ACTIVITY AND TOOK
THIS POOL OF CELLS AND USE A
FLORA FORD TO SORT THOSE CELLS
THAT HAD HIGH M TORC ACTIVITY.
AND YOU CAN TAKE THESE POOLS OF
CELLS AND PERFORM NEXT
GENERATION SEQUENCING AND COME
UP WITH A VARIETY OF SCORING
METRICS THAT YOU CAN PUT THE
VARIANTS INTO BASICALLY TWO
BUCKETS. WHOOPS. THE FIRST AND
WE CAN USE EMBEDDED IN THE
DESIGN, WE HAVE A NUMBER OF
SYNONYMOUS AND PROTEIN
TRUNCATING VARIANTS AND YOU CAN
USE THESE VARIANT TO SET YOUR
THRESHOLDS FOR WHAT YOU CONSIDER
TO BE PATHOGENIC OVER HERE AND
WHAT YOU CONSIDER TO BE BENIGN
OVER HERE. YOU CAN THEN TAKE
THOSE TWO HUNDRED VARIANTS AND
THIS IS WHAT JEFF AND KARINA
DID. THEY TOOK THOSE TWO
HUNDRED VARIANTS, PUT THEM
THROUGH THE SYSTEM, DID MULTIPLE
ITERATIONS, DID FIVE REPS OF
EACH OF THESE AND WITH SOME
CONFIDENCE YOU CAN -- YOU CAN
ASSIGN VARIANTS TO ONE CATEGORY
OR ANOTHER AND SO YOU CAN SEE
HERE THE PATHOGENIC AND LIKELY
PATHOGENIC VARIETY E VARIANTS
CLUSTER ON THIS SIDE AND THE
BENIGN OR LIKELY BENIGN VARIANTS
CLUSTER ON THIS SIDE WITH
SYNONYMOUS VARIANTS YOU CAN ALSO
SEE HERE IN GRAY THAT WE WERE
ABLE TO RECLASSIFY A NUMBER OF
THESE. SO IN THIS PARTICULAR
ASSAY WE COULD RECLASSIFY THESE
VARIANTS AS EITHER PATHOGENIC OR
BENIGN BASED ON THIS ONE METRIC
OF MTOR ACTIVITY AND THEREFORE
GENE FUNCTION. AND SO I ELUDED
EARLIER TO THE POWER OF
INTEGRATING THESE DIFFERENT
METHODS SO I THINK THE MAVE IS A
GREAT FIRST STEP IN TERMS OF
TRYING TO DETERMINE VARIANT
EFFECT. BUT I THINK IT'S BEST
USED IN CONJUNCTION WITH
MULTIPLE DIFFERENT TYPES OF
INFORMATION. AND SO I WANT TO
SHOW YOU AN EXAMPLE HERE OF
INTEGRATING THESE DIFFERENT
METHODS. WITH THE EXAMPLE OF
THE EPI-MVP WHICH IS LED IN THE
UNIVERSITY OF MICHIGAN. THIS
HAS BEEN A HUGE COLLABORATIVE
AND A FUN PROJECT TO WORK ON FOR
THE LAST COUPLE OF YEARS IT
CONSIST OF MYSELF AT
NORTHWESTERN, PROJECT ONE IS
BETTY ROSS AT CORNELL, PROJECT
TWO AND PROJECT THREE, DOWN ON
THE BOTTOM THERE ARE LED BY JACK
AT THE UNIVERSITY OF MI CHIGAN -
THESE ARE USING MACHINE LEARNING
AND THEN TEST OUR PREDICTIONS IN
MULTIPLE DIFFERENT SYSTEMS. SO
PRIMARY, IPS AND ANIMAL MODELS.
AND TO USE THIS ITERATIVE
PROCESS TO REALLY REFINE THE WAY
IN WHICH WE CAN CLASSIFY
VARIANCE IN CERTAIN SIGNIFICANCE
AND DETERMINE VARIANT EFFECT AND
SO WE'RE WORKING WITH FOUR
DIFFERENT GENES I'M GOING TO
SHOW YOU TODAY OUR RESULTS WITH
THE FIRST GENE WHICH IS STXBP 1
AND OUR FIRST STEP WAS TO BUILD
A CLASSIFIER. WE CURATED KNOWN
PATHOGENIC AND BENIGN VARIANTS
FROM THE LITERATURE. WE
ANNOTATED THEM WITH PROPERTIES,
PROTEIN STRUCTURE AND BUILT A
CLASSIFIER AND THIS IS SHOUP
HERE AND ESSENTIALLY WHAT I'M
SHOWING YOU IS THE SENSITIVITY
AND THE SPECIFICITY OF OUR
CLASSIFIER TO ACCURATELY
CLASSIFY A VARIANT AS
PATHOGENIC. SO THE DIAGONAL
LINE HERE WOULD BE JUST A COIN
TOSS OF HOW GOOD THE PREDICTOR
IS. AND THE CLOSER TO ONE THE
CLOSER YOU ARE TO A 100%
ACCURACY FOR THAT PARTICULAR
CLASSIFIER. WE NEVER WANT TO BE
AT 100% BECAUSE THEN SOMETHING
IS BROKEN AND DOESN'T GENERALIZE
WELL AND YOU GO BACK TO THE LAB
AND TRY TO FIX IT SO I BUILT IN
CLASSIFIER THAT WORKS PRETTY
WELL AND OUTPERFORMS ALL OTHER
PREDICTORS THAT ARE TRAINED ON
MUCH, MUCH LARGER GENE WIDE
DATASETS. AND SO WE WERE QUITE
EXCITED A BY THIS BUT OF COURSE
THE PROOF IS IN THE PUDDING AND
WE NEED TO TEST THESE PREDICTION
USING FUNCTIONAL ASSAYS AND SO
THIS IS A SYNAPTIC PROTEIN THAT
INTERACTS WITH A COMPLEX TO
RELEASE VESICALS AT THE SYNAPTIC
MEMBRANE AND SO BETTY'S GROUP
CAME UP WITH FOUR FUNCTIONAL
READ OOUT TO DETERMINE THE
ACCURACY OF OUR PREDICTIONS AND
SO THESE ARE THE FOUR DIFFERENT
ASSAYS THAT WE USED. MIKE AT
THE HETC WHICH IS THE OTHER CORE
GENERATED ALL THE VARIANTS.
EVERYTHING WAS BLINDED AND
QUANTIFIED BY TWO DIFFERENT
SCIENTISTS OVERALL WHAT WE HAD
SHOWN WAS A GOOD AGREEMENT
BETWEEN THE RAW FUNCTIONAL
SCORES AND THE PREDICTIONS AND
TO WALK YOU THROUGH ONE OF THE
OUTCOMES OF ONE OF THE ASSAYS,
SO THE EXPRESSION ASSAY WHAT I'M
SHOWING YOU HERE IS ALL THE VUSS
ON THE SIDE. THE WILD TYPE IS
OVER HERE AND IN GREEN ARE ALL
OF THE KNOWN BENIGN VARIANT
WHICH IS YOU CAN SEE CLUSTER
VERY NICELY WITH THE WILD TYPE
ALL OF THE KNOWN PATHOGENIC
VARIANTS HAD A DECREASE IN THE
AMOUNT OF EXPRESSION AND WHAT
YOU CAN SAY HERE IN LIGHT GREEN
AND LIGHT PURPLE OR PINK ARE THE
VUSS THAT WERE PREDICTED TO BE
PATHOGENIC, ALL CLUSTERED WITH
THE KNOWN BENIGN VARIANTS AND
THE PATHOGENIC VARIANT, THE
PREDICTED PATHOGENIC VARIANT
HAVE THE SAME PROPERTIES AND WE
DID THIS ACROSS FOUR DIFFERENT
ASSAYS AND OVERALL THERE WAS A
REALLY GOOD AGREEMENT BETWEEN EP
PE PRED AND THE FUNCTIONAL
READOUTS. AND SO AGAIN, WE ARE
PRETTY EXCITED ABOUT THIS. AND
THEN WE DID A WHOLE NEW DATA SET
AND SUDDENLY EP PE PRED WAS NOT
PERFORMING AS WELL AS SOME OF
THE OTHER GLOBAL PREDICTORS AND
SO WE WERE QUITE INTRIGUED BY
THIS AND DUG INTO THE DATA A
LITTLE BIT MORE AND WHAT WE
ACTUALLY FOUND WAS THAT THE
TRAININGINGS OR THE HOLDOUT
DATASETS THAT WE USED WERE FROM
PUBLISHED DATA AND THE VARIANTS
WERE CALLED PATHOGENIC IN THE
PUBLISHED DATA BUT WERE BEING
CALLED BENIGN BY EPIPRED AND SO
WHEN WE DUG INTO THIS WE FOUND
THEY TEND TO LOCALIZE IN CERTAIN
PARTS OF THE PROTEIN OR CERTAIN
AMINO ACID AND THAT MANY OF
THESE VARIANTS WERE ACTUALLY AT
RELATIVELY HIGH ALLELE
FREQUENCIES AND/OR THE
INDIVIDUAL HAD A VERY ATYPICAL
PHENOTYPE SO NOT INCLUDING
EPILEPSY BUT HAVING SOME OTHER
DISORDER. AND SO SO TO TEST
WHAT THESE VARIANTS ARE DOING
WE'RE NOW MODELING THESE IN
PRIMARY AND HOPEFULLY THE IPSC
MODELS AS WELL TO GET A FEEL FOR
WHAT THESE VARIETIES ARE DOING
BY I THINK THAT THIS EXAMPLE IS
A REALLY NICE, IT'S A REALLY
NICE EXAMPLE OF HOW WE CAN
ITERATE BETWEEN USING MACHINE
LEARNING APPROACHES AND
FUNCTIONAL APPROACHES. TO FIND
THE PARTS OF THE PROTEIN THAT
REALLY NEED A DEEP DIVE IN TERMS
OF RESOLVING PROTEIN FUNCTION.
BECAUSE THESE PARTS OF THE
PROTEIN ARE MANY OF THE
CLASSIFIERS STRUGGLE WITH. THE
ONLY ONE THAT DIDN'T WAS ALMA
AND WE KNOW THIS WAY OVERCALLS
ON PATHOGENIC VARIANTS IN MOST
OF OUR EPILEPSY RELATED GENES.
AND SO TO KIND OF SUMMARIZE THIS
FIRST PART OF THE TALK, I REALLY
THINK I WANTED TO HIGHLIGHT HOW
THE PATHOGENIC MECHANISM REALLY
DETERMINES THE APPROPRIATE
TREATMENT TYPE AND THAT WE
REALLY NEED TO BE THINKING ABOUT
MANY OF THESE GENES HAVE VARIANT
CLASS SPECIFIC AND NOT GENE
SPECIFIC PATHOGENIC MECHANISMS
AND SO OF COURSE GENE EDITING
WOULD BE THE HOLY GRAIL AND WE
COULD CHANGE THE VARIANT TO WILD
TYPE AND THAT WOULD BE GREAT AND
WE'RE GOING TO REQUIRE DIFFERENT
STRATEGIES TO BE DEPENDENT ON
THE PATHOGENIC MECHANISM. AND
SO, I THINK SOME OF THE MOST
CHALLENGING, SO ALL WE NEED TO
DO IS UPREGULATE THE AMOUNT OF
PROTEIN AND DOMINANT NEGATIVE
ARE GOING TO NEED A BIT MORE
THOUGHT AND SO THINGS LIKE ASO
DEPLETION WOULD BE IDEAL. BUT I
THINK ONE OF THE BIG QUESTIONS
IS WHETHER WE ALSO NEED TO
UPREGULATE TO GET TO 100% OF
WILD TYPE FUNCTION ESSENTIALLY.
BECAUSE WHAT WE'RE ASSUMING HERE
IS THAT LOSS OF FUNCTION IS NOT
ALSO ASSOCIATED WITH A
NEUROLOGICAL PHENOTYPE. AND WE
KNOW THAT THAT'S NOT TRUE. SO
IN THE LAST TWO MINUTES I JUST
WANT TO TOUCH ON ONE OF THE
OTHER CHALLENGES I THINK WE FACE
IN EPILEPSY IS THAT MANY OF THE
GENES DE -- DOSAGE SENSITIVITY
AND THAT BOTH TOO MUCH AND TOO
LITTLE PROTEIN IS DETRIMENTAL IN
TERMS OF NEUROLOGICAL FUNCTION.
AND I'D LIKE TO REALLY HIGHLIGHT
THIS WITH A SPECIFIC CASE, SO OF
CHD 2 WHICH IS THE EPILEPSY
RELATED GENE WHERE DE NOVO
PATHOGENIC LOSS OF FUNCTION
VARIETIES IN CHD 2 CAUSE A
CLASSIC AND FAIRLY RECOGNIZABLE
DEVELOPMENTAL. AND IMPORTANTLY
THE PATHOGENIC MECHANISM IS
HAPPEN LOW INSUFFICIENCY SO MOST
OF THE VARIANTS IS TRUNCATIONS.
SO HERE IS THE CLINICAL PICTURE
OF CHD 2 RELATED. MORE
RECENTLY, THROUGH A
COLLABORATION WITH ANN AND
VEEJAY WE IDENTIFIED THESE
INDIVIDUALS WITH DE NOVO
DELETION. IN INDIVIDUALS WITH A
MUCH MORE SEVERE NEUROLOGICAL
PRESENTATION THAN THOSE
INDIVIDUALS WITH CHD 2 VARIANTS.
AND SO THESE INDIVIDUALS ALL HAD
SEVERE HYPO TONE YA FROM BIRTH,
THEY'RE ALL NONVERBAL, NON
AMBULATORY AND HAVE SEVERE
DELAYS AND HAVE ATROPHY AS WELL
AS HYPO MYELINATION. SO WE WERE
INTRIGUED TO FIGURE OUT WHAT
EXACTLY WERE THESE DELETION
UPSTREAM DOING. AND THIS JUST
SHOWS YOU A CARICATURE OF THE
CHD 2 IN FRONT OF IT IS A, RNA
CALLED A CHASER AND YOU CAN SEE
THOSE THREE DELETION ALL
ENCOMPASS THE FIRST THREE AXONS
OF THIS LONG CODING CHASER AND
WE KNOW FROM THIS WORK IN ISRAEL
THAT IN MICE WHICH YOU DELETE
THIS CHASER YOU HAVE THE SEVERE
GROWTH DEFECTS AND SO WE TESTED
THIS FROM TWO DIFFERENT PATIENTS
AND SHOWED INDEED, IN -- AS WITH
THE MICE, HERE YOUR WILD TYPE
LEVELS ARE, HERE'S PATIENT ONE
AND PATIENT TWO YOU CAN SEE
THERE WAS A REALLY CONSISTENT
INCREASE IN THE AMOUNT OF CHD 2
PROTEIN AS COMPARED TO A WILD
TYPE SO TO A LEVEL ABOUT 1.8
FOLD AND SO OUR TAKEAWAY FROM
THIS IS THAT BOTH HAPPEN LOW
INSUFFICIENCY BUT ALSO THAT
OVEREXPRESSION OF CHD 2 CAN BE
ASSOCIATED WITH AN EVEN MORE
SEVERE NEUROLOGICAL PHENOTYPE.
THIS IS IMPORTANT FOR CHD 2 AND
FOR OTHERS. SO I SHOWED YOU THE
EXAMPLE OF SCN 2A AND MECP 2 IS
ANOTHER WELL-KNOWN GENE WHERE
THERE'S LET SYNDROME AND
DUPLICATIONS THAT CAUSED A
DISORDER IN MALES THERE WAS ALSO
A RECENT GENOME WIDE STUDY THAT
SHOWED THAT MANY HAPPEN LOW
INSUFFICIENT GENES ARE ALSO
SENSITIVE SO IF WE LOOK AT SOME
OF THE MOST COMMONLY HAPPEN LOW
INSUFFICIENT OR LOSS OF FUNCTION
GENES, FOR THE EPILEPSY RELATED
GENES, WE SEE THAT MANY OF THESE
ARE IN THE TOP TEN PER TENSI TI
OF SENSITIVE GENES WE NEED TO BE
CAREFUL ABOUT DESAMING SPECIFIC
GENE THERAPIES AND BEING
COGNIZANT OF TOO MUCH MAY ALSO
BE BAD.
AND ALSO TAILORING OUR
THERAPEUTICS TO BE ABLE TO
OPERATE WITHIN A VERY FINE
DOSAGE SENSITIVE WINDOW AND SO
LASTLY J TO CONCLUDE I THINK
I'VE -- KIND OF HIGHLIGHTED HOW
IT'S REALLY IMPORTANT IN THE
EPILEPSY GENES AND FOR SPECIFIC
VARIANTS TO THINK ABOUT HOW
THOSE MECHANISMS DETERMINE THE
APPROPRIATE TREATMENT STRATEGY.
>> TO TO CONSIDER THAT THEY ALL
NOT HAVE THE SAME DISH SHOWED
YOU ONE OR TWO ASSAYS. I THINK
MULTIMODAL IS ALSO KEY. WE NEED
TO BE USING A VARIETY OF
DIFFERENT ASSAYS. BECAUSE I --
GEORGE'S GROUP AND OTHERS HAVE
SHOWN THAT DEPENDING ON THE
ASSAY THAT YOU USE YOU CAN GET A
LOSS OF FUNCTION VERSUS A GAIN
OF FUNCTION EFFECT DEPENDING ON
THE ASSAY SO WE NEED TO WORK
TOGETHER TO TACKLE THE IMPORTANT
PARTS OF THE PROTEINS AND LASTLY
TO SHOW YOU THAT GENE DOSAGE IS
IMPORTANT FOR EPILEPSY RELATED
GENES THE WITH THAT I WILL END.
I WILL THANK MY LAB LAB. IT'S
BEEN A FABULOUS COLLABORATION OF
LOVE WORKING WITH EVERYBODY AND
LASTLY JUST TO SAY EPIPRED WILL
BE AVAILABLE SOON WHERE
EVERYBODY CAN COME IN AND PUT IN
YOUR MISSING VARIANTS AND FIGURE
OUT WHAT IT DOES. THANKS FOR
YOUR ATTENTION.
>> LORI: THANKS VERY MUCH. THAT
WAS WONDERFUL. WE HAVE ABOUT
FIVE MINUTES FOR QUESTIONS.
>> AUDIENCE: (SPEAKER FAR FROM
MIC).
>> GEMMA: CAN YOU SPEAK UP, I
CAN'T HEAR.
>> LORI: HOLD ON, GEMMA.
>> GEMMA: LORI, COULD YOU JUST
REPEAT THE QUESTION FOR ME?
>> AUDIENCE: I WORK WITH
JENNIFER AND I BUILT THIS. WHAT
AN AMAZING TALK. YOU SHOW NICE
DATA IN THESE HAPPEN ONE CELLS
BUT YOU CAN MODEL THE AFFECT OF
THE VARIANT
GREAT BY WAY OF BUILDING A
PIPELINE WHERE DE NOVO DIAGNOSED
CHILD WHO HAS TWO MONTHS CAN GO
THROUGH THAT PIPELINE TO MODEL
THE VARIANT. WE COULD USE THAT
SAME GUIDE RNA WITH
MODIFICATIONS AS A THERAPEUTIC.
SO QUESTION FOR YOU, DO WE NEED
TO DO THE MODELING OF THE PURE
OF THE NEURON BECAUSE IF THE
ANSWER IS YES WE CAN BUILD A
PIPELINE THAT COMPLEMENTS YOUR
PIPELINE WHERE AS SOON AS YOU
SHOW IN YOUR HAPLOID CELLS
THAT'S THE MUTATION WE CAN
REPAIR THAT INTO A MORE SPECIFIC
CELL TYPE, QUESTION FOR YOU WHAT
IS THAT CELL TYPE?
>> GEMMA: GREAT QUESTION I
COMPLETELY AGREE WITH YOU AND
THE GOAL OF THE MAVES IS TO KNOW
THE GENE AND WHAT IT DOES. THAT
IS OUR GOAL IS TO HAVE A GUIDE
RNA THAT EDITS THAT PARTICULAR
LOCUS READY TO GO BUT TO ANSWER
YOUR QUESTION, WHICH CELL TYPE
IS THAT? THAT WILL DEPEND ON
THE GENE AND SO FOR CERTAIN
GENES, AND, AGAIN, AND THIS IS
WHY I WAS CAREFUL TO POINT OUT
THAT IN THE HAP ONES THERE ARE
ONLY CERTAIN PROPERTIES OF THE
PROTEIN THAT WE CAN ASSAY.
THAT'S ONLY ONE READOUT AND SO
WE NEED TO HAVE MULTIPLE
DIFFERENT READ OITS AND MULTIPLE
CELLS IDEALLY WE WILL DO THESE
DERIVED NEURONS AND MAYBE TWO
NEURONS TO START TO DO THIS.
BUT TO ANSWER YOUR QUESTION A.
THAT WILL DEPEND. IT THAT'S
KIND OF, I HOPE WHAT GAIA IS
GOING TO TALK ABOUT IN THE THIRD
TALK IS WHAT ARE THE CELL TYPES.
>> AUDIENCE: TERRIFIC. WE HAVE
THE PIPELINES TO KNOCK THE
MUTATIONS AND LONGITUDINALLY. I
WOULD LOVE TO DIAGRAM WHAT YOU
HAVE DONE THANK YOU.
>> GEMMA: I'D LOVE TO CHAT.
>> LORI: THANKS, GEMMA, LET'S
HAVE ONE MORE QUESTION.
>> AUDIENCE: HI, I'M LEAH MYERS,
I REALLY LIKED YOUR TALK AND I
JUST WANT TO DO JUST SAY FOR
EVERYONE HERE THIS IS A REALLY
IMPORTANT TOPIC IN OUR COMMUNITY
RIGHT NOW. AS PRECISION
MEDICINE IS COMING DOWN THE
PIPELINE FOR US WE'RE IN
CLINICAL TRIALS. FOR CERTAIN
ONES AND WE ARE REALLY CONCERNED
ABOUT THIS AS A COMMUNITY.
BECAUSE WE -- WITH AL GEORGE
ANALYZING OUR VARIANTS AND
INDUSTRY GROUPS ANALYZING THE
CHANNEL WE'RE GETTING SOME
DIFFERENT RESULTS LIKE POLAR
OPPOSITE DIFFERENT RESULTS AND
THAT'S REALLY SCARY BECAUSE THEY
WANT TO PUT A KID IN A GENE
THERAPY TRIAL AND THE OTHER ONE
SAYING IT'S A COMPLETE LOSS OF
FUNCTION SO I JUST WANTED TO
EXPRESS THAT THIS IS A VERY
NEEDED TOPIC FOR THE PATIENTE
ADVOCACY GROUPS WE'RE WILLING
TO SUPPORT.
>> GEMMA: I THINK YOU HIT THE
NAIL ON THE HEAD. I THINK
WHAT'S REALLY IMPORTANT IS DATA
SHARING. RIGHT? WE NEED TO
MAKE SURE THAT EVERYBODY IS
SHARING THEIR DATA IN A ROBUST
WAY. AND I DON'T KNOW THE BEST
FORUM TAD TO DO THAT BUT I
THINK THAT'S SOMETHING WE HAVE
TO FIGURE OUT.
AND THIS IS SOMETHING YOU CAN
CHAMPION FOR US. SNA
>> AUDIENCE: I AGREE, WE DID
JUST PUBLISH WHERE IT WAS
ANALYZED IN EACH ONE AND WE DID
A DEEP DIVE INTO THEM AND I'M
PRESSING THE INDUSTRY GROUP TO
SHARE THEIRS BUT THAT'S REALLY
DIFFICULT FOR US TO DO AND SEEMS
LIKE WE'RE NOT MAKING A LOT OF
PROGRESS THERE BUT I AGREE.
IT'S THE ONLY WAY TO MOVE
FORWARD AND I DO THINK THERE ARE
SOME PEOPLE IN THIS ROOM THAT
ALSO HAVE OTHER IDEAS ON HOW WE
CAN PUT THAT DATA ALTOGETHER
LIKE THE PORTALS. THANK YOU.
>> LORI: THANKS, LEE YACLEAH.
ARE CONTEXT DEPENDENT. SO IT'S
WHAT ACTS ON THE INITIAL SEGMENT
VERSUS DENDRITES VERSUS CELL
BODY I THINK IT'S AN IMPORTANT
PROBLEM. LET'S MOVE ON, THANKS,
GEMMA. IT'S MY HONOR TO
INTRODUCE ISABEL AZNAREZ WHO IS
COFOUNDER OF STOKE THEIR PIEKTS
AND WILL TALK ABOUT THE
DEVELOPMENT OF THE FIRST GENE
MODIFYING THERAPY FOR EPILEPSY.
>> AUDIENCE: (APPLAUSE).
>> ISABEL: THANK YOU IT'S A
PLEASURE TO BE HERE AND REALLY
ENJOYED THE PRESENTATIONS TODAY
AND GEMMA ALWAYS A FANTASTIC JOB
AND SUPER IMPORTANT WORK. AND I
WILL TOUCH A LITTLE BIT ON THAT
IN THE NEXT FEW SLIDES. JUST TO
INTRODUCE, OH, FIRST I HAVE SOME
DISCLAIMERS. AS LORI MENTIONED
I'M A FULL-TIME EMPLOYEE OF
STOKE AS PART OF THIS
PRESENTATION I WILL BE MAKING
SOME FORWARD LOOKING STATEMENTS.
THE TECHNOLOGY THAT WE DEVELOPED
IS CALLED TANGO, TARGETED
AUGMENTATION OF NUCLEAR GENE
OUTPUT. A MOUTHFUL WHICH WE AIM
TO ADDRESS THE UNDERLYING CAUSE
OF DISEASES BY UPREGULATING
PROTEIN BY USING NUCLEOTIDES AND
YOU PROBABLY HEARD A LOT ABOUT
THIS IN THE VAST MAJORITY OF
APPLICATIONS TO DOWN REGULATE
GENE EXPRESSION. WE'RE TABLE
LEVERAGE THE COPY AND I WILL GET
INTO THE DETAILS IN A FEW
SLIDES. TO UPREGULATE FULLY
FUNCTIONAL PROTEIN. WE DO SO BY
USING NUCLEOTIDES TO PREVENT
WHAT WE CALL NONPRODUCTIVE
SPLICING AND AGAIN I WILL
EXPLAIN THAT IN THE NEXT SLIDE
TO PROMOTE THE PRODUCTION OF
PRODUCTIVE RNA WHICH WOULD THEN
LEAD TO AN INCREASED PRODUCTION
OF PROTEIN. BUT BECAUSE OUR
NUCLEOTIDES ARE LIKE ANY OTHER
AND OPERATE AT THE LEVEL OF RNA
THE TECHNOLOGY SELECTIVELY
UPREGULATE GENE EXPRESSION ONLY
WHERE THAT GENE IS EXPRESSED SO
WE DON'T NEED TO WORRY ABOUT
ATOPIC EXPRESSION OR
OVEREXPRESSION ITSELF WHERE THAT
GENE IS NOT NEEDED. AND THEN BY
TARGETING OR LEVERAGING THAT
WILD TYPE COPY IN THE CONTEXT OF
HAPPEN LOW INSUFFICIENT DISEASES
WE'RE ABLE TO DEVELOP ONE DRUG
FOR AN ENTIRE PATIENT POPULATION
OF COURSE PROVIDED THAT THE
MUTATION AFFECTING THE PATIENT
ARE LOSS OF FUNCTION MUTATIONS.
AND THEN AGAIN THE TYPE OF
MODALITY BEING NUCLEOTIDES WE
DON'T NEED TO WORRY ABOUT THE
SIZE OR THE FUNCTION OF THE GENE
AS WELL AS WE HAVE EVENTS TO
TARGET, WE CAN UPREGULATE THEIR
EXPRESSION. SO JUST BRIEFLY HOW
THE TECHNOLOGY WORKS. WE HAVE
THE HAPPEN LOW INSUFFICIENT
DISEASE WHICH YOU ALL KNOW THE
DISEASE IS CAUSED BY MUTATIONS.
AND THIS PARTICULAR EXAMPLE
THERE'S BOTH ALLELE CODE CONTAIN
A NONPRODUCTIVE AX ON, THERE ARE
MANY NAME TO THE SAME TYPE OF AX
ONS AND WHEN THESE AX ONS ARE
INCLUDED IN MRNA THEY LEAD TO
THE INTRODUCTION OF OF THIS.
AND THIS IS WHAT IS HAPPENING
HERE WE SEE THIS IS SPLICED IN
TWO DIFFERENT WAYS AND THE M RAN
LAN THAT CONTAINS THAT AX ON
GETS DEGRADED AND THIS IS
NATURALLY OCCURRING, THIS IS --
UP RELATED TO THE DISEASE STATE
AND MORE OFTEN THAN NOT THOSE
NONPRODUCTIVE SPLICING EVENTS
ARE THERE TO REGULATE GENE
EXPRESSION SO WE'RE ABLE TO
PREVENT THE INCLUSION OF THIS
AND THEN ALMOST SCLIFLY HAVE THE
PRODUCTIVE MRNA AND THE MUTANT
ALLELE IS STILL USELESS BUT THE
INCREASED MRNA LEVELS FROM THE
WILD TYPE ALLELE CAN NOW MAKE
MORE PROTEIN WHICH CAN THEN MAKE
UP FOR THE LOSS OF THE MUTANT
ALLELE AND BRING LEVELS BACK TO
HAVING EFFECT. SO THIS IS IN A
NUTSHELL HOW THE CONCEPT OF
TANGO WORKS. TO FIND THOSE
EVENTS WE DEVELOPED A
BIOINFORMATICS PIPELINE FOR
WHICH WE UTILIZE OUR DATASETS
AND THEN WE HAVE FOUND WHAT WE
CALL THE UNIVERSE OF
NONPRODUCTIVE SPLICING EVENTS
WHICH GO BEYOND THE AXONS, THERE
ARE ALL KINDS OF ALTERNATIVE
SPLICE SPLICING EVENTS AND THE
TRANSCRIPT DEGRADATION AND
QUESTION FOUND THEM IN 50% OF
CODING GENES. BECAUSE WE WANT
TO TREAT GENETIC DISEASES WE
CROSS-REFERENCE THOSE LISTS OF
GENES THAT CONTAIN NONPRODUCTIVE
SPLICING EVENTS WITH GENETIC
DISEASE, ET CETERA. AND WE
FOUND THAT 2900, THE DISEASE
CODES IN GENES ALSO HAVE THESE
NONPRODUCTIVE SPLICING EVENTS
THAT WE CAN LEVERAGE TO INCREASE
GENE EXPRESSION BY OF COURSE WE
CAN'T AND DON'T WANT TO
UPREGULATE 2900 DISEASE GENES
AND THIS IS WHEN IF THEY --
CONSIDERATIONS BECOME VERY, VERY
POOR AND A LOT OF THESE THINGS
WERE TOUCHED UPON BY GEMMA
EARLIER. BUT I WANT TO DOUBLE
DOWN ON SOME OF THOSE THINGS.
SO FOR US, IT'S IMPORTANT TO
UNDERSTAND THE GENETIC DISEASE
CAME UP ON THOSE LISTS. BECAUSE
ARE THEY A DOMINANT DISEASE. DO
THEY HAVE SUFFICIENCY OR USED TO
A DOMINANT NEGATIVE OR A GAIN.
OF COURSE DOMINANT ANYTHING GAVE
GAIN OF FUNCTION LIMITATIONS IS
OUT OF THE QUESTION FOR US AND
IT'S VERY, VERY IMPORTANT TO
KNOW THAT PRECISELY BECAUSE WE
DO NOT WANT TO HARM PATIENTS BY
UPREGULATING THEIR EXPRESSION.
IS A RECESSIVE DISEASE THAT
UPREGULATION IS COULD HAVE A
BENEFIT AND GEMMA POINTED IT OUT
ALSO SAME WITH THE NEXT DISEASE
WE HAVE THE SYNDROME IN OUR
PIPELINE AS WELL. THE BIOLOGY
IS A VERY IMPORTANT. GENOTYPE
PHENOTYPE CORRELATION, HOW MUCH
UPREGULATION IS NECESSARY. IF
TOO MUCH HOW MUCH IS TOO MUCH?
AND THEN, YOU KNOW, WHAT IS THE
EXPRESSION PATTERN OF THE GENE?
THE GENE IS VERY HIGHLY
EXPRESSED PRENATALLY AND
POSTNATALLY ALMOST NOTHING?
WELL THAT TELLS YOU THAT MAYBE
RESTORING A LEVEL AFTER A
PERSON, A BABY IS BORN, MAY NOT
DO THE TRICK. SO THAT SPEAKS TO
WHERE IS THE TREATMENT
OPPORTUNITY WINDOW BASICALLY.
THE DISEASE PREVALENCE OF COURSE
YOU MAY SAY, WELL, YOU'RE A
COMPANY, YOU NEED TO MAKE A
PROFIT BUT THE DISEASE
PREVALENCE IS ALSO IMPORTANT TO
DESIGN PROPER CLINICAL TRIALS TO
HAVE THE TREATING PHYSICIANS AND
TO BE ABLE TO HAVE ENOUGH
PATIENT TO HAVE A POWER AT
CLINICAL TRIAL SO IT'S AN
IMPORTANT FACTOR NO MATTER WHAT
UNLESS YOU DEVELOP A TREATMENT
AND THEN, YOU KNOW, OF COURSE
YOU DON'T NEED TO WORRY ABOUT
THAT, THE TARGET ORGAN, VERY --E
MODALITY BECAUSE WE NEED TO IF
WE CAN DELIBERATE INTO THE
DISEASE AND IF THAT'S A
CONSIDERATION THE CLINICAL
DEVELOPMENT IS ALSO WAY AHEAD OF
TIME. ARE THEY MODELS? ARE
THEY WELL VALIDATED MODELS THAT
CAN TRANSLATE INTO WHAT -- YOU
WILL BE -- WE WILL BE MEASURING
IN THE CLINIC AND THEN FROM THE
CLINICAL DEVELOPMENT, THERE ARE
END POINTS THAT ARE ALREADY
ACCEPTED BY THE FDA WHAT WOULD
BE THE DURATION OF THE TRIAL, ET
CETERA, ET CETERA. ALL OF THESE
ARE IMPORTANT CONSIDERATIONS
WHEN DECIDING WHAT TO TARGET.
WITH WHATEVER APPROACH YOU
REACH. ONCE WE DECIDE TO WORK
ON A TARGET WE WORK ON THE
PREDICTIONS. IDENTIFY THE HITS
AND PRIORITIZE A PIPELINE. WE
HAVE SEVERAL TARGETS IN OUR
PIPELINE. TODAY I'M GOING TO
TELL YOU WHAT I THINK IS SUPER
EXCITING STORY ABOUT TREATING
DRAVET SYNDROME. WE ARE
TARGETING WITH OUR BRAND NEW
NAME SOR REVENUE NEVER SEN. I'M
GOING QUIZ YOU. A LOT OF THE
BOXES, THAT WE WANTED TO CHECK
IN WHAT IS THE RIGHT TARGET FOR.
IT'S A CLEAR HAPPEN LOW INSIEVE
SI WHICH HALLS HAS -- WHEN IT
HAS MUTATIONS THAT LEAD TO GAIN
OF FUNCTION. AND -- BUT THE
PHENOTYPE ASSOCIATED WITH THOSE
MUTATIONS IS VERY, VERY
DIFFERENT AND SO WE'RE CONFIDENT
THAT WITH THE GENETIC AND THE
CLINICAL DIAGNOSIS, WE CAN
IDENTIFY THE RIGHT PATIENT WHICH
IS ARE THE MAJORITY OF THE
PATIENTS. THAT HAVE THE
INSUFFICIENCY. IT'S
SUFFICIENTLY PREVALENT TO HAVE
ENOUGH PATIENTS TO HAVE CLINICAL
TRIALS AND THERE'S A HIGH UNMET
NEED THE PATIENTS THAT ARE NOT
IN CONTROL WITH EPILEPTIC DRUGS
AND 20% OF PATIENTS DON'T REACH
TO ADULTHOOD BECAUSE OF
COMPLICATIONS SUDEP OR SEIZURE
COMPLICATIONS. DRAVET IS NOT
JUST A SEIZURE DISEASE. THERE'S
A LOT OF DIFFERENT COMPONENTS BY
TARGETING THE ROOT CAUSE OF THE
DISEASE WE'RE TABLE TREAT BOTH
THE EPILEPSY AND THE COGNITIVE
AND BEHAVIORAL ASPECTS OF IT.
SO ONE OF THE FIRST THINGS WE
NEEDED TO DO WAS TO DEMONSTRATE
AND CLINICALLY WHETHER WE HAVE
THE PROTEIN CODED LED TO A
PHENOTYPIC RESCUE AND WE DID
THIS WORK IN COLLABORATION AS
WELL AS. AND SO HERE WE USE
THAT AS VERY WELL-ESTABLISHED
AND ROBUST MOUSE MODEL THAT
PRESENTS WITH SEIZURES AS WELL
AS THE TWO OF THE PHENOTYPES
THAT ARE OF COURSE PRESENT IN
PATIENTS AND WE ADMINISTER THE
SEW REV NEVER SEN AND SEVEN
WEEKS OR FOURTEEN WEEKS LATER WE
MEASURE PROTEIN. THE PROTEIN,
WHAT WE WANT IT TO SEE IS
WHETHER WE CAN RESTORE PROTEINS
BACK TO NORMAL AND HERE WHAT
YOU'RE SEEING IS THE LINE AT
100% IS THE WILD TYPE LEVELS AND
THEN THE PLACEBO TREATED MICE
WERE HAVE THE PROTEIN LEVELS
AROUND 50%. AND WE SEE AN
INCREASE ALMOST BACK TO 100%
BOTH AT SEVEN WEEKS AND THAT
INCREASE WAS THE SAME ALMOST
ENTIRELY AT 14 WEEKS SO WE KNEW
THAT ONE DOSE WAS SUFFICIENT AND
THAT THAT AFFECT WAS HIGHLY
CONTROLLED. WHAT DID THIS DO TO
THE SUDEP PHENOTYPE OF THESE
MICE THE RED LINE IS THE MICE
AND THEN YOU SEE AROUND DAY
THIRTY BUT THE -- THE SEW REV
NONER SEN TREATED, ALL BY ONE
SURVIVED SO VERY CLEARLY THE
DOSE HELPS WITH THE SURVIVAL OF
THE MOUSE AND WE ALSO LOOKED AT
THE SPONTANEOUS SEIZURES, WE
IMPLANTED ELECTRODES IN THE
BRAIN. SO INTRACRANIAL AND WE
MEASURE SPONTANEOUS SEIZURES AT
TWO DIFFERENT TIME POINTS FROM
30 TO 20 AND 20 TO 40 AND YOU
SEE HERE AT THE EARLIER TIME
POINT YOU SEE THE TREATED MICE
HAVE NO SEIZURES WHATSOEVER
WHEREAS THE UNTREATED MICE HAVE
A SEIZURE FREQUENCY AND THIS
SHOWS A SIGNIFICANT REDUCTION IN
SEIZURE FREQUENCY FOR THE
TREATED MICE IN ORANGE COMPARED
TO THE DARK BLUE GRAYISH DOT.
SO AGAIN WITH A SINGLE DOSE OF
STK-001 WE WERE ABLE TO
SIGNIFICANTLY REDUCE THE SEIZURE
PHENOTYPE SO THAT MOUSE MODEL
DATA BOTH THE SEIZURES GAVE US
CONFIDENCE THAT THE UPREGULATION
WAS ABLE TO AFFECT THIS IN A
POSITIVE WAY AND WE'RE ABLE TO
RESTORE PROTEIN LEVELS IN THAT
EFFECT IT'S DURABLE AND THAT IN
THE PREMISE WE SEE THAT. AND
WHEN WE LOOK AT THE STUDIES WE
WERE ABLE TO HAVE A TALK READOUT
SUPPORT THE CURRENT DOSES THAT
WE HAVE ONGOING IN THE FIELD.
SO TO SWITCH GEARS AND SHOW YOU
A LITTLE BIT OF THE CLINICAL
DATA. I'M NOT A CLINICIAN SO I
WILL TRY TO DO MY BEST HERE.
THE CLINICAL TRIALS ARE SHOWN
HERE. WE HAVE THE TRIAL IN
WHICH WE -- THERE WAS A SINGLE
DOSE ARM AND A MULTIPLE DOSE ARM
OF DOSES UP TO 70 MILLIGRAM
THESE -- THE PATIENTS WERE DOSED
AND AFTER THE LAST DOSE, THERE
WAS A 6 MONTHS OBSERVATIONAL
PERIOD IN WHICH PATIENTS DID NOT
RECEIVE ANY SEW VE NEVER SEN
DOSES AND RIGHT AT THE GOING ALL
THE PATIENTS AT THE TRIAL WERE
CONTINUING THEIR ANTIEPILEPTIC
DRUGS AND MANY OF THESE PATIENTS
WERE ON THE THREE OR FOUR DRUGS
ALREADY AND STILL HAVING
NUMEROUS SEIZURES. AFTER THE
SIX MONTHS PERIOD THEY WERE ABLE
TO GO TO THE EXTENSION AND HERE
THE DOSES WERE 30 MILLIGRAMS 45
MIL GRAMS AND AGAIN PATIENTS
CONTINUE ON THEIR NORMAL
REGIMENT OF ANTIEPILEPTIC DRUGS.
I.
WILL WALK YOU THROUGH THE DATA.
HERE YOU SEE PATIENTS IN THE
INITIAL PHASE OF ONE, TWO OR
THREE DOSES FOLLOWED BY THE SIX
MONTHS OBSERVATIONAL PERIOD.
THE LINE IS NO CHANGE. THE RED
IS 45 MILLIGRAMS AND THE GREEN
IS 71 MILLIGRAMS AND THE DOSING
REGIMENT, THE FIRST DOSE AND
THEN TWO MONTHS THE SECOND DOSE,
ONE MONTH LATER THE THIRD DOSE
AND THE SIX MONTHS OBSERVATIONAL
PERIOD. SO HERE WHAT YOU CAN
SEE IS, FIRST THE EFFECT SEW
REVIEW NEVER SEN. YOU SEE THE
REDUCTION AND THE EFFECT
SUSTAINED BEYOND THE LAST DOSE
INTO THE SIX MONTHS OF
OBSERVATIONAL PERIOD. AND YOU
SEE THE DECREASE IN SEIZURES
WHICH IS A DRAMATIC DECREASE.
IN SEIZURES, IF WE ZOOM IN THE
PATIENTS WHO WERE DOZED WITH
DOSES OF 70 MILLIGRAMS ON THE
LEFT-HAND SIDE YOU CAN SEE
PATIENTS THAT RECEIVE ONE DOSE
OF 70 MILLIGRAMS AND THEN
OBSERVE THAT THREE MONTHS AND
THEN AT SIX MONTHS POST SINGLE
DOSE WHICH WE ALREADY SAW AN
EFFECT OF A SINGLE DOSE BUT WHEN
WE LOOK AT TWO AND THREE DOSES
AND COMBINED THE DATA BECAUSE
THERE WAS NO DIFFERENCE IN THE
EFFECT OF TWO OR THREE DOSES YOU
CAN SEE THAT IN THREE MONTHS
THERE'S AN 85% REDUCTION IN
SEIZURE FREQUENCY AND THAT
REDUCTION IS SUSTAINED THROUGH
THE SIX MONTHS OBSERVATIONAL
PERIOD. WE THEN GO INTO THE
EXTENSION PERIOD. ANYTHING
BELOW IS A REDUCTION AND THE
OPEN LEVEL EXTENSION IN ORANGE
ARE THE PATIENTS THAT WE SEE 30
OR 45 MILLIGRAM DOSES AND THEN
WENT ONTO THE LABEL EXTENSION 30
OR 45. AND THEN IN GREEN WE'RE
SEEING THE 70 MILLIGRAM COHORT
THAT RECEIVED THREE DOSES OF 70
MILLIGRAMS AND THEN WENT ONTO AN
OPEN LABEL EXTENSION OF 45
MILLIGRAMS JUST ONE DOSE WHEN
THE DATA HAPPENED. HERE YOU CAN
SEE FIRST OF ALL THE EFFECT FROM
THE INITIAL DOSING, SIX MONTHS
AND THEN THE OPEN LABEL
EXTENSION, IT SUSTAINED SO THE
EFFECT DIDN'T GO AWAY AS A
POTENTIAL PLACEBO EFFECT AND
SECOND THE 75 LOADING DOSE
FOLLOWED BY 45 MILLIGRAM OPEN
LABEL EXTENSION SEEMED TO
MAINTAIN THE SEIZURE FREQUENCY
REDUCTION WHICH IS REALLY
IMPORTANT FOR US TO SEE BECAUSE
IT'S VERY INFORMATIVE FOR WHAT
WE CAN DO IN THE TRIALS. NOW
MOVING ONTO TO COGNITIVE PARTS
OF THE DISEASE. PATIENTS, FIRST
OF ALL, SEIZURES DON'T CHANGE.
THEY CONTINUE TO HAVE SEIZURES.
THE SEIZURE FREQUENCY DOES NOT
CHANGE OVER TIME IN OUR HISTORY
STUDY AND FROM THE COGNITIVE
PERSPECTIVE HERE EVERYTHING IS
TO THE RIGHT. WHICH EVERYTHING
IMPROVES IN THE NATURAL HISTORY
EVERYTHING GOES TO THE LEFT AND
THINGS DEVIATE FROM THE NORM AND
SO WHAT WE SAW AFTER TREATMENT
AND THESE ARE PATIENTS THAT WENT
ONTO THE OPEN LABEL AND SAY THE
EXTENSION ON THE 30 MILLIGRAMS
AND 45 MIL GRAMS DOSE IS DATA
THAT DOES NOT INCLUDE THE 70
MILLIGRAM DOSE YET.
WE SAW A CLINICAL AND MEANINGFUL
IMPROVEMENT IN RECEPTIVE
COMMUNICATION, IN PERSONAL
SKILLS, INTERPERSONAL
RELATIONSHIPS, AND SOME SIGNS OF
IMPROVEMENT IN THE OTHER TWO
MEASUREMENTS. WE DID THESE
MEASUREMENTS SIMILAR TO WHAT
OTHER SECTION WAS DONE YESTERDAY
AND WE'RE SUPER EXCITED TO BE
ABLE TO SEE THAT OUR TREATMENTS
ARE ONLY ADDRESSED THE SEIZURE
FREQUENCY BUT THERE ARE
IMPROVEMENTS IN COGNITION IN
BEHAVIOR THAT ARE EXTREMELY
IMPORTANT. AND WE LOOKED AT
WHAT CLINICAL AND MEANINGFUL
IMPROVEMENTS IN THE OVERALL
POSITION AND THESE WERE
MEASUREMENT BY CLINICIANS AND
CAREGIVERS ON THE LEFT-HAND SIDE
ARE THE CLINICAL GLOBAL
IMPRESSION CHANGES AND AS YOU
CAN SEE IN THE DARK BLUE GRAY
THESE ARE THE NATURAL HISTORY
PATIENTS. AND THERE'S LITTLE TO
NO IMPROVEMENT ACROSS TIME BUT
THEN THE PATIENTS TREATED WITH
SEW REV NEVER SEN WE SEE A VERY
CLEAR IMPROVEMENT OVER TIME.
THE SAME IMPRESSION IN THE
NATURAL HISTORY STUDY DID NOT
SHOW ANY IMPROVEMENT WHEREAS
PATIENTS IN THE -- TREATED WITH
SEW REV UNER SEN WERE SHOWING
IMPROVEMENT. JUST TO SUM PRIZE,
SORRY, 50 DATA. SO ALL SINGLE
AND MULTIPLE DOSE AFTER 70
MILLIGRAMS WERE GENERALLY WELL
TOLERATED WHICH IS GREAT. WE
DID SEE TREATMENT EMERGING
ADVERSE EFFECTS. THAT WERE
MOSTLY PROCEDURAL AS WELL AS THE
PROTEIN ELEVATIONS. AND THEN
ALSO TREATMENT OH SEVERE ADVERSE
EFFECTS BUT THEY WERE NOT DEEMED
TO BE DRUG RELATED WITH THE
EXCEPTION OF THE PATIENT WHO
EXPERIENCED THIS. IN THE OPEN
LABEL EXTENSION WE DID SEE
ELEVATION OF CSF PROTEIN LEVELS
BUT THIS DOESN'T SEEM TO BE
SPECIFIC TO THE SEW REV NEVER
SUN AND THIS IS FOR SPINAL
MUSCULAR ATROPHY AND OTHERS HAVE
SEEN THIS PROTEIN ELEVATION AND
THERE IS NO CLINICAL CORRELATION
AT ALL WITH THIS ELEVATED
PROTEIN. AND SO WE ARE NOT
CONCERNED ABOUT THIS. SO JUST
TO SUMMARIZE, WE HAVE SEEN A
SIGNIFICANT REDUCTION IN SEIZURE
FREQUENCY DOWN TO 85%. WE ALSO
SEE A SUSTAINED EFFECT IN THE
OPEN LABEL EXTENSION AND WE SEE
IMPROVEMENT IN COGNITIVE AND
BEHAVIORAL PHENOTYPES OF DRUGS
IN THE PATIENTS. WE'RE
CURRENTLY GEARING UP FOR
CONVERSATIONS WITH THE FDA TO
FOLLOW OUR CLINICAL TRIALS AND
OUR DATA SUPPORTS A LOADING DOSE
OF 70 MILLIGRAMS FOLLOWED BY
MAINTENANCE DOSE OF 45
MILLIGRAMS EVERY FOUR MONTHS.
THAT I WOULD LIKE TO THANK YOU
FOR YOUR ATTENTION AND MORE
IMPORTANTLY THE FAMILY WHO IS EM
BARKED ON THIS ADVENTURE WITH US
AND TRUST IN US WITH THEIR KIDS.
THANK YOU.
>> I'M NOT A CLINICIAN SO THE
DATA ARE INCREDIBLY INSPIRING.
KRRGS. I THINK YOU SOLVED ONE
OF THE MAJOR CHALLENGES FOR A
BROAD FIELD OF TREATMENT FOR
EPILEPSIES AND I WOULD LIKE TO
CONFIRM THIS IS THE CASE. THERE
IS NO MONKEY.
>> OH, THERE IS?
>> THERE IS NO MONKEY THAT
YOU'RE USING.
>> OH, YES, SO, NO.
>> SO MY QUESTION IS, SOR --
>> YOU SOMEHOW MANAGED TO BRIDGE
A PLACEBO PHARMACOLOGY IN A
MOUSE MODEL WITH A STARTING DOSE
IN A HUMAN. SO IF YOU'RE AT
LIBERTY TO SAY JUST SO THAT
EVERYBODY CAN LEARN AS WE'RE
BUILDING WHATEVER DID YOU HAVE A
MY BIOMARKER? HOW DID YOU
BRIDGE?
>> ISABEL: GREAT QUESTION. NOW
THERE IS BUT NOT WHEN WE STARTED
SO THE MOUSE WE WERE ABLE TO
CONNECT THE DOTS BECAUSE THERE
IS TARGETING ENGAGEMENT AND
PROTEIN UPREGULATION IN THE
PRIMATE. TO --
>> AUDIENCE: DID YOU SAY THERE
IS EVIDENCE?
>> ISABEL: YES.
>> AUDIENCE: WHAT IS THAT
EVIDENCE?
>> ISABEL: YEAH. YEAH. THE
SEQUENCE THAT WE USE THE FULLY
CONSERVED ACROSS ALL SPECIES SO
MOUSE, NONHUMAN PRIMATES THAT
MADE CONNECTING THE DOTS VERY
EASY. THANK YOU.
>> AUDIENCE: THAT WAS THE
IDENTICAL THING DONE. IS IN THE
NORMAL MONKEY. THEY WERE ABLE
TO LOOK AT THE BREAKDOWN OF THE
RNA AND INCREASES IN THE
PROTEIN. BUT I HAVVHAVE A COUP
QUESTIONS. THE PROTEIN
INCREASE, THAT WAS THE HARBINGER
IN THE IMPLEMENT ASO, THAT'S THE
HARBINGER OF THE LEG WEAKNESS
HAVE YOU SEEN THOSE AFFECTS IN
YOUR ASO OR MOU?
>> ISABEL: YEAH, SHOULD HAVE
MENTIONED THAT, THIS IS FULLY
MODIFIED MOE, IT'S AN 18. AND
WE DIDN'T SEE, NO, NONE OF THAT.
AND THIS IS THE THING, EVEN
THOUGH THE CHEMISTRY MIGHT BE
THE SAME, WE KNOW THE SEQUENCE
HAS EFFECTS. THE SEQUENCE OF
THE ASOS. AND WE'VE SEEN IN
CLINICAL STUDIES WE PUT ASOS FOR
THE SAME TARGET IN SOME HAVE
VERY TRANSIENT BUT STILL SOME
ADVERSE EFFECTS IN MICE, IN WILD
TYPE MICE AND SOME DON'T. VERY
CLEARLY RIGHT FROM THE GET-GO
THE SAME CHEMISTRY LEAD TO TWO
DIFFERENT AFFECTS AND SOME MAY
HAVE THE SAME SIDE EFFECTS AND
SOME MAY NOT.
>> AUDIENCE: HOW MUCH WAS THE
PROTEIN ELEVATION?
>> ISABEL: LET ME GO BACK.
>> AUDIENCE: I CAN TALK TO YOU
MAYBE LATER.
>> ISABEL: I DON'T KNOW OFF THE
TOP OF MY HEAD.
>> AUDIENCE: THAT'S A RELATIVELY
SMALL AMOUNT AND I CAN TALK TO
YOU LATER. I'M INTERESTED IN
HOW MUCH MORE THAT IS THAN IN
NATURAL HISTORY. I A.M. ASS
ASSUME --
>> ISABEL: YOU CAN DO THE LINE
ACROSS AND IT DOESN'T GET BETTER
AND THIS IS THE COGNITIVE AND
BEHAVIORAL. AND SO, NOW, TRY TO
REMEMBER, YOU KNOW, THE OTHER
ONES WERE GOING ON THE OTHER
DIRECTION BASICALLY, YEP.
>> AUDIENCE: THEY'RE ACTUALLY
GOING DOWN.
>> ISABEL: MOST OF THEM ARE
GETTING WORSE. THE PATIENTS ARE
BASICALLY, THEY KEEP, THE
DISTANCE BETWEEN THE STANDARD
NORMAL, YOU KNOW, COGNITIVE IN
THESE PATIENTS, IT GETS WIDENED
BASICALLY OF THE AGE AND SO
THAT'S WHY THINGS GET WORSE AND
WORSE, YEAH. ABSOLUTELY.
WHOOPS. CAN I GO BACKWARDS?
YES, I CAN. YES I CAN. OH, THE
DIFFERENT ANTIEPILEPTIC DRUGS.
CLOSE TO 50% ARE ALREADY ON
THESE.
>> AUDIENCE: IF YOU CAN COMMENT
ON THE AGE OF THE PATIENTS THAT
WERE TREATED IN THE TRIAL AND IF
YOU SEE ANY DIFFERENCES IN THE
RESPONSE? AND THEN SECONDLY,
THE INCLUSION CRITERIA AS FAR AS
TYPE OF MUTATIONS YOU INCLUDED
BOTH THE TRUNCATIONS?
>> ISABEL: YEAH, YEAH, WE
INCLUDED THE TRUNCATIONS AND
THAT'S A GOOD QUESTION. WE KNEW
THERE WERE LOTS OF FUNCTIONS
BECAUSE OF THE CLINICAL
PHENOTYPE AND WHAT WAS KNOWN
ALREADY. BUT BECAUSE WE'RE
UPREGULATING BOTH, WE DIDN'T
KNOW THEY WERE GOING TO TAKE THE
SPOTS BUT WHEN WE SEPARATED,
THERE WERE NO DIFFERENCES SO WE
WERE SUPER EXCITED ABOUT THAT.
SO THAT WAS ONE OF THE
QUESTIONS. NOW I -- OH SO THE
PATIENTS ARE 2-18 AND I THINK I
HAVE ANOTHER SLIDE THIS THE
BACKUP JUST IN CASE. SO THIS IS
BROKEN DOWN IN DOSES. TWO
DOSES, THREE DOSES, TWO MONTHS,
THREE MONTHS, SIX MONTHS BASED
ON AGE. YOU CAN SEE IN THE
HIGHEST RESPONDING GROUPS, THEY
ARE 14 YEAR OLDS. AGAIN, NO
CLEAR EFFECT ON AGE EITHER.
YEP.
>> AUDIENCE: EXCITING DATA ON
THE TRIAL. I WAS VERY
INTERESTED IN THE POSSIBLE
VARIABILITY RESPONSE BETWEEN
PATIENTS. THERE WERE SOME THAT
RESPONDED, SOME DID NOT. DID
YOU SEE ANYTHING LIKE THAT?
>> ISABEL: OF COURSE THERE WAS
VARIABILITY AND IF WE GO TO, I
THINK. HERE IN THE SEIZURES,
FOR EXAMPLE, YOU CAN CLEARLY SEE
THAT NOT ALL PATIENTS RESPOND AT
EXACTLY 85% BUT THE VARIABILITY
ACROSS THE 70 MILLIGRAM GROUP
THIS IS WHERE THINGS GOT A
LITTLE BIT MORE NARROW SO THE
HIGHER THE DOSE THAN THE
VARIABILITY WOULD BE DOWN.
>> AUDIENCE: INTERESTING.
>> ISABEL: THANK YOU.
>> ONE MORE QUESTION.
>> AUDIENCE: CAN YOU COMMENT ON
WHAT SORTS OF PHASE THREE
DESIGNS ARE YOU CONSIDER
SOMETHING ARE YOU GOING A RUN IN
STUDY OR A RANDOM CONTROL TRIAL?
>> ISABEL: WE ARE CONSIDERING A
PLACEBO RANDOMIZED CONTROL.
THOSE ARE CONVERSATIONS WE'RE
GOING TO BE HAVING WITH THE FDA
TO UNDERSTAND, YOU KNOW, BUT,
YES, IT'S GOING TO HAVE A FULL,
YEP. THANK YOU. THANKS FOR THE
QUESTIONS.
>> AUDIENCE: (APPLAUSE).
>> LORI: I ADMIT THAT'S BIASED
BUT THAT'S PRETTY IMPRESSIVE.
NEXT IS DR. GAIA WHO IS GOING TO
TELL US HOW TO TARGET THE RIGHT
CELLS AT THE RIGHT TIME. GAIA,
THANK YOU
>> KATIE: THANK YOU. SO I WILL
TALK TODAY ABOUT SOMETHING WE
TAL
TALKED ABOUT WITH GENE THERAPY
DEVELOPMENT. ALL RIGHT, CAN I
GO ON? READY? OKAY. THIS ONE?
OKAY. THANK YOU. SO WE STARTED
THINKING WHY GENE THERAPIES
MIGHT BE INEFFECTIVE AND THIS IS
SOMETHING THAT MIGHT BE
POSSIBLE. THERE MAY BE
LIMITATIONS THAT WE ARE ADOPTING
SO WE ARE NOT ACHIEVING THE
CORRECT LEVEL OR GENE EXPRESSION
THAT WE WOULD LIKE IN THE CELL
SO IT'S TOO LOW OR TOO MUCH OR
LOW DELIVERY EFFICIENCY SO WE
ARE TALKING ABOUT THE IMPORTANCE
OF CHOOSING THE RIGHT AMOUNT TO
TARGET THE PART OF THE TRAIN
THAT WE WANT TO TARGET AND WE
MAY HAVE LOW SPECIFICITY, WE MAY
TARGET MOST OF THE BRAIN BUT NOT
THE RIGHT. WE WANT TO TARGET ON
THE RIGHT CIRCUITS. OR LAST ON
THE LIST, WE MAY HAVE A PROBLEM
IN TIMING IN GENE THERAPY
DELIVERY AND SO WHY TIMING IS
IMPORTANT? IT IS IMPORTANT IN
PATHOLOGY BECAUSE WE SHOULD KNOW
THAT, OR DO KNOW THAT THE
INITIAL PATHOLOGICAL MECHANISM
IS MAYBE A GENE MUTATION
FOLLOWED BY MANY CHANGES IN
SEQUENCE. SOME OF THEM ARE MORE
ADAPTIVE CHANGES AND SO THIS
MODIFICATION LEADS TO A
SITUATION THAT MAY BE DIFFERENT
FROM THE ONES THAT YOU INITIALLY
TARGETED SO WE MAY HAVE A DESIGN
IN GENE THERAPY STRATEGIES THAT
HAVE NOT EVIDENCE FOR THE
CONDITION OF THE BRAIN THAT WE
ACHIEVED. AND THIS IS EVEN MORE
IMPORTANT. WE CAN SEE THE
DEVELOPMENT TA AND EPILEPTIC
ENRECEIVE LOP PA THINK BECAUSE
THERE'S CHANGES IN THE PROCEDURE
BUT ALSO ADDING DISFUNCTION INTO
IN THE DEVELOPMENT PROCESS.
SO GENE MUTATION IN THESE
SPECIFIC JEEP MAY HAVE AN IM
IMPACT. AND THIS IS DURING THE
RODENTS AND SO IT IS PART OF THE
DEVELOPMENTAL PROPERTY THAT CAN
BE ALSO WORSENED BY THE
PROCEDURE AND SO WE BRING TO YOU
AGAIN A SPECIFIC EXAMPLE OF THE
DRAVET SYNDROME. AND THIS IS
SHOWN BY HAPPEN LO
INSUFFICIENCY. AND YOU SEE THIS
IN THE MAIN LOCALIZED IN THE
SPECIFIC AREA WHERE THIS IS
RELEVANT. AND THERE'S AN
ESSENTIAL ROLE BECAUSE YOU
LOCALIZE. WHERE THIS IS RELEVAN
THERE'S AN ESSENTIAL ROLE
BECAUSE YOU LOCALIZE. AND
INITIALLY, THIS SHOWED US IT'S
REACHING A NEURON AND IT IS WHY
THE SPECIFIC ACTIVITY OF THIS IS
FAILED. SO YOU CAN SEE THIS
TYPE OF MOUSE IN THE NEURONS ARE
NOT ABLE TO CONTROL. WHILE AT
LEAST AT THE FIRST GLANCE THE
NEURONS SEEM TO BE PRESERVED SO
INDICATING A FUNCTION SPECIFIC
OF THE NEURONS COULD UNDERLIE
THE BALANCE BETWEEN THE THIS
AND CAN CAUSE SEIZURES.
THE POWS START TO APPEAR AROUND
THE THIRD WEEK. SO MICE START
TO DIE. AND LATER ON THEY ALSO
START TO HAVE, APPEAR WITH
ANXIETY AND THEY ARE
HYPERACTIVE. SO BUT FEW YEARS
AGO AN IMPORTANT PAPER COME OUT
DESCRIBING THAT WHAT IS
CONSIDERED TO BE ALL MATTER OF
DISEASE, THE NEURON FUNCTION IS
TRANSIENT. IT APPEARS IN THE
ONSET OF DISEASE AND THIS HAS
COMPLETELY CHANGED THE VIEW THAT
WE HAVE IN THE PATHOLOGY AND IT
IS POSSIBLE SO PROBABLY TO
RECRUIT INTO THE SEGMENT OR
OTHER EDUCATION. AND SO WHAT IS
IN THE FEN PHENOTYPES. THERE IS
SOMETHING ELSE.
AND THE LAB SHOWED THAT WHILE
THE FIGHTING IS RECOVERED WHAT
IS THERE IS THE PROPAGATION OF
THE AX ON AND SO THERE IS MORE A
PROBLEM OF THE SUBMISSION INTO
THE NEURONS. AND THE OTHER
SIDE, WHAT YOU OBSERVE, IS THAT
THERE ARE SEQUENCES THAT ARE
EXCITABLE. AND ARE DESCRIBED
AND THESE ARE COMING FROM THE
CORTEX. SO YOU HAVE THE
CONDITION WHICH WE HAVE THE
NEURON FUNCTION AT LEAST AT THE
ONSET OF DISEASE AND LATER ON WE
HAVE THE COMPLETE CHANGED
SITUATION AND SO IN THIS
CONDITION PATIENTS WILL BE
SUFFICIENT TO JUST INTRODUCE
THIS AGAIN TO ACHIEVE. AND YES,
THERE'LL BE A CRITICAL WINDOW
FOR DELIVERY AND NOW WE HAVE THE
BEAUTIFUL REPRESENTATION SHOWING
THE BEAUTIFUL DATA GENE THERAPY.
THAT ACTUALLY WHEN WE STARTED
THE QUESTION, THERE WERE OF
COURSE MANY OTHER INTERESTS,
MANY GROUPS WORKING ON GENE
THERAPY STRATEGIES.
ESSENTIALLY, ALL WITH THE TWO
MAIN STRATEGIES POSSIBLE UP TO
YESTERDAY I WOULD SAY WHEN THESE
WERE ALSO A WAY, A GOOD WAY TO
GO. SO THERE WERE ESSENTIALLY
TO PLAN A NEW COPY OF THE GENE
OR BOOSTING EXPRESSION TO MAKE
IT -- PRODUCE WHAT IS REQUIRED
TO MAKE NEURONS TO WORK AGAIN.
AND SO TO OUR BEST IMPRESSION WE
THOUGHT WE COULD NOT DO JUST
SIMPLY HAVE A GENE STRATEGY SO
WE ARE CARRYING A SUBSET IN ONE
GENE SO IT CAN HAVE THE AX ON
AND SO THESE MICE WERE BORN BUT
THEY CARRY THE SEQUENCE AND BY
THE COMBINATION WE CAN STOP THIS
AND RESTORE A FUNCTIONAL ALLELE
IN TIME DURING THE PROGRESSION
OF DISEASE AND SO I MEAN,
GETTING INFORMATION FOR GENE
THERAPY DELIVERY. AND SO I WANT
ALSO TO EXPRESS THE FACT THAT WE
ARE LIKELY MIMICKING A GENE
THERAPY BASED ON THE MUTATION
BECAUSE WE ARE RELYING ON THE
SEQUENCE OF THE SAME GENE
BECAUSE WE ARE JUST DEACTIVATING
THE GENE AND NOT -- CLARITY, FOR
EXAMPLE, IN THE PROMOTER. SO
HOW WE COULD ACHIEVE THE CONTROL
OF TIME FOR THE ACTIVATION. WE
CAN DO THIS IN OTHER WAYS. BUT
WE DECIDE TO DO THAT USING THE
DELIVERY OF THE RECOME BY --
RECOME BY NICE BUT WE USE THE
VIRUS.
BETWEEN THE SYSTEMICALLY
CONSIDERING WHAT IS PRESENT.
AND USE THE BRAIN EFFICIENCY.
SO WE WE W RELEASE THIS AT C 2.
SO WE STRESSED THAT OUR STRATEGY
WAS ABLE TO INCREASE AND RESTORE
THE LEVEL OF THE PROTEIN AND SO
ESSENTIALLY WE SEE THAT OUR
SUBSETS FIRST OF ALL WAS
WORKING. SO WITH MICE, WE WERE
EXACTLY AT THE LEVEL OF THE
PROTEIN. AND IT WAS TRUE IN
DIFFERENT BRAIN COMPARTMENTS IN
THE CEREBELLUM WHILE WHEN YOU
DELIVER, WE COULD ACHIEVE AGAIN
THE LEVEL OF ONE IN THIS
COMPARTMENT SO WE ARE REALLY
RESTORING THE LEVEL OF THE
PROTEIN. AND SO GIVEN THIS IS
WORKING PROPERLY WE CAN START
OUR FUNCTIONAL PROPERTIES. SO
IN THIS THE MICE START TO DIE
AND WE WERE CHECKING TO RECORD
ABOUT THE ENZYME ASSESSING THE
SEIZURES PHENOTYPE JUST IN THIS
CASE BY THE OPTION AND WE COULD
SEE ESSENTIALLY THAT WE WERE
ABLE, WITH A SINGLE INJECTION WE
WERE ACTIVATING THE GENE. WE
COULD ACHIEVE THAT AND ALSO
FURTHER IN THE SEIZURE BUT THIS
WAS KIND OF EXPECTED BECAUSE WE
WERE KIND OF FIXING THE GENE LOG
EVEN BEFORE THE GENE STARTS TO
BE EXPRESSED BUT WHAT HAPPENS
LATER? THERE'S THE GENE
THERAPY, IN THIS CASE, SO MICE
WERE IN THE CHROMOSOME. AND
THEN AGAIN WE SEE A COMPLETE
RESCUE IN OUR TEEN TYPE AND THE
MICE WERE STILL DYING ALSO OF
THE SPECIFIC POINTS. AFTER GENE
THERAPY SO WHAT ABOUT THE
SEIZURES? SO, AGAIN, MICE IN
WHICH EXCEED 45, AND MICE WERE
PRETTY HAPPY IN THIS CASE WHICH
IS MORE EFFORT IN PLANTED AND
TWO IN THE DATA FROM THE CORTEX
AND SO THESE MICE FOR A LONG
TIME SO FOR TWO WEEKS AND WE
COULD HAVE SERVED AT OUR CONSOLE
ANIMAL LIKE MODEL WHERE THE
SEIZURES ALONG THE TWO WEEKS OF
OBSERVATION SO YOU SEE IN THE
VERTICAL LINE EACH MONTH AND THE
HORIZONTAL LINE YOU SEE THE
SEIZURE THAT MICE HAD DURING THE
TWO WEEKS. SO IT'S ANOTHER LOG
LIKE THE SEIZURE DIARY.
INSTEAD, WHEN -- IN MICE WE HAVE
ONCE THAT DEACTIVATED WE NEVER
HAVE THIS DURING THE TWO WEEKS
OF OBSERVATION. I JUST WANTED
TO PICK THAT AND ONCE THIS IS
INCREASED WE TREAT THE MICE AND
SUBJECT THEM TO THE SEIZURES AND
IF WE DIDN'T THE MICE HAVE THE
SEIZURE IN THIS CASE. ALL THE
CONTROLLED MICE HAD A SEIZURE
WHILE NONE OF THE MICE WERE
DEACTIVATED WITH P30. SO WE
HAVE THAT WITH THE PHENOTYPE
WHAT ABOUT THE REACTIVATION THAT
IS IMPORTANT ALSO FOR SUFFICIENT
RECOVERY. SO WE HAVE THE MICE
ACTIVITY IN OPEN SCALE SETS.
AND THEY LOOK AT THE MICE. SO
THEY HAVE THIS COMPARED TO
OFF-SITE ANIMALS WHILE MICE WERE
DEACTIV
DEACTIVATED. AND THEY ALSO HAVE
THE SOCIAL SKILLS. WE HAVE 30
MICE WHICH HAD THE SKILLS WHILE
OUR MICE. AND WE HAVE THE CAN
SEE THAT WHILE JUVENILE MICE
MAKE MORE MISTAKES INTO
NAVIGATING THE MAZE THE MICE
THAT WERE DEACTIVATED ARE MORE
PARTICULARLY IF YOU LOOK AT THE
NUMBER OF THE CHOICE YOU DO SEE
THAT THE MICE NEVER OVERCOME THE
LEVEL. DURING THOSE DATASETS
WHILE IN THE WILD TYPE THEY HAVE
THE TIME ALREADY AT THE FACTOR.
SO WHAT ABOUT LATER ON?
JUVENILE MICE CAN BE COMPARED TO
PATIENTS IN FEW YEARS AFTER
DIAGNOSIS BUT WHAT ABOUT
ADAPTATION SHOULD THEY BE
INCLUDED IN CLINICAL TRIALS AND
WE FIND THE WINDOW SO THAT WE
COULD EFFICIENTLY AND WE PERFORM
A LATE OBSERVATION OF THIS GENE
IN THE MICE AND SO IN THIS CASE
WE COULD HAVE THE ANIMALS EVEN
BEFORE ACTIVATION OF THE GENE
AND RECORD THE ACTIVITIES AND
SEE SEE THE MICE IN THIS PHASE
OF ABILITIES AND MICE WERE
UNDERLYING THEM. AND, AGAIN,
WHAT WE SAW WAS THAT THE
CONTROLLED MICE CONTINUE TO HAVE
SEIZURE FOR 21 DAYS AT LEAST
WHILE THE OTHER ONE HAVE A
SEIZURE AROUND ONE WEEK AFTER
THE THESE MICE CHALLENGE AGAIN
WITH AN INCREASING IN BODY
TEMPERATURE YOU CAN SEE THAT
THE, THE SEIZURE DETERMINED THE
USE WHEN THE BODY WAS BEING
BROUGHT BACK TO THE FUTURE. SO
TO SUM UP, WE CAN TELL THAT WHAT
WE LEARNED IS WE COULD RESCUE
THE SEIZURES AT BOTH THE
ALTERATION. AND SO THIS IS AN
INDICATION ALSO OF COURSE FOR
PATIENTS BECAUSE THESE MEAN THAT
AN OPTIMAL GENE THERAPY
ADMINISTERED AFTER DIAGNOSIS CAN
MAKE A DIFFERENCE AND IMPROVE
THE OUTCOME FOR BOTH SEIZURE AND
BEHAVIORAL ALTERATION. WE GOT A
VERY GOOD START IN TERMS OF SE
SURE RE -- SE SURE REDUCTION.
AND CONSIDERING THE ROLE OF THE
DEVELOPMENT WE HAVE THE PATIENTS
TO ENSURE OF THE PERIOD THAT A
TYPICAL WINDOW DEVELOPMENT TO
GET ADMINISTRATION OF THE
PHENOTYPE AND THIS IS
SPECIFICALLY FOR THE THERAPY.
TO DO THAT, I'M SORRY THIS SLIDE
IS ALL MESSED UP, ESSENTIALLY,
WE USE THE CONDITION NOT IN
MOUSE MODEL IN THIS CASE SO WE
HAVE THESE MOUSE IN WHICH IT CAN
BE INSERTED. IN THIS CASE WITH
A MOUSE EXPRESSING THE THIS.
AND ESSENTIALLY WE HAVE HAVE
CONTROL IN TIME TO PRODUCE THE
EFFICIENCY. SO IT'S THE
EXPERIMENT AS BEFORE AND SO WE
WERE MAINTAINING THE LEVEL OF
THE FUNCTION NUMBER ONE. AND
COMPARING, LOOKING AFTER THE
PHENOTYPE OF THESE MICE AND
COMPARING THAT TO MICE IN WHICH
WE HAVE THE SUFFICIENCY THAT WAS
USED. AND WE CONSIDER THAT IN
OTHER MICE SO WHAT WE CAN TELL
IS CLEAR IS THAT ALL THE MICE IS
NOT SUFFICIENT TO PREVENT
SEIZURES. IT'S NOT THE WINDOW
OF DEVELOPMENT TO GET RID OF THE
SEIZURES. AND ALSO WHEN THESE
MICE WERE CHALLENGED THERE IS NO
DIFFERENCE IN TERMS OF THERMAL
UP DUCTION SO THAT THE SEIZURE
IS COMPATIBLE AND ALSO IN TERMS,
TOO, ALL THE MICE HAVE TO DIE
AND IF WE MERGE THIS NORMALIZING
WHEN THE TIME OF ADMINISTRATION
WE DID SEE THAT IN ALL THESE AND
WHAT ABOUT BEHAVIOR IN THE
SIGNAL OF MICE WERE INTERACTING
SO THEY ALSO HAD THE SPECIAL
FUNCTION. THE OTHER THING THAT
CAME INTO CONTACT. SO
ESSENTIALLY WE DO SEE THESE
MICE, WE CONSIDER ARE TAKE MORE
TIME TO REACH THE PLATFORM.
THIS IS ONE TYPE. WHAT -- SO
MICE IN WHICH WE MAINTAIN A
NORMAL LEVEL OF NUMBER ONE AND
WE HAVE THE SUFFICIENCY, WE HAVE
THE PHENOTYPE. SO IN THAT
POSITION, THEY ARE LIKE MOST OF
THE MICE WHILE IN THE REST OF
THE STATE, THEY ARE MORE LIKELY
ONE SIZE. BUT IT DOES IMPRESS
ME THAT MICE, WE PROTECT THE
BRAIN AND IT IS RESCUED
COMPLETELY BY THE PERFORMANCE IN
THIS TEST, SO, AGAIN, WHAT WE
LEARNED FROM HERE IS THAT IN
ORDER TO PROTECT THE BRAIN FROM
SPECIFICALLY WHAT WE NEED TO
HAVE THE LEVEL, NUMBER ONE,
LIFELONG AND THIS GOES TO GET
PROTECTION FROM SEIZURES AND
ALSO THE PERFORMANCE IN THE
TEST. AND WHAT I SIGNATURE --
SUGGEST IS THERE PARTICULAR
WINDOWS.
AND FOR PARTICULAR GENES COMING
OUT NOW WE SHOULD SET THIS
POSSIBLY IN AN IDEAL WAY LIKE
USING THE GENETIC MODEL IN ORDER
TO GET RID OF THE MEDIATION THAT
THE GENE THERAPIES MAY BE AND
ALSO MAY BE MORE THE MESSAGE
THAT THE GENE, RELATED TO THE
POSSIBLE EPILEPTIC SYNDROME AND
I AM FINISHED NOW. AND
ESSENTIALLY WILL SHOW YOU THE
PLACE WHERE I COME FROM. THIS
IS MILAN AND THE TEAM WHICH I AM
WORKING WITH. VERY FASCINATING
WHAT THEY ARE DOING AND ALL THE
PEOPLE WHICH CONTRIBUTED AND
COLLABORATED TO THE WORK AND
THANK YOU FOR THE ATTENTION.
>> AUDIENCE: (APPLAUSE).
>> AUDIENCE: BEAUTIFUL WORK. I
WAS WONDERING IF YOU COULD
COMMENT ON WHETHER YOU THOUGHT
ALL CELL TYPES NEEDED TO BE
CORRECTED THAT YOU'RE TARGETING
WITH THIS? IT LOOKS LIKE YOU
USE A UBIQUITOUS PROMOTER OR
WHETHER YOU THOUGHT ABOUT USING
PREDRIVERS THAT HAVE DIFFERENT
CELL TYPES? TELL US A LITTLE BIT
ABOUT HOW HUTMUCH DO WE REALLY
NEED?
>> GAIA: VERY GOOD QUESTION AND
ALSO, FOR THE FIRST EXPERIMENT,
WHAT WE WERE TO DO WAS JUST
TARGETING ALL THE CELLS AROUND.
AND SO WE USE AND WE HAVE A
PROMOTER IN THE EXPERIMENTS BUT
WHAT IS REALLY IMPORTANT IS THAT
WE ARE RELYING ON THE EXPRESSION
OF THE GENE. SO IT WILL BE IN
ALL THE CELLS AND WE CORRECT THE
GENE LOSSES IN ALL THE CELLS
THEN IT WILL STILL BE RELATED TO
WHAT IS THE REGION OF THE GENE.
WHAT WE ARE DOING NOW IS ALSO
MAKE SPECIAL CONTROL SO WE ARE
ENTRUSTED WITH THE SPECIFIC CELL
TYPE PREDRIVER IN POSSIBLE WITH
THE CONVERGENCE WITH THE NEURONS
AND WE DO SEE THAT EARLY IN THE
DEVELOPMENT SO YOU TARGET THE
NEURONS WITH A RECOVERY TIME OF
PHENOTYPE BUT IT'S NOT CLEAR
LATER ON SO IN THE PHASE OF THE
DISEASE YOU SEE TARGETING ALL
THE NEURONS IS NOT SIEVE. SO
YEAH THIS IS WHAT WE GET.
>> AUDIENCE: THANKS THAT WAS
BEAUTIFUL. I HAVE THE OPPOSITE
QUESTION IS IT ENOUGH TO TARGET
ALL THE BRAIN AND I'M REFERRING
IN PART TO LORI'S WORK AND ALSO
WITH CARDIAC CONTRIBUTION TO NOT
JUST THE SEIZURES BUT THE SUDDEN
DEATH RISK
>> GAIA: THERE ARE STUDIES
COMING. HOW MUCH IS THE
CONTRIBUTION LONG-TERM. THERE
ARE STUDIES IN INACTIVATING THE
JEEP WAS STILL SUFFICIENT TO
ACHIEVE A PHENOTYPE SO IT'S THE
CONTRIBUTION TO THAT, YEAH. SO
>> THANK YOU, GAIA. I'D LIKE
THEM TO COME TO THE FRONT AND
THEN WE'LL PUT GEMMA BACK ON,
PLEASE. DO WE SEE GEMMA?
>> GEMMA: I HEAR YOU BUT I DON'T
SEE ME.
>> LORI: THERE SHE IS. OKAY.
LET'S HAVE A PANEL DISCUSSION.
GABBY.
>> AUDIENCE: HI, I'M GABBY, SO
GAY I CAN'T RECOLLECTS REALLY
EXCITING WORK. I HAVE A QUICK
QUESTION ABOUT IS THERE, YOU
KNOW, BECAUSE THERE'S SUCH A
SPECTRUM IN A LOT OF THESE
DISORDERS DOES THAT TIMEFRAME
FOR INTERVENTION VARY BASED ON
MUTATION-SPECIFIC? IS THERE
TIMEFRAMES THAT WILL VARY BASED
ON THE DIFFERENT CHALLENGES THAT
ARISE?
>> GAIA: I THINK IT'S BASED ON A
GENE FUNCTION SO DEPENDING ON
THE SEVERITY OF THE SEIZURES AND
ON THE CONTRIBUTION TO THE
ELEMENT THAT EACH GENE MAY HAVE
WE CAN GET VERY DIFFERENT KINDS.
SO WE CAN HAVE DIFFERENT
DEPENDING ON THOSE TWO FACTORS.
NOT THAT I SEE THE MUTATION BY
ON THE GENE.
>> AUDIENCE: HI, MY QUESTION FOR
ISABEL, INCREDIBLY EXCITING DATA
FROM THE TRIALS AND JUST A QUICK
QUESTION MAYBE IF YOU ACTUALLY
COLLECTED DATA ON NATURAL
PROCEDURE OR COGNITIVE FUNCTION
BUT HAVE YOU THOUGHT ABOUT
LOOKING FOR MOTOR FUNCTION LIKE
GI EFFECT IN YOUR PATIENTS?
>> GEMMA: YEP, CAN YOU HEAR ME
OKAY? CAN YOU HEAR IN HELLO?
YES. YES, SO MOTOR FUNCTION,
YES, FOR SURE. SORRY, I'M
CHEWING CANDY HERE. YES. WE'RE
LOOKING INTO THAT AND ACTUALLY
THE -- WE'RE LOOKING IN ALSO IN
CONVERSATIONS WITH THE FDA TO
START USING VIDEO MONITORING ON
THE MOTOR SKILLS AND STUFF LIKE
THAT TO BE ABLE TO MEASURE,
YEAH, THE DIFFERENT PHENOTYPE,
YEP.
>> AUDIENCE: CAN I NOT
COMPLIMENT THE ORGANIZERS ENOUGH
FOR THE PANEL. LISTENING TO YOU
SPEAK, GEMMA HAS AN END-TO-END
PIPELINE FOR DETERMINING WHAT
THE MECHANISM OF ACTION OF A
VARIANT IS. AND WHETHER OR NOT
IT CAN BE SENSIBLE. GAIA IS
DESCRIBING HOW TO FIGURE OUT
WHEN TO TREAT THE DISEASE AND
STOKE HAS THE SUBJECTS. SO IN
PRACTICAL TERMS WE'RE DOSING
INDIVIDUAL CHILDREN WITH
INDIVIDUAL ISSUES ONE BY ONE AND
THERE'S OTHERS DOING WHATEVER
THEY WANT TO DO AND MY QUESTION
TO YOU THREE, GIVEN THAT THIS IS
THE EASIEST, YOU CAN STILL DOSE,
YOU CAN'T UNEDIT A HUMAN BEING
IS NOW THE TIME TO START WORK
WITH FEDERAL SUPPORT, I'M SORRY,
AN OPEN ACCESS ASO COOKBOOK FOR
EPILEPSY. I MEAN INDIVIDUAL
MUTATIONS, GEMMA CAN I START
WITH YOU AND THEN MAYBE GAIA AND
ISABEL. I'M NOT TRYING TO BREAK
STOKE'S BUSINESS MODEL BUT TO
THE EXTENT THAT THERE CAN BE
LEARNING THAT OTHER PEOPLE CAN
START TO TAKE AWAY.
>> GEMMA: THE ANSWER IS YES AND
LORI CAN BACK ME UP HERE THAT
LITERALLY WE ARE THINKING ABOUT
SOMETHING LIKE THIS IN
SEPTEMBER, OCTOBER, THINKING
ABOUT HOW TO DEVELOP PIPELINES
TOWARDS ASOS FOR A VARIETY OF
RARE EPILEPSIES. SO -- AND KIND
OF INITIALLY SODIUM CHANNELS, I
WANT TO SAY ARE EASIER BUT ARE
EASIER AND SOME OF THE ION
CHANNELS ARE MORE CHALLENGING.
AT LEAST WITH THE ION CHANNELS
WE HAVE A READOUT. WE CAN LOOK
AT CHANNEL FUNCTION, LIKE WE
HAVE A GOOD GRASP ON HOW TO
ASSAY VARIANT EFFECT AND WE HAVE
A GOOD GOOD ASSAY TO FIGURE OUT
IF IT'S WORKING OR NOT AT LEAST
IN PRECLINICAL MODELS BUT FOR
THE OTHER EPILEPSY RELATED GENES
WE DON'T HAVE GOOD READOUTS AND
THAT IS WHERE WE REALLY NEED TO
BE FOCUSING AND SO, YEAH, LORI
CAN ALSO JUMP IN HERE BUT THAT
IS REALLY ONE OF THE GOALS OF
OCTOBER TO WRITE AGRANT TOWARDS
THIS AT LEAST WITH A VIEW IN THE
FUTURE TO TRANSLATE THAT.
I WOULD LOVE TO PUT TOGETHER A
BIG PLATFORM TO BE ABLE TO DO
THIS IN A SYSTEMATIC WAY THAT
LOTS OF GROUPS AREN'T
REINVENTING THE WHEEL. YES, I
WOULD LOVE THIS IDEA AND TO
STRATEGIZE ON HOW TO MAKE IT
HAPPEN.
>> LORI: COULD YOU COMMENT ON
WHAT ARE THE PITFALLS?
>> AUDIENCE: (SPEAKER FAR FROM
MIC). TO ME THAT'S THE KEY
QUESTION. HOW MUCH (SPEAKER FAR
FROM MIC)
>> GEMMA: WE PUBLISHED A COUPLE
PAPERS ALREADY ON THE CLINICAL
DATA THAT WILL BE PUBLISHED AS
WELL HOPEFULLY SOON. WE DO LIKE
TO PUBLISH AND PRESENT DATA. IN
TERMS OF THE -- DEVELOP A
PIPELINE FOR THESE ASL
DEVELOPMENT, SO IN ONE -- CAN --
THE TYPICAL -- OR THE BEST CASE
SCENARIO FOR NF1 IS TECHNOLOGY.
THAT IS WHERE EVERYTHING. IT
ALL STARTED. SO I KNOW THAT THE
OTS WHICH IS THE SOCIETY WHICH I
USED TO BE ON THE BOARD UNTIL
LAST YEAR WE PUT TOGETHER A
GUIDELINES TO -- HOW TO APPROACH
NF1 AND IT IS EXTREMELY -- I
THINK IT IS EXTREMELY POWERFUL
AND 100% ON BOARD WITH THESE
EFFORTS AND, YOU KNOW, AS A
COMPANY, IT'S A DIFFERENT STORY,
BUT ME AS A SCIENTIST AND AS A
PERSON I KNOW HOW TO USE THIS TO
MODULATE RNA PROCESSES I THINK
THE POTENTIAL TO DEVELOP THIS
USING THE NUCLEOTIDES IS
ABSOLUTELY GREAT. AND SO THERE
ARE THESE ALREADY THAT THE OTS
PUT TOGETHER TO HELP WITH THIS
DEVELOPMENT AND I THINK THE --
NOW THE NF 1 CONNOISSSORTIUM IS
TRYING TO BRING ALL THE DATA
TOGETHER SO NEW INVESTIGATORS
CAN LEARN FROM IT AND LEVERAGE
ALL THE KNOWLEDGE THAT HAS BEEN
DEVELOPED ALREADY.
>> AUDIENCE: YES A COUPLE MORE
QUESTIONS.
>> LORI: I HAD A QUESTION FOR
YOU. WHAT ARE THE PITFALLS.
YOU HAD GREAT SUCCESS WITH THIS
BUT NOT EVERYTHING HAS BEEN
SUCCESSFUL. ARE THERE -- HAPPEN
LOW INSIEVE VARIANTS THAT NOT
WORKED
>> ISABEL: IN TERMS OF
UPREGULATION THERE'S DIFFERENT
CONSIDERATIONS. THERE'S ONE
THING THAT GEMMA TOUCHED ON
TODAY AND GEMMA AND I -- AND WE
COLLABORATED ON THIS. SOMETIMES
THE WAY A GENE IS REGULATED IS
VERY COMPLICATED. AND THERE ARE
OTHER FORCES THAT, YOU KNOW,
MAKE -- AGAINST WHAT YOU'RE
TRYING TO DO AND THAT IS GENE
DEPENDENT AND WHAT YOU WERE
SAYING ABOUT THE TIMING OF
TREATMENT AND ALL THE THINGS A
LOT OF IT IS THE BIOLOGY OF THE
TARGET AND SO THERE IS THAT THAT
WE CAN FIND THOSE THAT MODULE
AND AT THE END OF THE DAY WE MAY
NOT SEE THE UPREGULATION AND
THAT'S BECAUSE THE -- THERE'S SO
MANY OTHER THINGS CONTRIBUTING
TO THE REGULATION OF THAT
PARTICULAR PROTEIN. SO THAT IS
SOMETHING WORTH THINKING -- CAN
FOO
FALL APART. THE SEQUENCE, AND
THIS IS BACK TO ONE OF THE
QUESTIONS I HAVE TODAY IS WHY
THEY NEED TO HAVE SOME SIDE
EFFECTS AND SOME DON'T AND WE
SEE -- WE HAVE A TON OF --
THOUSANDS AND THOUSANDS OF DATA
AND EVEN THOUGH THE CHEMISTRY
MIGHT BE IDENTICAL, THERE IS A
CLEAR EFFECT FROM THE SEQUENCE
OF THIS AND SOME GENES HAPPEN TO
BE VERY GC RICH IT'S JUST THE
NATURE OF THE GENE, THE PROTEIN
THEY'RE CODING AND WHEN YOU HAVE
VERY GC REACH ASOS IT'S GOING TO
BE A PROBLEM THROUGHOUT THE
DEVELOPMENT OF THAT TARGET. OF
THAT ASO AND THERE ARE A LOT OF
THINGS WHEN IT COME TO BUILDING
A PIPELINE TO TREAT DISEASES, NF
1, YOU KNOW, WHEN YOU
MODULATING, SPLICING, YOU DON'T
HAVE A LOT OF OPTIONS OF WHERE
TO PUT YOUR ASO, THE REGULATORY
SEQUENCES ARE WHERE THEY ARE AND
THE SEQUENCE IS WHAT IT IS.
WHEN YOU'RE KNOCKING DOWN A GENE
YOU HAVE YOUR ENTIRE TRANSCRIPT
AS AN OPTION SO THERE'S A LOT
MORE THAT YOU CAN DO BY
FORMATICALLY TO WEED OUT THE BAD
PLAYERS. AND SO DEPENDS ON THAT
AND WHAT YOU'RE TYING TO DO.
THE BIOLOGY OF THE GENE AND THE
ASO SEQUENCE ITSELF THOSE ARE
THE TWO PROBLEMS OR HURDLES THAT
SOMETIMES WE HAVE TO, YOU KNOW,
OVERCOME WHEN DEVELOPING
THERAPEUTICS.
>> LORI: THANK YOU, THANK YOU.
HOW MANY ARE ONLINE?
>> AUDIENCE: WE HAVE ONE
QUESTION FOR ISABEL. FOR
GEMMA'S POINT IS THIS SHARING
VARIANCE DATA?
>> ISABEL: PATIENTS THAT COME
ARE ALREADY GENOTYPES TO BEGIN
WITH? WE REPEAT IT AGAIN
BECAUSE WE WANT TO MAKE SURE AND
CONFIRM FROM THE GENETIC
PERSPECTIVE THAT PATIENTS HAVE
THIS. WE ALSO SPONSOR GENETICS
SCREENING VIA WHAT'S CALLED,
BEHIND THE SEIZURE BASICALLY
CONSORTIUM WHERE ANY PATIENT
THAT GOES INTO A PHYSICIAN'S
OFFICE AND IN -- WITH AT LEAST
ONE UNPROVOKED SEIZURE AND I
BELIEVE UP TO EIGHT YEARS OF
AGE, THEY GET FREE TESTING AND
WE'RE NOT ONLY THE COMPANY
SPONSORING THIS AND ALL THAT
INFORMATION MEANS THAT, YOU
KNOW, IT'S NOT OURS. IT'S
INFORMATION THAT WE CAN USE IT
BUT IT'S ALSO INFORMATION THAT
PHYSICIANS HAVE AND OTHERS ARE
HAVING. SO THE GENOTYPE, WE'RE
NOT THE ONLY ONES, GENOTYPING
THESE PATIENTS BUT THERE ARE
PHYSICIANS THAT HAVE THIS
INFORMATION AS WELL.
>> LORI: LET'S TAKE ONE MORE AND
THEN WE HAVE TO HAVE A BREAK,
VICKY, RIGHT, WE HAVE TO BREAK,
THANK YOU. ONE MORE QUESTION.
THANK YOU.
>> AUDIENCE: SO THIS CONCEPT OF
WHEN CAN THE ASSOCIATED
COGNITIVE AND DEVELOPMENTAL
PROBLEM BE ACTUALLY REVERSED. I
THINK IS REALLY, REALLY AN
IMPORTANT QUESTION AND I THINK
IT'S IMPORTANT FOR US TO
UNDERSTAND HOW WE'RE DOING THE
READOUT FOR THAT ACROSS THIS
DISORDER. YOU PROTECT
PRESENTED THE DATA BUT I WONDER
IF YOU HAVE DATA ON THE
PERFORMANCE MEASURES FOR THE FDA
TO USE TO MEASURE. NOT AS A
COMMISSION. IT IS ADMINISTERED
BY A CLINICIAN BUT THAT'S NOW
THE FDA SEES IT AND THEY WON'T
ACCEPT IT EXCEPT FOR AS A
CONTROL TRIAL I'M WONDERING
IF -- HAVE YOU BEEN USING ANY
OBJECTIVE, YOU KNOW,
PERFORM-BASED MEASURES LIKE THE
IQ TEST OR ANYTHING LIKE THAT
THIS AS WE GO INTO THIS IDEA
THAT WE HAVE THE EARLY ONSET OF
EPILEPSIES WE COME TO A WAY OF
HOW ARE WE GOING TO GET THOSE
HUMAN READOUTS BUT WE DON'T
ACTUALLY KNOW THAT THE TIMEFRAME
FOR REVERSING THINGS IN THE
MOUSE IS GOING TO CORRESPOND TO
THE HUMANS. THAT'S A QUESTION
THAT WE HAVE TO ANSWER. WE KNOW
IT PROBABLY DOESN'T BUT IN OTHER
DISORDERS WE HAVE TO ANSWER THAT
ONE BY ONE. SO I'M JUST CURIOUS
IF OFF YOU HAVE A MORE EXPANDED
OUTCOME.
>> ISABEL: I KNOW WE USED OTHER
MEASUREMENTS OTHER THAN -- I'M
NOT ON THE CLINICAL TEAM. I
DON'T KNOW FOR SURE. I CAN FIND
THAT OUT FOR YOU. IT'S A VERY
GOOD QUESTION. WHEN WE STARTED
THE CLINICAL DEVELOPMENT
SEIZURES WAS OF COURSE THE -- OF
COURSE THE PRIMARY BUT IT WAS
EASY AND ALREADY APPROVED.
ANYTHING COGNITIVE, WE HAD TO
DEVELOP OURSELVES IN USING THE
NATURAL HISTORY DATA HELPED A
LOT. IT HAD TO BE DESIGNED
SPECIFICALLY. NONE OF THE IQ
TESTS TOOK INTO ACCOUNT THE
DEVELOPMENTAL DELAY OF THESE
PATIENTS, YOU KNOW, ARE PRESENT
WITH AND SO IT -- THE FACT THAT
WE DID SEE A CHANGE IN COGNITIVE
CHANGE IN COGNITIVE AND BEHAVIOR
AND ALSO BASED ON THE DATA, THAT
GAVE US A LOT OF, ALSO, YOU
KNOW, HOPE. THAT THINGS CAN BE
CHANGED, YOU KNOW, EVEN DOWN THE
LINE AND SO NOW THAT OPENS UP
MORE OPPORTUNITIES FOR OTHER
DEVELOPMENT. I THINK IT MAY NOT
BE EXACTLY THE SAME COGNITIVE
TEST BUT THE FACT THAT THINGS
CAN BE CHANGED POSTNATALLY AND
AT THE COGNITIVE LEVEL OPENS UP
A LOT OF DOORS TO NEURAL
DISEASES AND THINGS THAT WE
DIDN'T THINK OF BEFORE.
>> AUDIENCE: THIS IS A HUGE
PROBLEM THAT WE NEED TO DISCOVER
IN THE FIELD. AND COVER ALL OF
THESE RANGES.
>> LORI: WE CAN TALK ABOUT THIS
ALL DAY BY WE HAVE TO END SO
LET'S THANK OUR PANEL ONE MORE
TIME.
>> AUDIENCE: (APPLAUSE).
>> LORI: AND NOW WE HAVE A BREAK
UNTIL 11:00.
>> VICKY: OKAY, SO WE -- HAVE A
SERIES OF SPEAKERS DURING THIS
SESSION. AND THESE ARE JUST
SOME OF THE QUESTIONS THAT WE
HOPE THAT THEY WILL ADDRESS. SO
FIRST OF ALL IS A PERSON WITH A
GENETIC CONDITION RECEIVING THE
APPROPRIATE TREATMENT FOR THEIR
DISEASE, DISORDER, GENE VARIANT
AND THESE ISSUES HAVE BEEN
RAISED IN SOME OF THE EARLIER
SESSIONS BUT WE WILL REALLY
FOCUS ON THIS AGAIN WHAT ARE
CONSIDERATIONS A PARENT MUST
CONSIDER WHEN WHETHER OR NOT
THEY ENROLL THEIR CHILD IN A
CLINICAL TRIAL WHAT ARE THE
EXPERIENCES OF PARENTS AND
CHILDREN WHO HAVE PARTICIPATED?
WHY DO WE NEED TO UNDERSTAND THE
NATURAL HISTORY OF A DISEASE?
IS REMOTE PHENOTYPING ESPECIALLY
FOR BEHAVIORAL AND COGNITIVE
ISSUES AN OPTION FOR PEDIATRIC
RESEARCH AN INTERVENTION. WHAT
ARE THE APPROPRIATE OUTCOME
MEASURES FOR GIVEN CLINICAL
TRIALS, GENETIC STRATEGY AND I
APPRECIATE THE DISCUSSION OF
HAVING SOME AGREEMENTS ON
COGNITIVE, BEHAVIORAL PATH. I
THINK THAT SOUNDS LIKE ANOTHER
WORKSHOP, STAY TUNED. AND
LASTLY, WHAT ARE -- I GUESS, NO,
SO WHAT ARE -- I ALREADY SAID
THAT, DIDN'T I AND SO WHAT ARE
THE ETHICAL CONSIDERATIONS OF
THE LAST KIND OF THINGS, WHAT
ARE THE ETHICAL CONSIDERATIONS
FOR INVESTIGATORS WHO ARE
PLANNING A CLINICAL TRIAL TO
TREAT A NEUROLOGICAL DISORDER
AND SPECIFICALLY EPILEPSY. SO
THE SPEAKER LINEUP THIS MORNING
YOU'LL HEAR FROM DENNIS LAL,
MARY ANN MESKIS COULD NOT BE
HERE BECAUSE SHE'S RUNNING HER
OWN CONFERENCE AT THE SAME TIME
BUT HAS GRASCIOUSLY AGREED TO B
ON ABOUT SPEAKING ABOUT TREATING
A GENETIC CONDITION AND TALKING
ABOUT HOW BEING INVOLVED IN AN
ADVOCACY GROUP, AND HAVING THEIR
OWN CHILDREN INVOLVED IN THE
TRIAL AND THEN HEAR FROM MELANI
WHO WILL TALK ABOUT INFORMED AND
EFFICIENT CLINICAL TRIALS DESIGN
USING NATURAL HISTORY DATA AND
MODELING. HEATHER WILL TALK
ABOUT CONSIDERATIONS FOR REMOTE
PHENOTYPING IN PEDIATRIC
RESEARCH, LAINNY ROSS WILL WRAP
UP THE SESSION FOR US REGARDING
GENETIC STRATEGIES TO TREAT RARE
NEUROLOGICAL DISORDERS AND WE
WILL BE JOINED BY ROSA WHO WILL
HELP ANSWER, I HOPE, SOME
REGULATORY ISSUES THAT HAVE COME
UP DURING THE COURSE OF THE
WORKSHOP. SO WITH THAT I AM
GOING TO TURN IT OVER TO DENNIS
LAL WHO IS AS THE UNIVERSITY OF
TEXAS, HOUSTON TO TALK ABOUT
ENHANCING GLOBAL RARE EPILEPSY
CARE. DENNIS?
>> I REALLY APPRECIATE TO BE
HERE. THANK YOU SO MUCH FOR THE
INVITATION. LIKE OFTEN I AM A
LITTLE BIT DIFFERENT THAN MOST
PEOPLE. BUT I HOPE IT WILL BE
ENTERTAINING AND SOMETHING FOR
EVERYONE. SO BEFORE I START
WITH THE TALK I JUST WANT TO
GIVE YOU SOME BACKGROUND WHERE
I'M COMING FROM SO YOU HAVE AN
UNDERSTANDING WHERE I'M GOING SO
MY LAB HAS BEEN INVOLVED I'M
TRYING TO UNDERSTAND WHAT
GENETIC BARRIERS DO ACROSS
DISEASE AND WE ALWAYS TRY TO
BRING IN THE BIOLOGY. FOR
EXAMPLE, I DON'T KNOW SO MUCH --
I DON'T REALLY LIKE MUCH THE,
YOU KNOW, THE CRITERIA BECAUSE
IT'S JUST A PROBABILITY BUT IF
WE KNOW WHAT THE PROTEIN DOES IT
CAN GO TOWARDS A WORKING
MECHANISM. WE HAVE ALSO
DEVELOPED ONLINE RESOURCES
SPECIFICALLY FOR EPILEPSY TO
UNDERSTAND WHY MUTATIONS ARE
PATHOGENIC AND DEVELOP DIFFERENT
FRAMEWORKS FOR THAT AND WHERE WE
CAN HIGHLIGHT WHAT WE CALL
ESSENTIAL REGIONS AND THEY ARE
OFTEN CORRELATE WITH OTHER KNOWN
FUNCTIONAL MECHANISMS SO AND WE
PROJECTED THOSE FOR MANY GENES
AND DEVELOPED ONLINE TOOLS.
THIS IS THE PATH WHEN I WAS
YOUNG AND AMBITIOUS TO THINK
THAT ONLINE TOOLS WOULD HELP TO
IMPROVE CARE BUT STILL BELIEVING
THIS BUT I THINK WE KNENEED TO E
IN A DIFFERENT DIRECTION. ONE
IS TO DEVELOP ALGORITHMS TO
ASSIST VARIANCE INTERPRETATION
AND PARTICULARLY AGGREGATING
INFORMATION FROM THE FUNCTIONAL
EXPERIMENTS AND TRY TO HARNESS
THE MANY EXPERIMENTS INTO A
SYSTEM. AND WE ARE REALLY
ENGAGED IN WHEN IT COMES TO
INFORMATICS TO UNDERSTAND WHY,
SOME ALGORITHMS WORK BETTER AND
WE HAVE STUDIES LIKE THIS ONE
AND TRYING TO WORK OUT WHAT
WORKS BEST AND THIS IS
INCREDIBLY COMPLICATED WHERE
WE'RE WORKING UNDER. SO THERE'S
NOT TOO MUCH RELEVANCE ON WHAT I
WANT TO TALK ABOUT TODAY BUT
OVER THE LAST TWO TO FOUR YEARS
WE, REALLY WHAT I DO IS USELESS
SO WE STARTED TO SHIFT A LITTLE
BIT GEARS AND TO MOVE TOWARDS
EDUCATION. AND TRY TO REALLY
WORK ON, BASED ON GUIDELINES
THAT ARE THERE. AND TO ENHANCE
THEM AND TO MAX OUT WHAT ONE CAN
DO. WHAT MANY PEOPLE DON'T KNOW
IS IF SOMEONE SAYS I CLASSIFY
THE PATIENT BASED ON ACMG THAT
CAN MEAN MANY DIFFERENT THINGS
AND THERE'S NO OBJECTIVE MARKER
FOR THAT SO SOME PEOPLE USE FIVE
CRITERIA AND SOME PEOPLE SPEND,
LIKE A RESEARCH PAPER LEVEL ON
USING THESE GUIDELINES TO
CLASSIFY IT AND IT'S LEAD TO
EXPERIMENTS SO WE GIVE A
WORKSHOP. OKAY, SO I HAVE A LOT
OF CONFLICTS TODAY WHICH BRING
ME ALSO INTO THIS ROLE, WHY I AM
DOING THE RESEARCH AND I AM --
THE PROGRAMS I'M DEVELOPING
TODAY, THEY ARE BASED ON THIS
CONTEXT. ON MANY OF THESE
CONFLICTS WHICH YOU CAN SEE HERE
I'M SOMEHOW INVOLVED IN THE
CLINICAL TRIAL MISS THE STUDY
DESIGN IN TERMS OF ENROLLING THE
PATIENTS FROM THE GENETICS
PERSPECTIVE SO HAVING THE
COUNTERPART OF THE CLINICAL
PERSPECTIVE PURELY FROM A
MECHANISM PERSPECTIVE OR
PATHOGEN PERSPECTIVE AND HAVING
A SECONDARY OPINION. OKAY, SO,
YOU KNOW, LET'S DO THIS A LITTLE
MORE SPECIFIC, SO WHY DO WE NEED
TO FOCUS ON THE INTERPRETATION
AND CLASSIFICATION. IT'S AS
SIMPLE AS THAT BECAUSE MOST OF
OUR GENETIC TEST RESULTS CANNOT
BE INTERPRETED TO A DEGREE THAT
WE KNOW THE PATIENT HAS A
DISEASE OR DOESN'T HAVE A
DISEASE. WE OFTEN OR MOST OF
THE TIME HAVE THE VARIANTS OF
SIGNIFICANCE WHICH IS WHAT GEMMA
MENTIONED THIS MORNING AND THIS
IS A RECENT VISUALIZATION FROM
THE PUBLICATION FROM OUR TEAM
AND YOU CAN SEE THE MOST
VARIANTS WHICH ARE CLINICALLY
REPORTED ARE OF UNKNOWN
SIGNIFICANCE EVEN IN THE BEST
KNOWN EPILEPTIC GENE. THAT'S
ONE PROBLEM. SO WITHOUT A
DIAGNOSIS WE CANNOT ENROLL
ANYONE OR SHOULD NOT. AND YOU
CANNOT GIVE THE FAMILY
CONFIDENCE OR CLOSURE. SO ON
THE OTHER HAND WITHOUT A
DIAGNOSIS. DIAGNOSIS IS ONE
PROBLEM BUT HAVING WORKED NOW IN
TWO HOSPITAL SYSTEMS IN THE U.S.
THE LAST TEN YEARS AND GIVING
WORKSHOPS AND BEING INVOLVED,
YOU KNOW, HAVING A PATHOGENIC
VARIANT IN THE REPORT DOESN'T
AUTOMATICALLY PRODUCE PATIENT
CARE AND THERE ARE MANY ISSUES
WITH THIS AND THIS IS
COMPLICATED BUT THIS IS A
PROBLEM THAT ALSO NEEDS TO BE
SOLVED BECAUSE THERE'S SO MUCH
KNOWLEDGE ALREADY THERE TODAY.
SO WHAT -- WHAT MY YOUNG MIND
THINKS ARE, INTEGRATIONAL, FOR
BETTER INTERPRETATION WE CAN USE
THE EXPERT KNOWLEDGE BUT IT'S
NOT DONE BECAUSE YOU CANNOT HAVE
ACCESS TO THE DATA OR HANDLE THE
DATA THAT'S THE PROBLEM AND
TYPICALLY IF YOU WANT TO DO THE
BEST INTERPRETATION POSSIBLE AND
CARE YOU NEED AN INTEGRATED TEAM
AND OFTEN, YOU KNOW, PEOPLE
DON'T KNOW THAT THIS IS NEEDED
THAT'S ALREADY PROBLEM MINUS ONE
AND EVEN IF YOU HAVE THE
RESOURCES WHICH IS SUPER RARE,
THEN IT'S ONLY FEW -- IT'S ONLY
THERE FOR A FEW GENES. AND
OVERALL WE'RE TALKING ABOUT RARE
DISEASE AND WE'RE TALKING ABOUT
FEW EXPERTS AND IT'S POSSIBLE
THAT IT'S EVERY CENTER AND EVERY
HOSPITAL YOU HAVE AN EXPERT. SO
WE NEED TO DEVELOP
INFRASTRUCTURE WHERE EXPERT
KNOWLEDGE COME TO EVERYONE NOT
THE OTHER WAY AROUND BUT THE
PATIENT HAS THE WORDS TO GET TO
AN EXPERT. NOT PEOPLE WHO
SUFFER WITH A DISABILITY. SO
WHAT ARE THE ISSUES? SO ONE OF
THE ISSUES IS, YOU KNOW, WE ARE
INCREDIBLY SUCCESSFUL IN
IDENTIFYING EPILEPSY GENES. SO
THIS IS AMAZING. BUT IT BRINGS
A PROBLEM. EVERY ONE OF THOSE
GENES COUPLED WITH A DISORDER
HAS IT OWN SPECTRUM, NEEDS,
REFERRALS AND OWN SUPPORT. SO
THERE IS NO PROGRAM WHICH
ENABLES YOU TO BE ON TOP OF THE
GAME, SIMPLY IN HUMAN LEVEL NOT
POSSIBLE. SO IT'S A CHALLENGE.
AND IT'S A CHALLENGE THAT IS
INCREASING SO THE SECOND THING
IS YOU NEED TO -- SO TO
ILLUSTRATE A BIT FOR EVERY ONE
OF THOSE GENES YOU NEED TO HAVE
THIS FOR THE GENE ITSELF OR THE
GENE NEED BUT YOU NEED TO HAVE
THIS ACROSS AGE GROUPS. IT'S
VERY DIFFERENT THAN HOW THE
DISEASE CAN PRESENT AND THE NEED
AND THE UNIT WHETHER IT'S A
TEN-YEAR-OLD OR A
FORTY-YEAR-OLD. IT'S COMPLEX.
EVEN WHEN WE TALK ABOUT THE GENE
WHERE A LOT OF RESEARCH IS GOING
IN WE NEED TO CONSIDER A LOT OF
THINGS, YOU KNOW, IN TERMS OF
CARE. AND THESE DECISIONS ARE
REALLY HARD. SO, IN THE EXAMPLE
YOU CAN SEE THAT YOU HAVE A
DISEASE WHICH IS DUE TO TOO MUCH
FUNCTIONING. AND YOU HAVE A
DISEASE WHICH IS DUE TO TOO LESS
OF A FUNCTION AND BOTH PRESENT
IN THE QUALITY OF LIFE. AND SO
AT THIS POINT OFTEN THE
REGRESSION IS NOT VISIBLE.
RIGHT? SO MOST CLINICIANS DON'T
SEE EVEN MORE THAN TEN PATIENTS
IN THEIR CAREER. EVEN AT LARGE
CENTERS. SO, YOU KNOW, WHEN WE
MOVE IN DISEASE MODIFYING
THERAPIES YOU NEED TO BE
CAUTIOUS AND TO BE WELL AWARE.
SO I DON'T SAY THIS BUT IT
REQUIRES A LOT OF KNOWLEDGE ONLY
A FEW PEOPLE HAVE. GIVING A
REAL WORLD EXAMPLE NONE OF THIS
IS RANDOMIZED CONTROL TRIALS.
YOU HAVE THE LITERATURE FROM
THOSE WHO ARE MEANINGFUL THAT
CAN HELP YOUR PATIENTS. WHERE
IT WAS SUGGESTED THAT THE
SODIUM CHANNEL BLOCKERS.
WHEREAS OTHERS IT SHOULD BE
AVOIDED. THERE'S A CERTAIN
LEVEL OF RESEARCH KNOWLEDGE AND
RESEARCH ABILITY TO READ THE
RESEARCH AND THE TIME YOU ENEED
TO HAVE TO INTEGRATE YOUR CARE.
AND THEN THERE'S THE FDA
APPROVAL. THERE'S THINGS
HAPPENING BUT IT CAN BE MAKE IT
HOT.
AND AT THE SAME TIME THERE'S
CLINICAL TRIALS AND THERE'S
DIFFERENT KINDS OF TECHNOLOGY
WHICH IS BEAUTIFUL THAT WE CAN
DO A LOT OF THINGS BUT IF YOU
CONTEND YOUR PATIENTS IN TERMS
OF SHOULD YOU DO IT IN YOU NEED
TO HAVE A LOT OF KNOWLEDGE AND
THIS IS INCREASING TREMENDOUSLY.
SO WHO HAS THAT? SO TO
ILLUSTRATE WHY GENETIC IS BETTER
THAN OTHER DOMAINS? THIS IS
WHAT IS HAPPENING AND
PARTICULARLY IN THIS FIELD. YOU
MIGHT BE THE WRITER'S MIND IN
TERMS OF READING AN MRI AND YOU
MIGHT BE STILL TODAY BUT KEEPING
UP WITH GENETICS THAT'S REALLY
HOT, YOU NEED THE TIME. TO GET
THE GRANTS AND THAT WILL TAKE
FOREVER. FOR CLINICIANS IT'S A
REALLY HARD CHALLENGE. NOT ONLY
DO YOU NEED HAVE THE TUITION IF
YOU WANT TO CARE FOR EVERYONE
YOU NEED TO HAVE THE TUITION FOR
MANY GENES UNDERSTAND THE
CLINICAL SPECTRUM ACROSS AN AGE
RANGE IT'S AN INCREDIBLE HARD
CHALLENGE TO PROVIDE THE BEST
CARE POSSIBLE FOR A SINGLE
PERSON SO YOU KNOW WHERE I'M
GETTING SO, AND TO MAKE IT EVEN
MORE COMPLICATED. THIS IS,
AGAIN, MIGHT BE COMPLETELY
WRONG. JUST THOUGHT ABOUT THIS.
SO WHAT WE PRESUME FOR THE NEXT
GENERATION OF CHILDREN IS WE
WANT TO PREVENT DISEASE. RIGHT?
SO PREVENT MEANS WE WANT TO GO
IN WITH, YOU KNOW, REALLY STRONG
ACTING THERAPY. AS EARLY AS
POSSIBLE BECAUSE WE'VE SEEN FROM
RESEARCH THERE'S THE BEST GAIN
SO THIS MEANS THE CLINICAL
TUITION YOU CAN BRING IN FOR
PERSON WHO HAS NOT OR JUST IS
ABOUT TO BE IN THE STAGE OF
DISEASE. BECOMES REALLY LOW SO
ALL THE VARIANT INTERPRETATION
IS REALLY MOVING TOWARDS
GENETICS. OKAY? SO WE NEED TO
BECOME BETTER AT THE SAME TIME
WHEN WE LOOK AT OTHERS WE NEED
TO FIGURE OUT MORE HOW -- OTHER
FACTOR BEYOND GENETIC CONSIST
MODIFY THE DISEASE PRESENTATION.
IS THERE AN OPPORTUNITIES WHERE
THE PERSON SAYS AS A CHILD MIGHT
WORK IN AN ADULT OR HAS BEEN
MODIFIED TO YEARS OF EXPOSURE TO
A DIFFERENT ONE. THERE'S A LOT
OF THINGS. OFTEN PEOPLE TALK
BACK ABOUT OTHER NEUROLOGISTS
BUT COULD IT BE THAT CLEARCUT
SYNDROME WHICH WE HAVE IN
PEDIATRICS ARE AN ADULT VERSION
ARE NOT SO MUCH CLEARCUT
ANYMORE. MAYBE THIS IS A
DIFFERENT GROUP. IT'S HARD TO
INTEGRATE THIS INTO CARE. SO,
AND I FOCUS REALLY ON THE
CLINICAL PART OF THE POINT
BECAUSE I GUESS WE HAVE MORE
NEUROLOGISTS LISTENING THAN
GENETICISTS BUT WE HAVE A LOT OF
CHALLENGES IN MEDICAL GENETICS
AND PARTICULARLY FOR THE
CLASSIFICATION PROBLEM. SO THE
GOOD THING IS IT'S MORE
STANDARDIZED AND GETTING BETTER
THAN EVER AND AT A RAPID PACE
BUT THERE'S SO MANY RULES. IT'S
A BIG COMPUTATIONAL CHALLENGE
AND HARD TO KEEP UP THERE. A
PATIENT WHO HAS THIS YESTERDAY
MIGHT HAVE TOMORROW, A NEW
RELEASE, HAVE BARRIERS. SO
IT'S, YOU KNOW, IT'S A --
OVERWHELMING AMOUNT OF
INFORMATION WHICH NEEDS TO BE
INCORPORATED IN ORDER TO PROVIDE
THE BEST CARE POSSIBLE. SO THE
BUSINESS ADMINISTRATION, WE'RE
LIVING IN AN AGE WHERE WE HAVE
INFORMATION OVERLOAD AND WE
DON'T YET HAVE THE SUPPORT WHICH
ARE CLINICAL GRADE AND HAVE BEEN
VETTED FDA APPROVAL. IT WILL
HAPPEN FOR SURE BUT AT THE
MOMENT WE DON'T. SO WHAT TO DO,
RIGHT? AND OUR RESEARCH, WE ARE
EXPLORING DIFFERENT TYPES OF
APPROACHES TO, YOU KNOW, DEAL
WITH THE PROBLEM, ALL AT A VERY
EARLY STAGE, FOR EXAMPLE HERE WE
TOOK FROM 10 MILLION PEOPLE, ALL
THE MEDICAL HEALTH RECORDS,
EVERY ENCOUNTER AND HAVE THE
TERMS AND SUPPLEMENT IT WITH THE
GENETIC DIAGNOSIS. AND THEN
LOOKED AT THE TRAJECTORY. HOW
MANY ENCOUNTERS THEY HAVE. YOU
CAN SEE THAT THE GENETIC
EPILEPSIES HAVE WAY MORE
ENCOUNTERS AS A WHOLE AND THEY
HAVE THE MOST ENCOUNTERS PER
PHYSICIAN A PERIOD WHICH IS
REALLY HARD FOR MANY FAMILIES.
WE SEE ALSO LIKE STRONG SIGNS OF
INFECTION. AND SO ON. SO YOU
CAN DO THIS KIND OF WORK WHERE
YOU TAKE NON CLINIC --
NON-RESEARCH DATA AND TRY TO
INCORPORATE IT INTO STRONG
HEALTH ASSISTANCE AND
INCORPORATE -- DO RESEARCH ON
THE FUTURE. BUT YOU KNOW THE
PEOPLE. SO THIS IS THE THING
THAT WE'RE BUILDING AT THE
MOMENT WHERE WE TRY TO
INCORPORATE THE DATA COMBINED
WITH THE ALGORITHMS FROM THE
RESEARCH WORLD TO THEN DO DAILY
UPDATING INTERPRETATION BECAUSE
THE PHENOTYPE IS IMPORTANT WITH
THE GENOTYPE. HOWEVER, YOU
DON'T HAVE ALWAYS AN EXPERT AND
YOU CAN'T EXPECT THE RESOURCES.
SO THIS WILL BE IMPLEMENTING.
SO WE HAVE THE SUPPORTS TO PUT
IN A CONFLICT WHERE YOU CAN
ENTER A VARIANT AND YOU WILL SEE
THE MRN. SO THE PATIENT WILL
IDENTIFY THIS. SO LONG STORY
SHORT, WE LOOK AT FOR EXAMPLE
THIS. AND WE LOOK AT THE TEST
RESULTS FOR PEOPLE WITH EPILEPSY
AND YOUNG AND OLD. AND ROUND
ABOUT 5.8% OF TESTS WE NEEDED TO
RECLASSIFY. SO, YOU KNOW, THIS
IS NOT SURPRISING, RIGHT? SO
THE MORE YOU GO BACK THE MORE
YOU HAVE TO RECLASSIFY THAT'S
WHY IT'S IMPORTANT TO REEVALUATE
EVERY TWO YEARS. SO YOU CAN SEE
HOW THINGS CHANGE IN THE FEW
TERMS ALSO THAT YOU KNOW THINGS
CAN BE LIKELY BENIGN HAPPENS
SUPER RARELY AND ONLY IN OLDER
REPORTS. SO YOU NEED TO CONTACT
YOUR PATIENTS VERY CAREFULLY SO
IT'S NOT SET IN STONE BUT THIS
IS ONLY HERE. THIS IS OKAY BUT
YOU WANT TO HELP ON THE GLOBAL
SCALE AND THERE ARE MANY, YOU
KNOW SH, MANY RESOURCES. AND W
HAVE THIS FROM THREE OR FOUR
YEARS AGO. I THINK THERE WAS
ONE PUBLICATION ON THIS. AND SO
THIS IS THE LARGEST RESOURCE FOR
MONOGENIC EXPERT CREATED GLOBAL
LY. WE HAVE ONE HUNDRED
THOUSAND PATIENTS. SOME OF THIS
IS IN THE PROBLEM AND SOME OF
THIS IS THE INVESTIGATORS. WE
HAVE THE FUNCTIONAL DATA HERE
AND OTHER THINGS. HERE NOW YOU
HAVE THE EDUCATIONAL RESOURCES.
AND ALL THE DATA THAT EXPLORE
MEDICAL RESEARCH AND WE HAVE
DEVELOPED A LOT OF TOOLS FOR
RESEARCH THAT LOOK LIKE THIS.
YOU CAN LOOK AT THE STRUCTURE
AND IF THE VARIANT -- IT'S A
FUNCTION OR THE PATIENT HAD
SEIZURES OR AUTISM OR WHATEVER.
THIS IS NEW. SO THIS WE
RELEASED THIS TWO DAYS AGO OR
THREE DAYS AGO. SO THIS IS
WORTH LOOKING AT. SO HERE'S AN
EXAMPLE FOR THE PORTAL. SO THE
MDA RECEPTOR GENE WHERE I DON'T
KNOW THROUGH THE ANALYSIS PART
WHERE WE INCLUDED THE LATEST
VERSE OF THE FIGURE AND THE
LATEST ONE IS GOING TO BE
PUBLISHED THIS YEAR.
AND HERE WE INCLUDED INFORMATION
FROM THE VARIANT INTERPRETATION
GROUP. SO WHERE THIS RESOURCE
HAS KNOWN THE LARGEST FUNCTIONAL
DATASET WHICH WAS SPECIFICALLY
LOOKED AT BASED ON VERY
CONSERVATIVE ESTIMATES BY THE
EXPERTS IN THIS CASE.
INTEGRATED FOR CLINICAL
INTERPRETATION. AND THEN WE
HAVE THE LARGEST PATIENT COHORT
HERE ALL EXPERT CURATED.
EVERYBODY HAS LOOKED AT THIS AND
WE HAVE ALL THE LATEST
BIOINFORMATICS. WE HAVE THE
GENERAL DATABASE FOR VARIOUS
POPULATION OF THE UK BIOBANK,
AND, YEAH, AND THIS YOU CAN
ACCESS AUTOMATICALLY, YOU CAN
TYPE IN THE BARRIERS AND THEN --
WHICH YOU KNOW GIVE AS AN
EXPERT. IF YOU KNOW BETTER
OVERRIDE NOW ON ALL THE FIGURES
SO THIS IS FOR THE GENERAL
COUNSEL. IF YOU THINK, FOR
EXAMPLE, THE FULL FREQUENCY IS
WHATEVER AND FOUR TIMES IS NOT
FREQUENT ENOUGH OR TOO FREQUENT
BECAUSE THE PATIENT HAS A
DIFFERENT PHENOTYPE YOU CAN
DERIVE THAT AS WELL. YOU CAN
LOOK UP BASICALLY ALL THE
RESOURCES FOR THE VARIOUS
INTERPRETATIONS AND THEN YOU CAN
SEE THE PATIENTS WHICH ARE
SUBMITTED IN OUR DATABASE. YOU
CAN GET THE BASIC IDENTIFIED
INFORMATION AND THEN YOU CAN NOW
MODIFY ALL THE CRITERIA WHICH
HAVE BEEN BY DEFAULT BEEN USED.
FOR EXAMPLE, YOU CAN CHANGE THE
INHERITANCE AND CHANGE THE
CRITERIA HERE AT THE BOTTOM. SO
LOOKING FOR THE GENETIC
COUNSELOR OR PEOPLE WHO DO ON A
RESEARCH BASIS AND VARY IN
CLASSIFICATION. YOU CAN CHANGE
ALL THE CLASSIFICATION HOW YOU
WANT AND YOU ALWAYS HAVE THE
BEST DATA THERE IS. SO IT'S
IMPORTANT TO BRING THIS HUMAN
EXPERT KNOWLEDGE IN. SO YOU CAN
CONSIDER ALL THE EFFECTS OF
WHICH MIGHT BE RELEVANT FOR THAT
VARIANT OR PATIENT IN THAT VERY
MOMENT. AND HOWEVER YOU CAN
INTEGRATE
INTEGRATE. THERE'S THE
POPULATION DATA AND THE NORMAL
FREQUENCY SO, AGAIN, HERE'S THE
PATIENT DATA WHICH WAS
AUTOMATICALLY HERE APPLIED AND
HERE'S THE ALGORITHM YOU'LL SEE
IN GREEN THE PATIENT VARIES IN
THE MIDDLE AND IN RED, THE
REGISTRY DATA SO THE LARGEST
DATASET THERE IS AND YOU CAN GET
AN INTUITION IF YOU'RE A PATIENT
OF INTEREST IT'S BEHAVING MORE
LIKE THE POPULATION ONE. THE
COMPUTE MUTATION, IF YOU HAVE A
PROTEIN STRUCTURE IF OFF LOT OF
PATIENT VARIANTS IN THE REGION
AND WE HAVE THE FUNCTION AND THE
DATA. THAT'S THE BEAUTY ABOUT
THIS. BECAUSE OF TIME I AM
GOING TO MOVE A LITTLE BIT
AHEAD. JUST CHECK IT OUT. IT'S
PUBLICLY AVAILABLE FOR EVERYONE.
OKAY. AND ALTHOUGH ONLY ONE HAS
BEEN PUBLISHED WE HAVE 150 DAILY
USERS AND WE ARE STARTING NEXT
WEEK A STUDY WHERE WE WILL CHECK
THE PERFORMANCE STUDY OVER THIS
BUT IN GENERAL IF YOU HAVE THE
COUNSEL AND YOU HAVE THE GENES,
YOU CAN DO SOMETHING WITH THE
BEST DATASET THERE IS WHICH YOU
CANNOT GET BY THE WAY AND WE
HAVE THE CLASSIFICATION IN FIVE
MINUTES WHICH OTHERWISE WOULD
TAKE YOU FOUR HOURS OR SO AND
YOU NOT HAVE THE AMOUNT OF DATA
LIKE THERE IS IN THIS PORTAL AND
WE NEED IT TRANSLATED IN
MULTIPLE LANGUAGE WHICH WE
HAVEN'T DONE YET BECAUSE WE NEED
FUNDING. SO, YOU KNOW, ONE PART
OF, YOU KNOW, MOVING FORWARD IS
DEFINITELY, YOU KNOW, GETTING
DATA ORGANIZED, BRINGING IT TO
THE SAME PLACE, MAKING IT
ACCEPTABLE FOR EVERYONE AND ONCE
YOU HAVE THIS YOU CAN DO QUITE A
BIT OF RESEARCH WITH THIS DATA
ONCE IT'S TOGETHER. THERE'S TO
REASON WHY YOU SHOULDN'T COMBINE
IT. AND SO IF YOU HAVE THE
SOURCES AGAIN, IT ENABLES PEOPLE
WHO CANNOT DO PROTEIN STRUCTURE
ON THAT THING SO THE VARIANCE IS
ON THE STRUCTURE AND WITH SOME
GOOD CLINICAL QUESTIONS ON THE
VARIANT TYPES AND THIS IS, YOU
KNOW, YOU BASICALLY CHANGE THE
GAME BEFORE IT'S ONLY, YOU KNOW,
DATA ANALYSIS ONLY FOR THOSE WHO
REALLY LIKE DATA BUT AT THE
MOMENT YOU DEVELOP USER
RESOURCES AND ENABLE SCIENTISTS,
PARENTS WHO CARE ABOUT THEIR
CHILDREN TO LEARN ABOUT THE DATA
THERE IS AND EXPLORE A LITTLE
BIT AND SO I THINK THE MORE
PEOPLE HAVE THE CAPACITY TO
ACCESS DATA AND USE THE
RESOURCES, THEN, YOU KNOW, WE
CAN, YOU KNOW, GET GREATER
COVERAGE. OKAY, SO HERE'S AN
EXAMPLE, ONCE WE HAVE ALL THE
DATA THE GENE TOGETHER, WE HAVE
A THOUSAND PEOPLE WHERE WE HAVE
INFORMATION IF THEY EITHER HAVE
THE CAPACITIES, THE MINOR
EPILEPSY OR THE SYNDROME AND IF
THEY HAVE THE GENOTYPE AND
PHENOTYPE WHERE THERE'S SPECIFIC
REGIONS. AND WHAT WE NOTICE IS
THERE'S A GREAT DIFFERENCE
BETWEEN DISEASES. IT WAS WAY
MORE WIDE. IF YOU READ THE
LITERATURE YOU GET IT OUT BUT WE
SEE IT SUDDENLY ONLY CLEARCUT
WHEN YOU LOOK AT THE DATA AND
THEN WE THOUGHT, HEY, MAYBE
THAT'S ALSO YJEANEGENETIC AND T
THINGS APPARENTLY DON'T HAVE AN
INTERACTION AFFECT AND WE PUT IT
TOGETHER UNDER A SIMPLE TOOL.
AND SO THIS TOOL HAS NOT BEEN
TESTED BLINDED TWICE AND I WANT
TO PUSH REALLY THAT ONE OF THE
BLIND COHORTS WAS REALLY AT THE
HIGHEST LEVEL TO THE RESEARCH
AND WE WERE NINE OUT OF TEN
TIMES CORRECT JUST FOR THE
SEIZURE ONSET AND GENETIC
VARIANCE. SO THIS IS SOMETHING
WHERE I AM REALLY CONSIDERING
ENHANCING WITH A COUPLE MORE
ITEMS AND DOING CLINICAL TRIAL.
THIS IS REALLY OUTSTANDING IN
TERMS OF ALL EPILEPSY RESEARCH.
OKAY, SO AND THE MOST IMPORTANT
THING HERE IS FOR GENE THERAPY.
SO THIS IS THE SEIZURE ONSET AND
GENETIC TEST RESULTS SO WHAT
ELSE CAN WE DO IN ONCE YOU HAVE
A LOT OF DATA TOGETHER SUDDENLY
YOU SEE PATTERNS WHICH YOU NEVER
WOULD BE -- THOUGHT THAT YOU
COULD SEE THEM. SO THIS IS JUST
A BIG PUSH THAT WE HAVE TO HAVE
ONE MASTER. DUE TO PREDICTION
MODELS WE HAVE THIS. AND WE HAD
AN INTERESTING THING TO USE FOR
OUR PREDICTION MODELS FOR
EXAMPLE, YOU SEE HERE IF THE
PERCENTAGE OF PEOPLE. AND YOU
HAVE DIFFERENT GROUPS HERE.
THIS IS IS VERY SIMILAR TO THIS
ONE. AND WALK AS WELL AND
SIMILAR TO WHAT THIS IS IN THAT
GROUP. BUT IF WE LOOK NOW AT
USED WORDS OR COMBINED WORDS
SUDDENLY VERSION IT WURNT SO
WELL SO YOU GET THESE ACROSS THE
DIFFERENT FIFTEEN TYPES AND YOU
CAN UNDERSTAND NOW A LITTLE BIT
MOREOVER THE DISEASE PROGRESSION
AND YOU CAN EVEN THINK ABOUT
BASKET TRUCKS, IF YOU WANT TO
SOMETHING VERY CHEAP AND
EFFICIENT YOU WANT TO LOOK
AROUND ONE YEAR TO ONE AND A
HALF YEAR YOU GET A LOT OF
CHANGE HERE. WHEREAS YOU DID
NOT -- YOU SEE LESS CHANGE IN
THE OTHER GRIPES. YOU CAN SEE
WHAT YOU WOULD LIKE TO PUT
TOGETHER. SO YOU CAN ALSO LOOK
AT WRITING COMMUNICATIONS SO
HERE, FOR EXAMPLE, UNAFFECTED
CHILDREN, SO THE SIBLINGS OR THE
PEOPLE WITH AUTISMIC SEE THERE
AND YOU SEE HOW IT ALREADY
STARTED TO DEVIATE FROM HERE AND
YOU CAN SEE IN THE DIFFERENT
GENETIC DISORDERS YOU CAN
PREDICT THE FUNCTIONS AS BEFORE.
I OFTEN HERE COMMUNICATION IS
THE BIG BUCKET WHERE IT'S HARD
TO SEPARATE AND WHERE THERE ARE
CHALLENGES IN IDENTIFYING END
POINTS WHICH ARE CLINICALLY
USED. AND, FOR EXAMPLE, I HAVE
A LARGE PATHOLOGIST IN MY TEAM
WHO SAID WHY DON'T WE BREAK
LANGUAGE DOWN AND SEE IF THERE'S
DIFFERENT ANSWERS. LOOK IF WE
LOOK AT DIFFICULTY TO ANSWERING
QUESTIONS, EFFICIENCY. SO YOU
SEE A LOT OF THEM ARE OVERLAP
AND THESE ARE AT LEAST 50
PATIENTS SO IT'S RATHER GOOD
DATA BUT IF YOU LOOK AT AUDITORY
PROCESSING AND SPEECH AND
MOVEMENT THEY SUDDENLY SPREAD
OUT. ALL THE INFORMATION WHICH
YOU CAN E USE FOR PREDICTION
MODELING.
THIS IS ALL YOU KNOW, POPULAR
BECAUSE DATA IS TOGETHER.
HERE'S ANOTHER EXAMPLE IF YOU
ARE A PARENT OF A CHILD WITH
THIS. DOES YOUR CHILD HAVE AN
EYE CONDITION? IF THEY DO, MOST
WILL SAY YES. HOWEVER FOR TRAN
INDICATED THEY WILL SAY NO. THE
INTERESTING THING IS THIS IS ONE
VERSION TO LOOK AT THIS.
BUT YOU CAN ALSO ADD WHEN YOU
HAVE THESE RESOURCES, WHEN, FOR
EXAMPLE, DO THE -- SO FOR THOSE
WHO HAVE AN EYE CONDITION WHEN
DO YOU, YOU KNOW -- WHEN DID IT
START AND YOU CAN SEE, FOR
EXAMPLE, NOT ONLY DO THEY HAVE
MORE BUT THEY HAVE IT EARLIER SO
YOU CAN COMBINE ALL OF THESE AND
DEVELOP EYE RHYTHMS. THEY
HAVEN'T DONE THIS YET BUT
THEY'RE WORKING ON IT. MY LAST
PART TO CLOSE OUT WHY I BELIEVE
THIS IS A RESOURCE THAT IS NOT
ONLY RELEVANT FOR INCLUSION OF
CLINICAL TRIALS AND INCLUDING
PEOPLE IN THE RIGHT CARE BUT AND
RESEARCH BUT ALSO FOR THE
CLINICAL TRIAL AND THIS IS WHERE
I'M MOST INTERESTED. IMAGINE WE
HAVE AN APPROVED DRUG AND THE
CLINICAL TRIAL WAS DESIGNED LIKE
THIS. YOU KNOW CHILDREN AND WE
HAVE FOR CERTAIN REASONS HAVE TO
REMOVE PEOPLE WHO HAD SURGERY.
THESE ARE YOUR END POINTS.
THAT'S A REAL SCENARIO, I GUESS,
RIGHT? IMAGINE THE DRUG IS
APPROVED. YOU HAVE SO MUCH MORE
QUESTIONS, WHAT ARE THE ADVERSE
EFFECTS, SHORT-TERM? LONG-TERM?
SINL EVERYONE -- SUDDENLY
EVERYONE HAS A RANK.
WE NEED TO HAVE DATA FLOWING TO
SEE THIS. SO, YOU KNOW, ALSO WE
NEED TO FIGURE OUT HOW DO WE
MEASURE WHAT TYPICAL AND
ATYPICAL BUT WE NEED TO HAVE A
NATURAL HISTORY RUNNING ALREADY
AND THE DATA NEEDS TO BE THERE.
JUST GO ON AND IN PARALLEL WE
HAVE TO LABEL THOSE INDIVIDUALS
AND SEE IF THERE'S DEVIATIONS
ACROSS THOUSANDS OF PHENOTYPES.
OTHERS FROM HIGH GRADE. SO, YOU
KNOW, YOU KNOW, THE QUESTION IS
WILL THE DRUG WORK IN OTHER
PATIENTS? OLDER ONES? WHAT IS
THE END POINT THERE? OTHER
RESOURCES MIGHT GIVE YOU SOME
IDEAS, YOU KNOW? AND BROADER
PATIENT POPULATION. YOU KNOW,
YOU KNOW, THESE WHO HAVE BEEN
EXCLUDED RIGHT FROM THE
BEGINNING AND SO ON AND SO
FORTH. BEFORE I READ THE
STUDIES, OVER THE NEXT TWENTY
YEARS LET'S PUT IT TOGETHER AND
DO LIKE RETROSPECTIVE RESEARCH.
WHICH IS THE NEXT GENE WHERE
THIS WILL BE TESTED IN? THERE'S
THE PATHWAY SET UP AND YOU CAN
ADD YOUR BIOLOGY, THIS IS THE
NEXT GENE WHICH SHOULD -- THE
DRUG SHOULD BE TESTED IN BUT YOU
COULD ARGUE THE PHENOTYPE. THEY
HAVE THE SAME COMPUTATION AND
THE END POINT WORKED THE SAME.
LET'S LOOK AT THIS. THEY ARE ON
THE SAME PATHWAY AND THE
CLINICAL INTERPRETATION IS THE
SAME LET'S GO IN THERE WITH THE
NEW DRUG AND GET IT APPROVED
THERE BUT WE CANNOT MAKE THE
SAME DECISION FOR THIS I CLOSE
AND THANK YOU SO MUCH FOR GIVING
ME THE OPPORTUNITY TO SPEAK.
>> AUDIENCE: (APPLAUSE).
>> AUDIENCE: I JUST WANT TO MAKE
ONE COMMENT ABOUT THE UTILITY,
THE IMPORTANCE OF WHAT YOU'RE
DOING. AND JUST SHARE WITH YOU
THAT THE FIRST PATIENT,
COMMERCIAL PATIENT WHO IS GOING
TO BE TREATED, CAN BE TREAT AT
MOUNT SINAI IN BOSTON. THE
INSURANCE COMPANY HAD TO RELEASE
THE VECTOR, AGREE, PATIENT HAD
ONE PATHOGENIC ALLELE AND ONE
VARIETY OF UNKNOWN SIGNIFICANCE
ON THE OTHER ALLELE, INSURANCE
COMPANY RREFUSED TO RELEASE.
THEY FOUND A PATIENT WHO WAS
HOMOZYGOUS AND WAS CLINICALLY
AFFECTED THEREFORE THEY RELEASED
IT. ONCE YOU DO HAVE THE DRUG
THIS IS ALSO VERY IMPORTANT.
>> AUDIENCE: I HAVE A BASIC
QUESTION FROM THE CLINICAL
PERSPECTIVE. WHICH IS -- OH, A
BASIC QUESTION FROM THE CLINICAL
PERSPECTIVE WHICH I ACTUALLY
MEANT TO ASK GEMMA EARLIER BUT I
THINK I CAN ASK YOU AS WELL WITH
ALL OF THE CHANGES OVER TIME AND
HOW WE ARE CLASSIFYING VARIANTS
AS DATA FUNCTION VERSUS LOSS OF
FUNCTION AND IT'S THE SAME
VARIANT WE'VE BEEN WORKING ON
FOR YEARS AS LONG AS SOMETHING
CHANGES IT'S EITHER GAINED OR
MIXED OR SOMETHING CHANGES. IS
THERE ANY WAY TO HAVE SOME
OVERSIGHT? THESE WERE
CLINICIANS WHILE WE'RE WAITING
FOR ALL OF THOSE GENES THERAPIES
WHILE WE TRY TO LOOK AT OUR
BASIC MEDICATION. I WILL GIVE
AN EXAMPLE FROM THE SDM 2A WHICH
SOME OF THE -- ALL OF THE TRIALS
ACTUALLY HAVE BEEN RELYING ON A
COMBINATION OF THE CLINICAL
PHENOTYPES AND THE GENOTYPE IN
ORDER TO LEARN WHETHER WE ARE
GOING TO BE USING -- WE ARE
GOING TO BE CALLING THE
INVESTIGATIVE FUNCTION BUT THEN
WITH THE NEW PAPER THAT JUST
CAME OUT, FROM AL GEORGE'S LAB,
SOME OF THESE WERE ANOTHER
FUNCTION HOW DO WE LOOK AT THAT.
HOW DO WE READ A PAPER NOW AND
DECIDE WHETHER THIS IS WHAT WE
SHOULD CALL IT OR NOT?
>> DENNIS: I CANNOT ANSWER THIS
BECAUSE IT IS VERY COMPLICATED
AND EVERY GENE IS DIFFERENT. I
CAN ALWAYS COMPARE TO EPILEPSY
SURGERY. PEOPLE DO HAVE AN
INTEGRATIVE TEAM TYPICALLY WHERE
MANY DIFFERENT PERSPECTIVES ARE
SHARED. AT THE END, THE
CLINICIAN TAKES ON THE
RESPONSIBILITY AND DOCUMENTS
AND, YOU KNOW, VERY THOROUGHLY
WHAT THE REASONS WHERE THERE'S
THE DECISION. AND THE -- YOU
CAN DO THIS IN YOUR OWN CENTER
BUT YOU CAN ALSO SEEK
COLLEAGUE'S OPINION TO ENHANCE
YOUR OWN CURRENT ASSESSMENT AND
IT'S A LITTLE BIT ALL OVER THE
PLACE LIKE THIS, RIGHT? AND
THERE'S NO STANDARD. SO I THINK
THE FIRST STEP WE HAD FOR THE
RECEPTOR IS THAT THERE WAS A
PAPER LAST YEAR PUBLISHED BY
STEVE AND ALSO A LITTLE BIT OF
US. BUT TINY WHERE THE TITLE
WAS THIS IS HOW YOU CLASSIFY
GAIN AND LOSS OF FUNCTION IN THE
RECEPTORS. AND SO THIS IS NOT
EXISTING FOR THE SODIUM
CHANNELS. AND IN THE SODIUM
CHANNELS WE ARE POINTING AT MORE
THE PROBLEM AND NO ONE AT THE
MOMENT IS REALLY COMFORTABLE TO
SAY THIS IS -- INSTEAD OF ASSAYS
AND THE SET OF, YOU KNOW, YEAH
SO, WE NEED -- THAT'S PRACTICE
GUIDELINES FOR THE MOLECULAR
PART AS WELL AS THE CLINICAL
PART AND THERE SHOULD BE A
DATABASE BECAUSE THEN YOU CAN
INTEGRATE IT INTO COMPUTATIONAL
SLOPE. SO OTHER THAN THAT, IT'S
ALWAYS TOO QUIET IF SOMEONE IS
MAKING A SEARCH AND THE SEARCH
CAN BE HIGH QUALITY BUT CAN ALSO
BE A FIVE MINUTE SEARCH WHILE
DOING AN OPEN CHART, RIGHT? SO
WE NEED TO ORGANIZE. THAT'S --
I AM REPEATING MYSELF BUT
THERE'S NO CLEAR SOLUTION. SNAD
TH
.
>> AUDIENCE: THIS WORK IS REALLY
GROUND BREAKING AND APPRECIATED.
SINCE YOU'RE USING DOLLY AND
YOU'RE USING NATURAL LANGUAGE
PROCESSING CAN YOU EXPAND MORE
ON THE ROLE THAT AI IS GOING TO
BE PLACED IN ALL OF THIS?
BECAUSE I HEARD YOU SAY THAT WE
NEED TO HAVE A WORKFORCE OF
CLINICAL GENETICISTS AND
COUNSELORS. TO ENABLE THIS TO
BE AVAILABLE TO SOCIETY. I'M
NOT SO SURE THAT THAT'S EVEN
FEASIBLE. SO CAN YOU -- I KNOW
YOU'VE THOUGHT A LOT ABOUT THIS.
CAN YOU EXPAND THE ROLE OF AI?
>> DENNIS: PERSONAL OPINION, CAN
BE COMPLETELY WRONG. SO I THINK
AUBS AI IS MORE IMPORTANT FOR
COMMON DISEASE.
TYPICALLY THE CLINICAL
EXPRESSION IS VERY WRONG AND
IT'S RARE WHICH IS WHY PEOPLE
DON'T RECOGNIZE IT BUT I HAVE
THOSE WHO HAVE ACCESS TO A LOT
OF DATA AND PATTERNS CLEARLY.
THE EVIDENCE REQUIRES THAT WE
HAVE A RECORD CLEARLY INDICATING
WHO HAS WHICH DISEASE WHICH IS A
BIG PROBLEM AT THE MOMENT. SO I
THINK IF YOU COMBINE HIGH
QUALITY DATABASES AND HEALTH
RECORDS WHICH ARE WELL TAKEN
CARE OF, YOU CAN DEVELOP THE
CHATGPT STYLE OF REPORT SYSTEMS
WHICH BEAT CLINICIANS AND
RECOGNIZE A GENETIC DISEASE VERY
PAST BECAUSE HARDLY ANYONE HAS
SEEN IN THEIR CAREER MORE THAN
TEN PATIENTS. SO YOU CANNOT BE
AN EXPERT ON THOUSANDS. SO
THERE'S A LOT OF OPPORTUNITY BUT
THE PATH TOWARDS BRINGING THE
DATA TOGETHER, HAVING EXPERT
CURATION AND HAVE THE RIGHT
MECHANISM IN PLACE TO BENCHMARK,
THERE'S NO AGREEMENT ON HOW TO
IDENTIFY THIS RIGHT? AND THIS
IS TYPICALLY WHEN YOU LOOK AT
THE RESEARCH. IT'S BECAUSE IT
IS WHAT IT IS. AND I WOULD
DEFINITELY ADVOCATE TO GO TO THE
SPACE AND GIVE THE RESEARCH IF
PEOPLE NEED THE RESEARCH AND
HAVE THE CLINICAL COMPONENT, THE
CURATION, AS WELL AS THE AI PATH
AT THE END AS WELL. I THINK
IT'S DEFINITELY THE WAY TO GO.
WE NEED TO BRING KNOWLEDGE TO
THE DOCTOR AND NOT THE DECISION,
KNOWLEDGE AND THEN THE
INDIVIDUAL CAN TAKE KNOWLEDGE
BASED ON WHAT IS MEANINGFUL AND
WHAT IS NOT.
>> AUDIENCE: I HAVE A COMMENT
AND A CHALLENGE. I AM PART OF A
COLLABORATION OF 140. I AM FROM
AN EPILEPSY COORDINATION AND WE
GIVE ACCESS OF COMMUNICATION,
RESEARCH, GRANTS, MONEY, MY HOPE
IS THE YOU'LL CHECK IT OUT. I
WANT TO COMMEND DR. LAL WHO HAS
SPENT A LOT OF TIME WORKING WITH
OUR NETWORK AND DID SOME PRELIM
FAIR ANALYSIS IN ADVANCE OF THE
CONFERENCE THAT WE HAD LAST YEAR
AT THE AMERICAN EPILEPSY SOCIETY
TO REALLY THINK STRATEGICALLY
ABOUT NEW AND INNOVATIVE WAYS
THAT WE CAN CLUSTER ACROSS THESE
TWO PIECES. FIRST THANK YOU TO
DR. LAL FOR THAT WORK AND THE
CHALLENGE HERE, I'M A LAYPERSON
SO NOT A SCIENTIST BUT MY
TAKEAWAY FROM A LOT OF THIS
CONFLICT SO FAR IS THIS
DISCUSSION ABOUT MECHANISM, WHAT
COMMUNITY DISORDERS, CAN'T BE
ADDRESSED ONE AT A TIME, WE NEED
TO BE THOUGHTFUL IN WHAT WE
DEVELOP, SO HOW DO WE AS A
COMMUNITY MARRY AN ANALYSIS LIKE
WHAT DR. LAL HAS DONE LOOKING AT
THESE DISORDERS WITH THE
PLATFORMS THAT WE'RE DISCUSSING
TO ADVANCE AND I JUST WANT TO
THANK EVERYBODY IN THIS ROOM AND
ONLINE FOR THINKING ABOUT THAT.
THERE ARE A LOT OF CAREGIVERS
AND ADVOCATES THAT CARE
PASSIONATELY TO TRY TO FUND THIS
WORK ONE AT A TIME AND WE'RE
LOOKING TO YOU TO HELP US DO
THIS MORE SYSTEMATICALLY WITH
THE INFRASTRUCTURE AND TAKE
ADVANTAGE OF WHAT EXISTS OR WHAT
WE CAN DEVELOP DOWN THE ROAD.
THANK YOU.
>> VICKY: THANK YOU, DENNIS.
>> AUDIENCE: (APPLAUSE).
>> VICKY: SO DO WE HAVE MARY ANN
ON LINE?
>> MARY: I AM HERE, VICKY.
>> VICKY: I SEE YOU. SORRY
WE'RE RUNNING A LITTLE LATE. I
KNEW YOU'RE RUNNING YOUR
CONFERENCE. MARY ANN MESKIS IS
THE EXECUTIVE DIRECTOR OF THE
DRAVET SYNDROME FOUNDATION AND
WILL TALK ABOUT IT BECOMING A
TREATABLE GENETIC CONDITION,
THANK YOU.
>> MARY: THANK YOU. TODAY I
WILL SPEAKING ABOUT THE
CONTRIBUTIONS OUR ORGANIZATION
HAS MADE TO ADVANCE US TO THE
STAGE, THE OBSTACLES WE
ENCOUNTER WHEN CONSIDERING
UPCOMING TREATMENT OPTIONS AND
THE TREATMENTS THAT WE
ANTICIPATE OUR ROLE -- OKAY.
AND SO ASCROLLINGS (SPEAKING AT
ONCE) AS WE GET CLOSER TO
BECOMING A TREATABLE GENETIC
CONDITION I WILL BE SPEAKING
ABOUT THE CONTRIBUTIONS AS
ORGANIZATION HAS MADE. THE
OBSTACLES WE MAY ENCOUNTER AND
THE PERSISTING CHALLENGES POST
COMMERCIALIZATION ALONG WITH
WHAT WE ANTICIPATE OUR ROLE WILL
BE IN SUPPORTING FAMILIES I AM
MARY ANN MESKIS I WAS A FOUNDING
MEMBER IN 2009 AND CURRENTLY
SERVE AS THE EXECUTIVE DIRECTOR.
OUR MISSION IS VERY IMPORTANT TO
ME BECAUSE MY YOUNGEST SON
ELLIOT, EXCUSE ME, WHO IS NOW 24
YEARS OLD HAS DRAVET SYNDROME.
FOR THOSE UNFAMILIAR, IT IS AN
EPILEPTIC ENCEPHALOPATHY THAT
MANIFESTS. YOU ALL, I AM SO
SORRY, I THINK I SEPTEMBER --
SENT OVER THE WRONG VERSION OF
THIS. -- SENT OVER
THE WRONG VERSION OF THIS. IF
YOU WANT TO GIVE ME TEN MINUTES
TO FIND THE RIGHT VERSION AND
SEND IT OVER.
>> IF YOU HAVE YOUR PRESENTATION
YOU CAN SHARE IT FROM YOUR
COMPUTER AND WE CAN GO FROM
THERE.
>> MARY: PERFECT. LET ME PULL
IT UP FOR YOUR REALLY QUICK.
>> AWESOME. LOVE THE PAINTING
IN THE BACKGROUND.
>> MARY: THANK YOU, I'M IN A
HOTEL. LET'S SEE. IT'S THIS
ONE. SO HOW SHOULD I SHARE THIS
WITH YOU? WHAT IS THE BEST WAY
ON MY SCREEN?
>> (FIXING PRESENTATION).
>> IF WE BREAK FOR LUNCH NOW CAN
YOU DO IT LATER
>> I WILL FIND IT AND SEND IT
OVER.
>> SO CAN YOU BE BACK ON AT 1
O'CLOCK EASTERN?
>> ABSOLUTELY.
>> OKAY, THANKS SO MUCH. ALL
RIGHT, SO LET'S BREAK FOR LUNCH
AND WE'LL TAKE MARY ANN AFTER.
THANK YOU. BE BACK AT ONE
O'CLOCK.
>> MARY: OKAY WHEN I SEND THAT
OVER WHO SHOULD THAT GO TO. . .
WE'LL SHORTEN THE PANEL
DISCUSSION AFTER THE SESSION AND
SHORTEN THE WRAP UP AT THE END
BUT OUR GOAL IS TO GET YOU OUT
BY 3:00 BECAUSE I KNOW SEVERAL
PEOPLE HAVE FLIGHTS.
WITH THAT I'LL INTRODUCE MARY
ANN AGAIN AND WHAT SHE'S GOING
TO TALK AND I'LL CHANGE HER
SLIDES FOR HER SO TAKE IT AWAY.
>> THANKS, VICKI.
I APPRECIATE YOU HAVING ME SPEAK
TODAY AND LET ME SERVE AS THE
POSTER CHILD AS SOMEONE WHO
SHOULD NOT TRY TO RECORD THEIR
SESSION WHILE SICK AND THREE
DAYS BEFORE THEIR CONFERENCE.
SO IT'S GREAT TO SEE EVERYONE.
I'M MARY ANN MESKIS AND SERVE AS
THE EXECUTIVE DIRECTOR OF OUR
ORGANIZATION.
I HAVE A 24-YEAR-OLD SON WITH
GERVAIS SYNDROME AND HAVE BEEN
IN THIS NOW OVER TWO DECADES.
IT'S BEEN VERY EXCITING TO SEE
THE PROGRESS OUR COMMUNITY HAS
MADE AND TODAY I'M HERE TO TALK
ABOUT ABOUT WHAT IT'S BEEN LIKE
TO MAKE THIS A TREATABLE
CONDITION.
I WANT TO TALK ABOUT
CONTRIBUTIONS OUR ORGANIZATION
HAS MADE TO THIS AND WHAT WE
HELPED WITH WORKING WITH BIO
TECH IN HELPING IN RECRUITMENT
FOR CUTTING EDGE TRIALS AND
OBSTACLES IN CONSIDERATION
THERAPIES AND WHAT WE'LL SEE
WILL BE PERSISTING CHALLENGES
POST COMMERCIALIZATION WITH ROLE
OUR ADVOCACY GROUP WILL LIKELY
CONTINUE TO PROVIDE IN
SUPPORTING FAMILIES.
SO WHAT ISD -- SO PHOR OUR
PATIENTS IT'S NOT JUST
SIGNIFICANT SEIZURES OR MULTIPLE
SEIZURES AND ACROSS THE SPECTRUM
OF DED HE IS AND IMPACTS THE
PATIENTS AND CAREGIVERS AND
FAMILIES.
IT'S CLASSIFIED AS A RARE
DISEASE.
WE HAVE AN ESTIMATED INCIDENT
RATE OF APPROXIMATELY 1 IN 15,
700 AND SHOW INSUFFICIENT IN
GENES AND WITH THE COMORBIDITIES
THE PATIENTS HAVE UP TO 25% TO
20% MORTALITY RATE WITH 50%
BEING ATTRIBUTED TO SUDEP AND
PROLONGS SIEZURE RELATED DEATHS
AND OUR CHILDREN ARE ALWAYS
EXPERIENCING CHALLENGES AND OUR
FAMILIES PUT THEIR CHILDREN TO
BED AT NIGHT AND DON'T KNOW IF
THEY'LL WAKE UP AND FRAMES THE
URGENCY FOR NEW AND BETTER
TREATMENTS.
WHEN WE LOOK AT TREATMENTS FOR
SEIZURES AND OVER ALL QUALITY OF
LIFE IT'S GIVEN HOPE AND
OPTIMISMD OUR FAMILIES ARE TIRED
OF THEIR CHIRP BEING A GUINEA
PIG AND HAVE A SUBPAR QUALITY OF
LIFE AND THE FAMILIES ARE
EXHAUSTED FROM THE CONSTANT CARE
REQUIRED IN ORDER TO TAKE CARE
OF THEIR LOVED ONE PROPERLY.
YOU WHEN WE FOUNDED OUR
ORGANIZATION WE THOUGHT OF WAYS
WE COULD BE A CONVENER WITHIN
THE FIELD.
WE ACTIVELY SOUGHT OUT THE
RESEARCHERS OR CLINICIANS THAT
WE KNEW THAT WERE SEEING THESE
PATIENTS.
MANY OF THEM ARE NOW PART OF OUR
SCIENTIFIC AND MEDICAL ADVISORY
BOARD AND FELT THOSE ARE THE
INDIVIDUALS WE NEEDED TO TALK TO
TO HELP US UNDERSTAND WHAT OUR
FUTURE PRIORITIES AND FOCUS
AREAS SHOULD BE.
THROUGH OUR FUNDFAISING EFFORTS
WE'VE BEEN ABLE TO HAVE A ROBUST
PROGRAM AND EXCITED AS OF LAST
YEAR 2023 WE HAD BEEN ABLE TO
PROVIDE $9.1 MILLION IN SEED
GRANTS AND THAT'S OVER A 15 YEAR
TIME PERIOD AND ALLOWED US TO
RECOGNIZE OR TO LOOK AT THE GAPS
IN THE FIELD AND MAKE SURE WE'RE
SUPPORTING THE MOST VITAL
RESEARCH INITIATIVES.
IN ADDITION WE DO A ROUNDTABLE
WITH OUR SCIENTIFIC ADVISORY
CO-CHAIRS FOR KEY OPINION
LEADERS, RESEARCHERS AND EVEN
INDUSTRY MEMBERS WITH A FOCUS ON
OUR DISEASE STATE AND GIVES US A
FORUM TO TALK ABOUT THE
ADVANCEMENTS, WHAT ARE PROGRESS
AND WHAT ARE OTHER PRIORITIES
NOT BEING MET AND AS IT A NICE
BAROMETER TO TAKE BACK TO OUR
BOARD OF DIRECTORS SO SAY THIS
IS WHAT WE INTO HE HAD TO FOCUS
ON.
IT'S BEEN INSTRUCTIONAL IN
SHAPING OUR RESEARCH ROAD MAP
AND GUIDING OUR FUNDING
DECISIONS.
WE RECOGNIZE NONE OF THIS COULD
HAPPEN WITHOUT OUR PATIENTS AND
EDUCATE OUR FAMILIES AND MAKE
THEM UNDERSTAND HOW IMPORTANT IT
IS TO SHARE THE PATIENT
EXPERIENCE SO THOSE LIVING ON A
DAILY BASIS CAN UNDERSTAND HOW
MANY UNMET NEEDS ARE IN OUR
COMMUNITY.
WE HAVE A PATHWAY TO COMMUNICATE
INFORMATION OUT TO THEM.
EARLY ON WE THOUGHT WE COULD
IDENTIFY WHAT EXISTING RESOURCES
ARE OUT THERE AND THINK WHAT
AREAS WE COULD CURRENTLY TRY TO
TACKLE AS WELL AS WHAT WE THESED
TO DO THREE, FOUR, FIVE YEARS
DOWN THE LINE.
WE'VE BEEN FORTUNATE BECAUSE
THERE HAVE BEEN GREAT
INDIVIDUALS WORKING IN OUR FIELD
PRIOR TO DSF COMING TO FRUITION
IN 2009.
THERE WERE THINGS IN PLACE AND
WE TRIED TO LEVERAGE THOSE AND
WORK THROUGH A COMBINATION OF
RESEARCH FUNDING, STRATEGIC
PARTNERSHIPS AND DIRECT ACTION
TO TRY TO ADDRESS THE GAPS AND
MAKE OUR DISEASE STATE EASY FOR
ANYONE TO RESEARCH OR LOOK AT
DRUG DEVELOPMENT FOR.
WE SECURED AN ICD10 COHORT
DISEASE STATE AND THERE'S THREE
AND HAVE A PATIENT FOCUSSED DRUG
DEVELOPMENT MEETING WITH FDA IN
2022 AND CONTINUE TO LOOK AND
SEE WHAT ARE ANY TOOLS MISSING
WE CAN OFFER TO MAKE PROGRESS
FASTER IN OUR FIELD.
THANKS TO THE COLLABORATIVE
EFFORT OF NOT JUST DSF BUT THIS
ENTIRE COMMUNITY WE HAVE A
WEALTH OF RESOURCES DEDICATED TO
RESEARCH IN DRAVET SYNDROME AND
THE RESOURCES HAVE HELPED US
ALLOWING DRUG DEVELOPERS IN EACH
PHASE OF THE DEVELOPMENT AND
HAVE BEEN SURPRISED WHEN WE HAD
PHARMACEUTICAL COMPANIES COME TO
US AND PUT THEM IN TOUCH WITH
TOP RESEARCHERS MADE IT A
DISEASE TO TARGET.
HERE YOU SEE PART OF OUR
STRATEGIC APPROACH TO MAXIMIZING
OUR RESOURCES WAS LOOKING AT
WHAT GRANTS ARE OUT WE CAN COVER
AND IT COVERS 65 GRANTS IN THE
PAST 15 YEARS.
WE FELT IF WE WERE STRATEGIC NOT
ONLY COULD WE BRING ADDITIONAL
RESEARCHERS TO OUR FIELD THEN
GIVE THEM THE CRUCIAL SUPPORT,
HELP THEM COLLECT THE INITIAL
DATA THEY NEEDED TO GO ON AND
SECURE LARGER FUNDING AND HAVE
BEEN PLEASED TO SEE IT PLAYED
OUT LIKE WE HOPED.
THE $9 MILLION RESULTED IN AN
ADDITIONAL $23 MILLION IN NIH
LEVEL FUNDING GOING TO
RESEARCHERS WORKING SPECIFICALLY
IN DRAVET'S SYNDROME.
IT'S BEEN A HUGE BOON TO OUR
COMMUNITY BECAUSE IT'S DIFFICULT
FOR OUR FAMILIES TO FUND RAISE
SO IT'S BEEN MOTIVATED FOR THEM.
IN ADDITION WE'VE BEEN FORTUNATE
OVER 75% OF THESE GRANTS HAVE
LED TO PUBLICATIONS AND THAT'S
HELPED TO EXPAND AND DEEPEN OUR
UNDERSTANDING OF DRAVET'S
SYNDROME WHICH HAS BEEN HELPFUL
AS WELL.
I WOULD LIKE TO THINK EVERYONE
HERE UNDERSTANDS THE ROLE OF
PATIENT ADVOCACY GROUPS IN
CLINICAL TRIALS AND THEIR
IMPORTANCE BUT OF COURSE I'M
GOING TO TALK ABOUT IT.
WE CAN'T HAVE ANY OF THESE
ADVANCEMENTS WITHOUT OUR
PATIENTS.
SO THESE GROUPS PLAY SUCH A
CRUCIAL ROLE IN CLINICAL TRIALS
ENSURING WE'RE THINKING WHAT THE
PATIENT NEEDS AND PERSPECTIVES
ARE THAT WILL BE INTERGRAL TO
THE DEVELOPMENT OF NEW
THERAPIES.
THE NIH ESTIMATES 5% FOR RARE
DISEASES WILL BE APPROVED AND
WE'RE FORTUNATE SINCE 2018 OUR
PATIENT COMMUNITY HAS HAD THREE
NEW DRUGS COME TO APPROVAL WITH
INDICATIONS FOR DRAVET'S
SYNDROME TARGETED ON SEIZURE
REDUCTION AND HELPED SOME
PATIENTS IN OUR COMMUNITY BUT
UNFORTUNATELY WE'RE STILL IN A
POSITION AS MANY DEEs NOT EVERY
TREATMENT HAS THE SAME EFFICACY
LEVEL FOR EVERY PATIENT.
SO THERE ARE PATIENTS TRULY
SUFFERING, HAVE NO TYPE OF
SEIZURE CONTROL AND WE STILL
HAVE A LOT OF UNMET NEEDS EVEN
WITH THESE THREE NEW DRUGS.
WE ALSO WANT TO THINK ABOUT IS
THERE A POSSIBILITY OF WAYS TO
SLOW DOWN THE PROGRESSION OR
POSSIBLY REVERSAL OF DISEASE AND
EXCITING TO SEE SOME TREATMENT
COME TO CLINICAL TRIAL AND WANT
OUR PATIENT COMMUNITY UNITED AND
HAVE EVERYTHING THEY NEED AT
HAND TO MAKE DECISION TO
PARTICIPATE IN CLINICAL TRIALS.
WE'RE ALWAYS WORKING TO
AWARENESS OF DRAVET'S SYNDROME
AND CONNECT FAMILIES IN OUR
ORGANIZATION AND ALSO MAKE SURE
THEY'RE AWAY OF TRIAL
OPPORTUNITIES THERE.
WE DO THIS THROUGH THINGS LIKE
OUR WEBSITE, NEWSLETTER, SOCIAL
MEDIA CHANNELS.
WE HAVE FAMILIES THE OPPORTUNITY
TO LET US KNOW IF THEY'D LIKE TO
BE AVAILABLE TO SHARE THEIR
INPUT ON TRIAL DESIGNS OR
ANYTHING TO HELP THE DRUG
COMPANIES UNDERSTAND WHAT WOULD
BE MOST HELPFUL IN TRIAL DESIGN
AND WHAT OUR PATIENTS WANT.
AT THE END OF THE DAY WE WANT
THE DRUGS TO SUCCEED.
WE'RE MORE THAN HAPPY TO SHARE
WHATEVER INFORMATION WE CAN TO
MAKE THAT HAPPEN.
WE'VE DONE THING SUCH AS
REPRESENTING OUR COMMUNITY AS A
WHOLE BY ENGAGING IN
CONVERSATIONS WITH THE FDA
INCLUDING OUR EXTERNALLY LED
DRUG DEVELOPMENT MEETING AND TRY
TO WORK TO EDUCATE AND FOSTER
TRUST WITHIN OUR COMMUNITY.
I THINK WHEN YOU'RE TALKING
ABOUT A DISEASE LIKE THIS WHERE
OUR PATIENTS ARE ON MULTIPLE
DRUG EVERY DAY AND STILL NOT
GETTING GOOD RESULTS.
THERE CAN BE A PERCEPTION OF
FRUSTRATION ON THE CAREGIVER'S
PART BECAUSE THEY THINK THE DRUG
COMPANIES ARE JUST MAKING MONEY
OFF MY CHILD AND NO ONE CARES
THEY'RE SUFFERING WHILE WE KNOW
THAT'S NOT TRUE.
WHEN YOU'RE IN THE DEPTHS OF
THAT AND DESPERATE AND SAD THAT
CAN HAP EN.
WE TRY TO REMIND PARENTS AND
CAREGIVERS THIS IS ALL OF US
TOGETHER SO IF THINGS AREN'T
WORKING WE HAVE TO SPEAK UP AND
SHARE THE PATIENT EXPERIENCE AND
HAVE TO BE WILLING TO
PARTICIPATE IN CLINICAL TRIALS
OR NOTHING WILL GO FORWARD.
AND WE TRY TO ON A REGULAR BASIS
BY EDUCATING OUR COMMUNITY
MEMBERS WITH NEW COMMUNITY
MEMBERS JOINING OR PARENTS THAT
MAY HAVE MISSED THE MESSAGE AND
IT'S AN ONGOING EDUCATION WE
OFFER THE COMMUNITY.
SO FOR THOSE NOT FAMILIAR WITH
STOKE THERAPEUTIC STK001 THEY
HAVE TARGETED AUGMENTATION OF
NUCLEAR GENE OUTPUT AND INCREASE
INCREASING OUTPUT FROM HEALTHY
GENES AND COMPENSATING FOR THE
NON-FUNCTIONING COPY OF THE GENE
AND THIS IS AN ADEAL -- IDEAL
AND ASOs ARE HELPING INCREASE
THE PROTEIN PRODUCTION FROM THE
HEALTHY COPY OF THIS GENE AND
HOPING WHEN IT'S RESTORED YOU
MAY SEE A SLOWING OR COMPLETELY
STOP IN THE DISEASE PROGRESSION.
THIS NOVEL APPROACH ALLOWED THEM
TO -- WE'RE HOPING THIS WILL
ALLOW THEM TO PURSUE DISEASE
MODIFYING TREATMENT FOR MULTIPLE
SEVERE DISEASES BUT WERE EXCITED
WHEN I THEY CAME TO US AND SAID
THEIR GOAL WAS TO DEVELOP THAT
FIRST DISEASE MODIFYING THERAPY
TO ADDRESS THE GENETIC CAUSE OF
DRAVET'S SYNDROME AND YOU CAN
IMAGINE THE EXCITEMENT IN OUR
COMMUNITY.
THE MONARCH STUDY WAS THEIR
PHASE I/II STUDY AND ESTABLISHED
TOLERABILITY OF STK001 AND AN
ANTI-SEIZURE TREATMENT.
IT'S IMPORTANT TO TALK ABOUT THE
PROCESS OF THE PATIENT AND
FAMILIES HAVE TO GO THROUGH.
STK001 IS DELIVERED VIA A NEEDLE
INTO THE SPINE.
THOUGH OUR COMMUNITY IS PRETTY
SAVVY WHEN IT COMES TO CLINICAL
TRIALS THIS IS DIFFICULT THAN
WHAT WE'RE USED TO AND MORE
PAINFUL THAN A TYPICAL SHOT OR
ASKING A CHILD TO SWALLOW A
PILL.
PARTICIPANTS HAVE TO GIVE CSF
FLUID SAMPLES THROUGHOUT VIA
LUMBAR PUNCTURES AND THERE'S
OFFICE VISITS AND THREE
INTRATHECAL INJECTIONS AND FIVE
CSS COLLECTIONS.
WHEN YOU BREAK IT DOWN IT'S A
PRETTY SIGNIFICANT ASK FOR OUR
PATIENTS PARTICULARLY SINCE MOST
OF OUR PATIENTS HAVE TO TRAVEL
LONG DISTANCE TO SEE A
SPECIALIST AND THEY WOULD BE
CONDUCTING THE TRIALS.
I HOPE YOU UNDERSTAND THAT LEVEL
OF INVASIVENESS AND THE
COMMITMENT TO PARTICIPATE.
I THINK IT HELPS TO FRAME UP THE
DESPERATION OF OUR COMMUNITY
THAT THE TREATMENTS THAT ARE OUT
THERE ARE NOT GOOD ENOUGH AND WE
NEED BETTER.
THE PATIENTS THAT WERE IN
MONARCH FOLLOWING THAT WHO MET
THE STUDY CRITERIA DID CONTINUE
ON IN AN ONGOING OPEN LABEL
EXTENSION.
WE'RE AWAITING NEWS ON STOKE AND
WHEN THEY'LL ME OF ON TO PHASE
III WHICH WE ANTICIPATE THEY'VE
NOT MADE A COMMITMENT BUT WE
THINK SOME TIME IN 2025.
WE'VE BEEN FORTUNATE TO HAVE THE
DISEASES COME TO MARKET AND PART
OF OUR SUCCESS IS NOT ONLY
SETTING UP THE STRUCTURE
BENEFICIAL TO THE COMPANIES BUT
HAVE HIGH STANDARDS.
IF SOMEONE IS ASKING OUR PATIENT
COMMUNITY TO PUT FORTH THEIR
CHILD THERE NEEDS TO BE A
RECIPROCAL EXCHANGE.
WE WANT YOU TO LEARN FROM US
BECAUSE AT THE END OF THE DAY WE
WANT THE NEW TREATMENTS.
WHAT'S BEEN BENEFICIAL WITH US
WITH STOKE THERAPEUTICS IS THEY
ENGAGED WITH US EVEN BEFORE THEY
DECIDED WHAT THEIR TARGET WOULD
BE AND IT'S BEEN A POSITIVE
EXPERIENCE FOR US.
THEY'VE DEMONSTRATED A GENUINE
INTEREST IN OUR COMMUNITY, THEY
WANT TO KNOW THE NEEDS AND
PRIORITIES OF OUR PATIENT
COMMUNITY AND LOOKED FOR INPUT
ON TRIAL DESIGN NOT JUST FROM
OUR IMMEDIATE STAFF BUT TALKED
TO THE BROADER COMMUNITY AND
WERE ALWAYS OPEN AND RECEPTIVE
ANYTHING WE SAID WOULD NOT WORK.
WE FEEL FORTUNATE WE'VE BEEN
ABLE TO WORK WITH A COMPANY IN
THIS WAY.
IT GAVE US A HEAD START BECAUSE
AGAIN IT'S A NEW TYPE OF
THERAPY.
WHAT DID WE NEED TO DO TO
PROACTIVELY EDUCATE OUR
COMMUNITY AND START TO ADDRESS
THE QUESTIONS WE ANTICIPATED
WOULD COME TO THE TOP AS WELL AS
CONCERNS OUR EDUCATIONAL
OPPORTUNITIES TO HELP PEOPLE
UNDERSTAND WHAT THEY'D BE PA
PART -- PARTICIPATING IN AND
THERE'S A SHARED DESIRE TO SEE
THE TRIALS SUCCEED.
FOR COMPANIES HESITANT IN
ENGAGING WITH PATIENT GROUPS IT
SHOULD BE YOUR FIRST STOP.
WE WANT TO MAKE SURE YOU DESIGN
THE TRIAL OUR PATIENTS ARE GOING
TO BE INTERESTED IN SO THAT
THERE'S NO IMPEDIMENT WHETHER
RECRUITMENT OR INTEREST.
IT'S IMPORTANT TO HAVE THOSE
EARLY DISCUSSIONS.
AGAIN BECAUSE WE'RE TALKING
ABOUT THIS NEW MORE INVASIVE
TREATMENT I WENT TO OUR PARENT
SUPPORT GROUP ON FACEBOOK AND
ASKED PARENTS IF THEY'D MIND
SHARING THEIR TRIAL EXPERIENCE
TO HELP SHED LIGHT ON WHY THIS
IS SUCH A BIG ASK ON OUR
FAMILIES ON THE MONARCH STUDY.
WE HAVE AN OBLIGATION BEYOND NOT
JUST ENSURING SAFETY OF PATIENTS
DURING CLINICAL TRIALS BUT WHAT
ELSE CAN WE DO TO HELP ALLEVIATE
THE BURDEN.
I HAVE A SERIOUSLY ILL CHILD IF
YOU ASK THEM TO COME ACROSS THE
COUNTRY THERE'S A LOT OF TRAVEL
INVOLVED AND MOVING PIECES THAT
MAKE IT HARD FOR FAMILIES TO
PARTICIPATE.
I ASKED FOR PARTICIPANTS WHO
RESPONDED BACK IF THEY'D BE
WILLING TO SHARE RESPONSES TO
INQUIR
INQUIRIES THAT WE HEAR TIME AND
AGAIN FROM OTHERS IN THE TRIAL
BECAUSE WE ANTICIPATE THERE WILL
LIKELY BE OTHER TRIALS DOWN THE
PIPELINE WITH SIMILAR INVASIVE
TREATMENT PROTOCOL AND WANT
FAMILIES TO THINK ABOUT THAT AND
FIND THEIR COMFORT ZONE.
I WAS HOPING THE NEXT SLIDES
HELP UNDER SCORE THE CRUCIAL
CONSIDERATIONS AS WE MAKE
PROGRESS TOWARDS THESE
TRANSFORMATIVE TREATMENTS.
WHEN I ASK WHY A CAREGIVER
DECIDED TO HAVE THEIR IT CHILD
PARTICIPATE IN THE TRIAL I THINK
THE ANSWERS HIGHLIGHTED THE
BURDEN AND LACK OF OPTIONS.
THE FAMILIES MENTIONED WANTING
TO INCREASE THE OVERALL-QUALITY
OF LIFE FOR THEIR CHILD AND FELT
THEY DIDN'T HAVE OTHER OPTIONS
OR CHOICE THIS IS WILL ALL THAT
WAS FOR AVAILABLE FOR THEM.
HERE YOU SEE QUOTES FROM
FAMILIES WHEN I ASK WHAT TOP
CONCERNS WERE AROUND CHILD
PARTICIPATION.
THOUGH WE'RE TALKING ABOUT
PRETTY INVASIVE MEASURES
FAMILIES ARE STILL WILLING TO
CONSIDER THEM AND HAIRING THE
PROTOCOL DOESN'T MAKE THEM SAY
YES OR NO BUT LOOKING AT HOW
MUCH SUFFERING THEIR CHILD HAS
AND IN PARTICULAR REGARDING
THEIR PARTICIPATION IN STK001 I
THINK YOU CAN SEE IT'S EF
DEPARTMENT THEY'RE WILLING TO
THINK ABOUT IT AND MOST ARE
WILLING TO MOVE FORWARD WITH IT
THOUGH THERE'S A LOT OF OUT
THERE FOR THEM TO BE CONCERNED
ABOUT NOT JUST UP TRIAL FOR THE
INVASIVENESS OF THE
ADMINISTRATION.
THERE'S AN EMOTIONAL AND
PHYSICAL STRAIN AND RIGHT NOW
UNFORESEEN LONG-TERM HEALTH
IMPLICATIONS WE DON'T KNOW ABOUT
SO IT'S A BIG LEAP OF FAITH
WE'RE ASKING THEM TO MAKE.
WHEN I ASK ABOUT THINGS THAT MAY
HAVE AFFECTED THEIR WILL
PARTICIPATION AND THIS WOULD
MAKE IT EASIER FOR FAMILIES.
CONDUCTING CLINICAL TRIAL FOR A
RARE DISEASE HAS UNIQUE
CHALLENGES LUKE I'D MENTIONED,
TRAVELLING TO CARE TO TOP
CLINICIANS OFTEN THE WILL TOP
INVESTIGATORS IN THE TRIALS IS A
HEAVY BURDEN AND NOW WE'RE
ASKING THEM TO DO EIGHT, NINE,
10 VISITS IN A YEAR.
WE HAVE TO BE THOUGHTFUL AND
EXPLORE EVERY OPPORTUNITY TO
REDUCE THE BURDEN ON PATIENTS
AND THEIR FAMILIES.
THESE CAN BE THINGS LIKE
TELEHEALTH IS THERE ADDITIONAL
TESTING LOCALLY THAN TRAVELLING
AND WE HAVE TO BE CREATIVE.
AS WE'RE TALKING ABOUT NEW
TREATMENTS WE HAVE TO REALIZE
SOME THINGS THAT WORKED FOR
TRIALS IN THE PAST IT WILL BE
MORE DIFFICULT IN THE SITUATION
AND WE HAVE TO BE FLEXIBLE AND
DO WHAT'S RIGHT FOR THE PATIENT
FAMILIES.
WE OWE THAT TO THEM.
AND HEALTH DISPARITIES WILL
PRESENT ANOTHER LAYER OF
COMPLEXITY.
THE FAMILIES PARTICIPATED AND
NOT JUST STK001 HAVE A CERTAIN
LEVEL OF PRIVILEGE TO BE ABLE TO
PARTICIPATE AND WE NEED TO
ADDRESS THE BROADER SYSTEMIC
ISSUES TO MAKE SURE WE HAVE
EQUITABLE ACCESS.
I WOULD HATE TO THINK THERE WILL
BE A LIFE CHANGING MEDICINE AND
THEY WON'T BE ABLE TO ACCESS IT
BECAUSE OF THAT.
HERE'S WHERE WE ASK ABOUT FUTURE
TRIAL PARTICIPATION.
THIS IS BECOMING SCARY BECAUSE
IF WE FOLLOW THE STANDARD
PROTOCOL WITH THE FDA LIKELY
WE'LL HAVE TO -- SORRY, I WENT
OFF TOPIC.
SO WE KNOW WHEN OUR FAMILIES
TRAVEL IF WE CAN PREVENT THESE
PROLONGED STAYS OVERNIGHT
AFFECTING NOT ONLY HAVING THE
PATIENT THERE AND TRYING TO KEEP
THEM ENTERTAINED OUTSIDE THEIR
HOME ENVIRONMENT BUT IT AFFECTS
CARE CAN GIVER WORK SCHEDULES
AND SIBLINGS' SCHEDULES.
AND FAMILIES ARE CHALLENGED WHEN
THEY'RE OUT OF THEIR HOME
ENVIRONMENT OR IF THEY HAVE TO
FAST FOR A PERIOD OF TIME.
WE NEED TO THINK HOW TO MAKE
THIS EASIER FOR OUR PATIENT
FAMILIES GOING FORWARD.
AND THIS IS A LOT BUT I THINK WE
ALSO NEED TO THINK ABOUT IF
THERE ARE PLACEBO ARMS IN THESE
TRIALS AGAIN IT'S NOT TAKING A
PILL.
WE'RE ASKING FOR PRETTY INVASIVE
THINGS TO BE DONE WITH THE
POTENTIAL YOUR CHILD IS NOT
GETTING THE MEDICATION.
IT'S BEEN A CONVERSATION GOING
ON IN OUR COMMUNITY.
YOU CAN SEE WE HAVE PEOPLE FROM
THE QUOTES ON BOTH SIDES THAT
WOULD NOT PARTICIPATE BECAUSE
THEY FEEL THEY'RE ALREADY
PUTTING THE PATIENT SO MUCH AND
OTHERS ARE WILLING TO GO THROUGH
IT TO GET MEDICATION BECAUSE OF
THE QUALITY OF LIFE FOR THEIR
CHILD IS SO TERRIBLE.
WE HAVE TO THINK ABOUT THIS AND
NOT EXPLOIT A CAREGIVER'S
DESPERATION AND WHAT ARE THE
ETHICAL IMPLICATIONS OF THE
TRIAL DESIGN AND REMAIN
ALIGNMENT WITH THE FDA
EXPECTATIONS BUT IS THERE AN
OPPORTUNITY TO WORK WITH PATIENT
ADVOCACY GROUPS TO BETTER
UNDERSTAND THE CHALLENGES FOR
OUR COMMUNITY AND PHARMACEUTICAL
COMPANIES AND WE CONSIDER ARE WE
ABLE TO APPROACH THIS IN A
DIFFERENT WAY TO ACCOMMODATE THE
NEW TREATMENTS.
THIS COULD INVOLVE REFRAMING
PREVIOUS STANDARDS TO MAKE IT
EASIER FOR PATIENT
PARTICIPATION.
CAN WE USE NATURAL HISTORY DATA
OR KNOWN DISEASE RISK IN THE
REASSESSMENT INSTEAD OF PLACEBO
GROUPS?
WHEN WE TALK ABOUT SCIENTIFIC
INTEGRITY IT NEEDS TO BE
BALANCED WITH TO THE BURDEN
WE'RE PUTTING ON THE CAREGIVERS
AND PATIENTS.
AND A COUPLE CONSIDERATIONS.
I KNOW I'M OVER TIME I'LL SKIM
THROUGH THESE QUICK.
OUR GROUPS STILL NEED TO DO OUR
PART.
SO WE NEED TO WORK ON DOING
EARLY DIAGNOSIS, MAKING SURE OUR
PATIENTS GET ACCESS TO CARE AND
ADDRESSING THE IT WILL PAYER
ISSUES WHEN WE TALK ABOUT NEW
TREATMENTS AND WE DON'T
UNDERSTAND WHAT THE RESPONSE
WILL BE FOR PAYERS.
THAT'S SOMETHING HIGH ON OUR
PRIORITY LIST.
THOUGH THE TREATMENTS ARE
EXCITING THERE'LL BE CRUCIAL
SUPPORT FOR FAMILIES BECAUSE NOT
EVERY PATIENT WILL RESPOND
OPTIMALLY AND SOME MAY STILL
EXPERIENCE DISEASE BURDEN IF
THEY DO RESPOND.
WE NEED TO BE THINKING ABOUT
THIS, ACKNOWLEDGING THE
POTENTIAL OUTCOME AND ENSURING
WE HAVE CONTINUAL SUPPORT
SERVICES AVAILABLE TO HELP OUR
COMMUNITY REGARDLESS OF WHERE
THEY ARE THROUGHOUT THEIR
TREATMENT JOURNEY.
HAPPY TO ANSWER ANY QUESTIONS.
>> THANK YOU, MARY ANN.
MANY DOES ANYONE HAVE ONE QUICK
QUESTION.
OKAY, THANK YOU FOR JOINING US.
>> THANK YOU.
SO MOVING ON THE NEXT SPEAKER IS
MELANIE QUINTANA FROM BERRY
CONSULTANTS WHO IS GOING TO TALK
ABOUT INFORMED AND EFFICIENT
CLINICAL TRIAL DESIGN USING
NATURAL HISTORY.
>> THANK YOU ALL FOR INVITING ME
TO TALK TODAY AND I'M GOING TO
SWITCH GEARS AND TALK ABOUT WILL
STATISTICAL SCIENCE AND HOPE TO
EXCITE YOU WITH STATISTICS AFTER
LUNCH.
IN PARTICULAR I'M GOING TO TALK
BASED ON MY EXPERIENCE IN
DESIGNING CLINICAL TRIALS FOR
RARE GENETIC DISEASES.
OFTEN MANY OF THESE ARE IN
ADULTS BUT SOME IN PEDIATRICS AS
WELL.
TWO CASE STUDIES I WANT TO TALK
ABOUT IS DESIGNING CLINICAL
TRIALS IN FAMILIAL FRONTAL
TEMPORAL DEMENTIA MOST ARE
FAMILIAR WITH AND ALSO
EXPERIENCE IN DEVELOPING A
CLINICAL TRIAL FOR A DISEASE
CALLED GNE MYOPATHY.
A RARE GENETIC MUSCLE DISEASE.
SOME COMMON THEMES FOR THE
COMPLEXITIES IN DESIGNING
CLINICAL TRIALS FOR RARE
DISEASES AS ALL OF YOU ARE AWARE
THERE'S A GREAT AMOUNT OF
HETEROGENEITY IN PROGRESSION AND
DIFFERENT END POINTS TEND TO BE
AFFECTED AT DIFFERENT STAGES IN
THE DISEASE AND COMMON SOLUTIONS
TO THIS IS TO WILL ENROLL ONE
HOMOGENOUS SUBSET AND BOTH ARE
NOT IDEAL IN THE RARE DISEASE
SETTING FOR GENE THERAPIES.
WE DON'T WANT TO MAKE A RARE
DISEASE BY MORE RARE BY ONLY
ENROLLING A SUBSET AND OFTEN
TIMES THE SAMPLE SIZE NEEDED IS
NOT FEASIBLE.
SO SOME SOLUTIONS I'LL TALK
ABOUT THAT WERE COMMON BETWEEN
THE TWO TYPES OF DISEASES WHEN
WE WERE DESIGNING CLINICAL
TRIALS ARE A, NATURAL HISTORY
DATA AND DEVELOPING DISEASE
PROGRESSION MODEL WITHIN THE
NATURAL DATA TO KNOW WHAT YOU'RE
WORKING WITH.
KNOW IF THE DESIGN YOU'RE
PROPOSING IS POWERED.
WHAT ARE THE RIGHT END POINTS,
HOW DO THEY MEET AND SYNERGY
WITH ONE ANOTHER AND NATURAL
HISTORY IS INVALUABLE IN
DESIGNING CLINICAL TRIAL FOR
RARE DISEASE.
THE OTHER COMMON THEME IS MORE
INNOVATIVE DESIGN.
MORE POWERFUL ANALYSIS METHODS
THAT MAKE USE OF ALL THE DATA
AVAILABLE AND COLLECTED THROUGH
THE CLINICAL TRIAL USING
ADAPTIVE DESIGN TO STOP EARLY
FOR SUCCESS OR FUTILITY AND ALSO
MAKE USE OF OTHER DATA SOURCES
OR DOING WILL PLATFORM TRIALS
WHERE YOU CAN BORROW INFORMATION
ACROSS DIFFERENT INTERVENTIONS
THAT ARE BEING TESTED.
I'M GOING TALK VERY SPECIFICALLY
ABOUT MY WORK IN DEVELOPING
CLINICAL TRIALS FOR FAMILIAL
FTD.
I WAS UNFORTUNATE ENOUGH TO WORK
WITH COLLABORATORS WITH A
NATURAL HISTORY STUDY AND
COLLABORATORS IN EUROPE WITH THE
IT GENFI STUDY AND PUT THEM
TOGETHER TO HAVE A WEALTH OF
INFORMATION ON FAMILIAL FTD.
WE HAVE INFORMATION ON THREE
GENETIC MUTATIONS, C9, GRN AND
MAPT AND HEALTHY CONTROLS IN
YELLOW.
ALONG WITH THE END POINTS.
WE HAVE WHAT TENDS TO BE THE
PRIMARY CLINIC OUTCOME MEASURE
WHICH IS THE FTDRDR AND WE HAVE
DIFFERENT IT NEUROPSYCH MEASURES
AND MRI MEASURES AND FLUID
BIOMARKERS AND WE HAVE PRIOR
YEARS OF ONSET.
OUR PRIOR BELIEF WHEN SOMEONE
WILL HAVE CLINICAL ONSET OR WHEN
THEY DID.
IF SOMEONE STARTED OR HAD
SYMPTOMS IT'S BASICALLY WHEN THE
PATIENT RECALLS THEIR FIRST
SYMPTOM.
IT NOT THE AVERAGE AGE OF ONSET
FOR THAT MUTATION.
HERE'S SOME THOUGHTS OF SOME
DATA WE HAVE AND THE END POINTS
FOR ALL THE MUTATIONS AT
CLINICAL ONSET.
WE HAVE THIS RAPID PROGRESSION
IN THE END POINT.
BELOW THAT IS NFL YOU SEE THE
SMALL INCREASE IN AGING THAT IS
NORMAL AND THE RAPID INCREASE
SIMILAR TO CLINICAL ONSET.
SO OUR GOAL OF DISEASE
PROGRESSION MODELLING IS TO TWO
DO THINGS.
ONE IS TO TAKE ALL THE
INDIVIDUAL SNAPSHOTS OF THE
DISEASE FROM ALL OF THE
DIFFERENT PARTICIPANT AND TAKE
THE PUZZLE AND PUT THE PIECES
TOGETHER TO ALIGN THEM ALL IN
WHAT WE CALL DISEASE AGE OR
DISEASE STAGE AND ONCE ALIGNED
PUT THEM TOGETHER AND CAN
ESTIMATE HOW THE END POINTS MOVE
IN RELATION TO ONE ANOTHER.
ON THE TOP IT YOU CAN NOW WE'VE
ALIGNED PEOPLE BASED ON OUR
POSTERIOR WILL ESTIMATE IN WHERE
THEY ARE IN THEIR DISEASE AND
SEE A MORE CLEAN PATTERN OF
PROGRESSION THE MUTATION
CARRIERS TEND TO PROGRESS
RAPIDLY AND C9 AFTER BUT THE
BOTTOM PICTURE GOT A LITTLE BIT
MESSED UP BUT THIS IS ALSO THE
PICTURE OF NFL.
YOU CAN SEE THE MOST RAPID
INCREASE IN THE GRN PARTICIPANTS
AND THE OTHER PIECE.
AND ESTIMATING THE SURVEYS SHOWS
END POINTS TO UNDERSTAND HOW
THEY MOVE IN SYNERGY AND WHAT
END POINTS MAY START TO LOOK
ABNORMAL IN THE DISEASE COURSE
BEFORE CLINICAL SYSTEMS AND WITH
THE GRN PARTICIPANTS NFL STARTS
TO RISE EVEN 10 YEARS PRIOR TO
CLINICAL ONSET AND THE FRONTAL
REGION AND GRN AND THE C9
PICTURES ARE SIMILAR TO NFL AND
MRI START TO LOOK ABNORMAL EVEN
20 YEARS PRIOR TO CLINICAL
ONSET.
WITH MAPT YOU DON'T SEE THE NFL
RISE AS MUCH PRIOR TO ONSET BUT
TEND TO SEE THE NPL REGION IN
PARTICULAR START TO ATROPHY
EARLY ON.
SO GREAT A GREAT PUBLICATION OUT
IN NATURE TALKING ABOUT THE
DISEASE PROGRESSION MODELS.
I ENCOURAGE YOU TO READ THAT IF
YOU'RE INTERESTED.
WHAT I WANT TO TALK ABOUT MORE
IS HOW WE USE THE PROGRESSION
MODELS TO DESIGN MORE CLINICAL
TRIALS IN THREE WAYS.
ONE IS TO USE THE MODELS OR
CONCEPT OF DISEASE STAGING TO
LOOK AT INDIVIDUALS LIKELY TO
PROGRESS OVER THE COURSE OF THE
DISEASE.
WE CAN USE THE MODELS TO DO
REALISTIC MODEL BASED SIMULATION
TO UNDERSTAND THE OPERATING
CHARACTERISTICS OF OUR PROPOSED
CLINICAL TRIAL AND FINALLY USING
THEM OR THE MODELLING FRAMEWORK
TO DEVELOP MORE POWERFUL
ANALYSIS TOOLS.
SO FIRST FOR USING AS A TARGETED
ENROLLMENT TOOL AS I THINK MOST
ARE FAMILIAR AND WE TALKED A
LITTLE BIT ABOUT TODAY EARLIER
ON IT'S IMPORTANT TO FIND THE
ENROLLMENT CRITERIA.
IF WE ENROLL INDIVIDUALS TOO
EARLY BEFORE THEY START TO
CLINICALLY MANIFEST WE WOULD
HAVE NO POWER OR TOO LATE THE
TREATMENTS MAY NOT BE AS
EFFECTIVE.
WE WANT TO TRY TO ENROLL
PARTICIPANTS IN THE SWEET SPOT
WHERE MAYBE WE BELIEVE THEY'LL
PROGRESS ON CLINICAL END POINTS
DURING THE COURSE OF THE TRIAL
BUT WELL LIKELY STILL BENEFIT.
AND WE CAN TAKE OBSERVED VALUES
ON DIFFERENT MEASURES WHEN A
PATIENT WALKS IN THE DOOR.
SAY A PATIENT HAS GRN MUTATION
AND HAVE NO EVIDENCE OF CLINICAL
SYMPTOM AND THEIR MLI FRONTAL
REGION IS ATROPHIED.
THEIR NFL IS TWO STANDARD
DEVIATIONS ABOVE CONTROL AND
TAKE THAT TOGETHER WITH WHAT WE
KNOW ABOUT THE DISEASE AND
LEARNED ABOUT THE DISEASE IN THE
PROGRESSION MODEL TO TRY TO
ESTIMATE WHERE WE THINK THE
PARTICIPANT IS IN TERMS OF THEIR
DISEASE SPECTRUM.
HERE'S THAT DATA THE BIG DOTS
ARE THE BASELINE VALUES THAT I
MENTIONED AND SO WE CAN JUST USE
THOSE BASELINE VALUES OR VALUES
AT SCREENING TO TRY TO SEE WHERE
THEY FIT IN THE CURVE.
SO THIS IS AN EXAMPLE OF AN
INDIVIDUAL WHERE.
WE WOULD PREDICT TWO YEARS FROM
CLINICAL ONSET AND WHAT WE CAN
THEN OBSERVE THEREAFTER IS THEY
STILL REMAIN WITH NO CLINICAL
ONSET UP TO THREE YEARS AFTER
BASELINE AND THEN START TO
ELEVATE THEREAFTER.
THIS IS ANOTHER EXAMPLE OF
ANOTHER DRN PARTICIPANT AND NFL
AND MRI IN THE FRONTAL TEMPORAL
REGION.
NO EVIDENCE OF CLINICAL SYMPTOMS
AND MODELLING WOULD PREDICT
THEY'RE A YEAR POST ONSET BUT
HAVEN'T OBSERVED CLINICAL
SYMPTOMS YET AND YOU CAN SEE
AFTER BASELINE THE BLACK LINE
AND BOXES PROGRESS QUITE RAPIDLY
OVER THE NEXT COUPLE YEARS.
SO THE ABILITY AT BASELINE OR
SCREENING TO ESTIMATE WHERE WE
BELIEVE A PARTICIPANT IS WITH
RELATION TO ONSET COULD ALLOW US
TO ACTUALLY BROADEN OUR
ENROLLMENT CRITERIA AND IT'S
COMMON TO ENROLL POPULATIONS
PRESYMPTOMATIC WITH AN A GLOBAL
.5 OR CDR GLOBAL OF 1
SYMPTOMATIC AND WHAT YOU CAN SEE
IS THE PROGRESSION RATES
THEREAFTER FOR THOSE
INDIVIDUALS.
CRD GLOBAL .5 IS A PROGNOSTIC OF
FUTURE PROGRESSION.
SOME INDIVIDUALS DO NOT GO ON TO
PROGRESS AND SOME INDIVIDUALS
PROGRESS QUITE RAPIDLY SIMILAR
TO THE CDR GLOBAL 1.
SO BY USING THIS WILL WILL WILL
CONTEXT ESTIMATED AT SCREENING
WE CAN BROADEN THAT ENROLLMENT
CRITERIA AND ENROLL INDIVIDUALS
WHO HAVE A CDR GLOBAL VALUE OF 0
BUT PREDICTED TO HAVE ONSET
WITHIN 3 YEARS.
YOU CAN SEE THIS GROUP LOOKED
SIMILAR TO THE CDR GLOBAL .5
GROUP AS A PROGNOSTIC FOR FUTURE
PROGRESSION AND SLIGHTLY BETTER
AND WE GET A HIGHER PROPORTION
TO PROGRESS THEREAFTER.
SO THAT'S A WAY TO SORT OF USE
THE DISEASE AGE OR PROGRESSION
MODEL TO BROADEN ENROLLMENT
CRITERIA AND FOCUS ON
INDIVIDUALS LIKELY TO PROGRESS.
THE SECOND AREA WE USE THE
MODELS IS FOR CLINICAL TRIAL
SIMULATION.
EVERY CLINICAL TRIAL THAT WE
DESIGN WE USE SIMULATION.
JUST LIKE AN AIRPLANE PILOT
WOULD NOT FLY HIS FIRST FLIGHT
WITHOUT SIMULATING THOUSANDS OF
FLIGHTS BEFORE HAND, WE WOULD
NOT DO A CLINICAL TRIAL WITHOUT
SIMULATING THOUSANDS OF CLINICAL
TRIALS BEFORE HAND.
THIS INVOLVED SOME MECHANISM TO
GENERATE REALISTIC PATIENT-LEVEL
DATA TO SOME SORT OF MODEL OR
ASSUMPTION TO TAKE IT AND
SIMULATE DATA AND RUN THE
PROPOSED ANALYSIS WITH THE DATA
AND SIMULATED AFFECTS THOUSANDS
OF TIMES UNDER DIFFERENT
ASSUMPTION TO UNDERSTAND THE
OPERATING CHARACTERISTICS.
AS AN EXAMPLE OR ILLUSTRATION,
WE CAN TAKE THE DISEASE
PROGRESSION MODELS FOR
PARTICIPANTS AND USE THOSE TO
SIMULATE DATA LIKE I HAVE
PICTURED HERE ON THE RIGHT.
AND WE CAN USE THE CONCEPT OF
DISEASE IT STATE AND NOW AND
VARIABLE AND UNOBSERVED.
AND SAY A PARTICIPANT WALKS IN
THE DOOR AND SIMULATE THEY'RE A
YEAR PRIOR TO ONSET.
ON THE LEFT YOU CAN SEE OVER THE
NEXT YEAR AND A HALF WE ESTIMATE
THEY'LL FALL ON THE BLACK CURVE
HIGHLIGHTED AND SAMPLE AROUND
WITH VARIABILITY AROUND WHAT WE
ESTIMATED IT TO BE AND WHAT YOU
OBSERVED FOR THE PARTICIPANT IS
THE TRAJECTORY WE HAVE IN THE
MIDDLE.
THEY'RE PROGRESSION OVER THE
COURSE OF THE TRIAL AND DO IT
FOR SIMULATING TREATED
PARTICIPANTS.
SAY WE RANDOMLY SAMPLE A
SUBJECT.
THERE ARE DISEASE AGENTS CLOSE
TO TWO YEARS POST ONSET.
IF THEY WERE NOT TREATED WE
WOULD THINK THEY WOULD LOOK LIKE
THE GRAY LINE BUT NOW WE'RE
APPLYING A TREATMENT AFFECT SAY
30% AND FOLLOW THE BLUE LINE.
SO WE CAN SIMULATE AROUND THE
BLUE LINE WITH WILL MEASUREMENT
ERROR AND RECORD WHAT WOULD BE
OBSERVED IN THE CLINICAL TRIAL.
WE CAN DO THIS HOWEVER, MANY
TIMES FOR HOWEVER MANY PATIENTS
YOU PLAN TO ONREL -- ENROLL IN
THE CLINICAL TRIALS AND CAN TAKE
THIS DATA SET THROUGH OUR
PROPOSED ANALYSIS METHOD WITH
ASSUMPTIONS AND WHAT WE SEE WHEN
WE DO THE REALISTIC CLINICAL
TRIAL SIMULATIONS OFTEN TIMES IN
RARE DISEASE WE ARE VERY UNDER
POWERED FOR A TRIAL THAT IS
USEFUL.
THIS WAS AN EXAMPLE OF A
PROPOSED CLINICAL TRIAL AND A
RANDOMIZED CLINICAL TRIAL WITH
75 PARTICIPANTS, 2:1
RANDOMIZATION FOLLOWED FOR A
YEAR AND A HALF AND WE FOUND FOR
CLINICALLY MEANINGFUL STATISTICS
WE'RE UNDERPOWERED.
THIS IS OUR LAST PIECE TO BE
INNOVATIVE AND EFFICIENT AND
USING ALL THE DATA AT HAND.
GOING BACK TO THIS IDEA OF
DISEASE STAGING, IT'S SOMETHING
THAT WE CAN DO AND USE ALMOST AS
A CO-VARIATE AND WE KNOW MORE
THAN YOU OBSERVE ON THE PICTURE
ON THE LEFT.
WE CAN TRY TO IT WILL PREDICT
WHERE THIS BLUE PARTICIPANT IS
IN THEIR DISEASE COURSE AND CAN
DO THAT WITH MANY OUTCOME
MEASURES.
WE MIGHT KNOW THE NFL AND BRAIN
IMAGING AND TRY TO ESTIMATE
WHERE THEY ARE IN THEIR DISEASE
COURSE.
NOW WHEN WE DO THAT, WHEN WE
ADDRESS BY DISEASE STAGE WE CAN
EXPLAIN THE HETEROGENEITY IN THE
DATA AND SEE A MUCH CLEARER
PATTERN IN THE CONTROL DATA AND
SEE WILL VERY CLEARLY THAT THIS
TREATED PARTICIPANT PROGRESSES
MUCH LESS THAN WHAT YOU WOULD
EXPECT FOR THE SIMILAR CONTROL
COUNTERPART.
TAKING THE CONCEPT OF DISEASE
STAGING AS A VARIABLE TO ALIGN
OUR PARTICIPANTS TO EXPLAIN THE
HETEROGENEITY IN THE DATA AND
SEE A CLEARER PICTURE IF THE
TREATMENT WORKING OR NOT.
HERE WE'RE EXPLAINING WHY WE
THINK WE DIDN'T OBSERVE ANY
CHANGES IN THIS ONE.
AND WE SLOWED PROGRESSION IN
THIS PARTICIPANT.
JUST BY DOING THIS SLIGHTLY
INNOVATIVE METHOD YOU CAN GO TO
OVER 80% POWER IN YOUR CLINICAL
TRIALS.
I'M NOT SAYING GO HOME AND USE
THE EXACT METHOD BUT WE'RE
TRYING TO SAY BE THOUGHTFUL
ABOUT THE ANALYSIS METHOD YOU
USE AND DATA AT HAND AND
ACCOUNTING FOR INDIVIDUALS CAN
GIVE YOU MORE POWER TO DETECT
THE TREATMENT EFFECT.
THIS COMES WITH A WORD OF
CAUTION.
YOU SHOULD UNDERSTAND THE
ASSUMPTIONS GOING IN TO THOSE
ANALYSES METHODS.
FOR INSTANCE, THIS ASSUMPTION IN
THIS ANALYSIS METHOD WE HAVE
THIS COMMON SWELLING AND DISEASE
PROGRESSION OVER TIME AND COMMON
ACROSS ALL INDIVIDUALS
INDEPENDENT OF DISEASE STAGE BUT
GOING BACK TO TREATING TOO LATE
WHAT IF THE INDIVIDUALS FURTHER
FROM ONSET THE TREATMENT DOESN'T
WORK AS WELL.
WHAT IF WE DON'T SEE AS MUCH
SLOWING IN THOSE INDIVIDUAL?
WE DID SIMULATIONS AND BASICALLY
AS YOU TAKEAWAY THE INDIVIDUALS
ADDING TO THE EFFECT BECAUSE
THAT'S THE BIGGEST DIFFERENCE WE
CAN SEE, YOU START TO LOSE
POWER.
FOR INSTANCE IF THERE'S NO
BENEFIT IN INDIVIDUALS WHO ARE
FOUR YEARS PAST ONSET WE'RE NOW
MAJOR UNDER POWERED AGAIN AND
NEED TO GO BACK TO THE DRAWING
BOARD.
IT'S EXTREMELY IMPORTANT YOU
UNDERSTAND THE ASSUMPTIONS THAT
GO INTO THE MODEL AND
SENSITIVITY OF THE POWER
CALCULATIONS TO THOSE
ASSUMPTIONS.
YOU CAN GO BACK TO THE DRAWING
BOARD AND CAN APPLY THE DISEASE
AGE CRITERIA ON THE OTHER SIDE
TOO SAYING WE WANT TO ENROLL
THOSE WITHIN FOUR YEARS PAST
ONSET TO GET MORE POWER OR YOU
MIGHT SAY OKAY BECAUSE WE DON'T
BELIEVE IT WORKS AS STRONGLY IN
THOSE FAR FROM ONSET MAYBE WE
NEED DO A TWO OR THREE YEAR
STUDY BUT YOU CAN BE WELL
INFORMED OF WHAT YOU'RE TRUE
POWER OF YOUR STUDY IS.
IN SUMMARY THIS MAY NOT FIT
EVERYONE'S EXACT NEEDS BUT THE
MESSAGE IS THAT NATURAL HISTORY
STUDIES AND DISEASE PROGRESSION
MODELLING IS IMPORTANT WHERE
EVERY PATIENT MATTERS SO MUCH.
WE COULDN'T DO THIS WITHOUT DATA
SHARING IN A COMPETITIVE SPACE
SO EVERYONE NEEDS TO SHARE THEIR
DATA IN A PRECOMPETITIVE SPACE
TO LEARN AS MUCH AS POSSIBLE.
IT'S IMPORTANT IN RARE DISEASE
WE'RE ABLE TO BE MORE CREATIVE
AND THINK MORE THOUGHTFULLY HOW
WE ANALYZE OUR DATA.
WHAT THAT MEANS IS YOU'LL HAVE
TO INVEST IN THE INNOVATION UP
FRONT.
CAN'T GIVE YOUR STATISTICIAN A
DAY TO GIVE YOU A SAMPLE SIZE
CALCULATION.
A LOT OF THE WORK TAKES YEARS SO
INVEST THE TIME AND INNOVATION
UP FRONT AND IT SPEAK WITH
PARTNERS EARLY AND OFTEN.
INNOVATIVE APPROACHES MAY BE NEW
TO DIFFERENT PEOPLE.
MAY BE NEW TO REGULATORY BUT YOU
CAN SHOW IN SIMULATIONS AND GET
COMFORTABLE WITH IT OVER TIME.
AND I'LL LEAVE YOU WITH THESE
LAST COUPLE REFERENCES JUST ON
DISEASE PROGRESSION AND
MODELLING AND HAPPY TO TAKE
QUESTIONS.
>> OUR NEXT SPEAKER IS HEATHER
HAZLETT FROM THE UNIVERSITY OF
NORTH CAROLINA TO TALK ABOUT --
SO WE'RE IN THE FINAL STRETCH.
THANK YOU TO RICK VICKY AND THE
WORKSHOP ORGANIZERS AND I FEEL
LIKE I'VE LEARNED SO MUCH
PROBABLY MORE THAN I'LL LET YOU
LEARN BY MY SPEAKING HERE TODAY
BUT I'LL TALK ABOUT REMOTE
PHENOTYPING.
TECHNICAL DIFFICULTIES I'M A
FAST SPEAKER SO I'LL CATCH US UP
ON TIME.
REMOTE PHENOTYPING CAN MEAN
DIFFERENT THINGS AND WANTED TO
LIST WHAT PEOPLE INCLUDE
SOMETHING TO DO WITH THEIR
COMPUTER ON THEIR PHONE OR
CALLING OR VISITING THEIR HOME
AND CONSIDER THE REMOTE WAY TO
PHENOTYPE AND THE TELEASSESSMENT
THAT'S BECOME MORE POPULAR IN
RECENT YEARS.
FINALLY WEARABLES ARE
CONSIDERABLE PHENOTYPING.
THANKS WILL TO COVID I THINK A
LOT OF US IN RESEARCH HAD TO
LEARN ABOUT REMOTE PHENOTYPING
BECAUSE COVID SHUT EVERYTHING
DOWN.
FROM OUR RESEARCH PERSPECTIVE WE
NEEDED FAMILIES TO COME AND SEE
US AND HAD TO WORK AROUND WHAT
HAPPENED WHEN WE COULDN'T SEE
FAMILIES, WE COULDN'T BRING THEM
TO OUR CENTER, WHAT COULD WE DO
TO GET DATA FROM THEM EVEN
REMOTELY.
SO WE HAD TO LOOK AND INSTITUTE
A LOT OF DIFFERENT NEW
METHODOLOGIES.
WHAT WE FOUND WHEN WE TRIED TO
DO THAT WAS THERE ARE
LIMITATIONS.
THERE'S JUST NOT A WORLD OF
THINGS TO CHOOSE FROM BUT WHEN
YOU DEAL WITH PEDIATRIC
POPULATIONS IT'S HARD.
THERE ARE BENEFITS.
IT DOES TO OUR ADVANTAGE THINK
ABOUT HOW TO DO THIS IN A GOOD
WAY BECAUSE YOU'RE ABLE TO REACH
A BROADER RESEARCH GEOGRAPHIC
AREA FOR YOUR STUDIES.
IT DOES AS IT MARY ANN MENTIONED
CREATE BURDEN ON FAMILIES.
THEY DON'T HAVE TO TRAVEL TO
YOUR CENTER AND CAN INCLUDE MORE
RARE DISEASE POPULATIONS THAT
ARE LOCATED AND SPREAD ACROSS
THE COUNTRY.
IT CAN INCLUDE NON-ENGLISH
POPULATIONS BECAUSE MORE
MEASURES ARE SUITED FOR SPANISH
AND CLINICAL TRIALS.
IT DOES EXPAND YOUR MONEY.
IT CAN BE DONE ON A BROAD SCALE
AND IT'S VERY MUCH SUITED FOR
THAT REASON, GENETIC STUDIES,
CLINICAL TRIALS, ASSESSMENT
REPOSITORIES AND MORE EFFICIENT.
SO IT ALSO ALLOWS FOR A LOT OF
CROSS-SITE COLLABORATIONS.
WE HAVE INDIVIDUALS IN OUR
NETWORK ACROSS THE U.S. AND
COLLABORATORS ARE ALL ACROSS THE
U.S.
THAT REMOTE ASSESSMENT, REMOTE
DATA GATHERING AND PHENOTYPING
ALLOWS US TO DO THIS AND I PUT
THIS AS A BEE IN THE BONNET FOR
SOME TRAINEES AND INVESTIGATORS,
IT CREATES A LOT TO DO BECAUSE
AGAIN AS I MENTIONED, THERE'S
NOT EVERYTHING AVAILABLE AND
EVERYTHING THAT IS AVAILABLE
HASN'T NECESSARILY BEEN USED IN
THIS WAY.
SO JUST BECAUSE YOU'RE USING AN
INSTRUMENT THAT THEN GIVEN IN A
CLINIC 100 TIMES OVER AND WE
WANT TO JUST NOW SEND IT TO A
FAMILY AND CONVERT IT TO RED CAP
A FORM THEY COMPLETE ON THEIR
COMPUTER, THAT MAY WORK
DIFFERENTLY THAN WHAT YOU THINK
IT DOES.
THERE'S A GREAT WEALTH OF DATA
FOR PEOPLE TO LOOK AT AND THINK
ABOUT THE VALIDITY QUESTIONS.
SO THERE ARE SOME CONSIDERATIONS
AND AGAIN I'M NOT GOING TO HAVE
THE ANSWER OF LIKE HERE'S YOUR
REMOTE BATTERY BUT GIVE AN
EXAMPLE AND CONSIDERATIONS OF
PEOPLE THINKING THINK ABOUT HOW
TO DO THIS AND WHAT TO THINK
ABOUT.
THE FIRST AREA YOU NEED TO THINK
ABOUT IS THE AGE RANGE.
THERE ARE LIMITATIONS
PARTICULARLY FOR PEDIATRIC
POPULATIONS ON THE TYPE OF DATA
YOU CAN GATHER.
ESPECIALLY IF IT'S PERFORMANCE
BASED.
THE YOUNGER THE CHILD THE MORE
YOU'LL DEAL WITH A PARENT OR
CAREGIVER REPORT VERSUS DIRECT
OBSERVATIONS AND NEED TO THINK
ABOUT THE DOMAINS AND SOME ARE
MORE SUITED TO REMOTE DATA
GATHERING THAN OTHERS.
ON THAT LIST IS COGNITIVE AND
THAT IS AS A PSYCHOLOGIST THE
HARDEST ONE.
I THINK WE'VE HAD THE BIGGEST
STRUGGLE HOW TO DEVELOP
COGNITIVE OR DEVELOPMENTAL LEVEL
REMOTELY IS CHALLENGING.
ALSO WHETHER YOU NEED TO HAVE A
MEASURE REPEATED ACROSS MULTIPLE
TIME POINTS AND COLLECT
CROSS-SECTIONAL OR LONGITUDINAL
DATA AS YOU'RE TRACKING
OUTCOMES.
AND WHETHER YOU'RE SATISFIED
WITH THE OBSERVATION OR IT CAN
BE A CAREGIVER REPORT.
THOSE ARE ALL CONSIDERATIONS.
THERE'S MORE.
THERE ARE SOME THINGS OFF THE
SHELF.
THERE ARE THINGS YOU CAN
PURCHASE THAT ARE OUT THERE YOU
CAN USE.
PRIMARILY QUESTIONNAIRES AND
EXPERIMENTAL MEASURES AND WILL
IT WILL MEASURES AND YOU HAVE TO
BE CAREFUL WHEN YOU'RE GETTING
OFF THE SHELF INSTRUMENTS YOU'RE
PAYING ATTENTION TO THE
LICENSING AND PURCHASING OFTEN
INVOLVED AND THAT GETS TO THE
NEXT THING WHICH IS COST.
PER EACH COST OR A SCORING
PROGRAM YOU NEED TO PURCHASE AND
SOME PERSONNEL COSTS.
THESE WILL NEED TO BE DELIVERED
IN SOME WAY.
YOU CAN'T QUITE TAKE THE HUMAN
OUT OF THE EQUATION.
SOMEBODY NEEDS TO E-MAIL
SOMETHING OR SET UP A VISIT.
DO THAT TELEVISIT AND WHAT LEVEL
OF EXPERTISE DO YOU NEED THAT
PERSON TO HAVE TO BE A LICENSED
CLINICIAN OR RESEARCH ASSISTANT.
THAT IS ALL COSTLY.
YOU WANT TO THINK ABOUT AND AS I
MENTIONED BEFORE BUT WANT TO
REPEAT HERE, SPANISH SPEAKING
MEASURES AND OTHER LANGUAGES TOO
CREATES AN ADDITIONAL LEVEL OF
COMPLEXITY.
YOU HAVE TO BE ABLE TO
ADMINISTER THOSE MEASURES AND
INSTRUMENTS IN THAT LANGUAGE OF
INTEREST OR HAVE SOME TRANSLATED
MATERIALS.
THOSE THINGS ARE ALSO MORE
EXPENSIVE.
THIS IS WHERE I'LL SHOW AN
EXAMPLE.
I'M TALKING ABOUT THIS REGISTRY
THE BRAIN GENE REGISTRY WITH A
JOINTLY FUNDED PROJECT, THE
INTELLECTUAL DISABILITIES
RESEARCH CENTERS.
THERE WERE A NUMBER FUNDED TO
POOL RESOURCES THINKING ABOUT
HOW TO COLLECT DATA AND MAKE A
REGISTRY FOR INDIVIDUALS THAT
HAVE RARE GENES ASSOCIATED WITH
BRAIN DEVELOPMENT.
THERE WERE THREE AIMS.
ASSOCIATED AGE AIM 1 THE
PHENOTYPING.
WE HAD A GROUP IN BOSTON HELPING
WITH THE CURATION.
THESE ARE RARE GENES THEY NEEDED
TO THINK ABOUT CURATION AND
WHAT'S KNOWN AND HOW THEY WERE
ON THE LIST OF GENES WE
INCLUDED.
AND THE REGISTRY NEEDS TO BE
CREATED.
THAT WAS AN INFRASTRUCTURE
BUILDING THAT HAPPENED AT WASH
U.
WILL AND I'LL TELL YOU A LITTLE
BIT ABOUT WHAT WE DID.
THE RATIONALE WAS POWER IN
NUMBERS.
WE NEEDED THE CENTERS LOOKING
FOR THESE RARE GENES TO GET
ENOUGH OF A SAMPLE OR COHORT SO
ADVOC
INVESTIGATORS COULD LOOK AT THEM
AND THERE'S HUNDREDS OF GENE
ASSOCIATED WITH NEURAL
DEVELOPMENT AND MAYBE A CENTER
WOULD SEE ONE OR TWO.
YOU NEED MORE PEOPLE LOOKING.
THAT SMALL SAMPLE SIZE CREATES A
CHALLENGE FOR RESEARCH.
SO THESE ARE THE CENTERS THAT
WERE INVOLVED IN THE BRAIN GENE
REGISTRY WE'RE IN THE TAIL END
IN THE TRIPLE ENROLLMENT RIGHT
NOW.
WE WERE PRETTY SUCCESSFUL IN
GETTING THE 13 CENTER TO
CONTRIBUTE DATA AND WHAT WAS
INVOLVED AND THEY NEEDED TO LOOK
FOR PATIENTS THAT HAD SOME OF
THESE GENES WE HAD ON OUR LIST.
THEY HAD TO ENROLL THESE
PATIENTS.
THEY HAD TO COLLECT THEIR
E.H.R., ELECTRONIC HEALTH
RECORDS, PRIMARILY GENETIC TEST
REPORTS AND CONDUCTED
PHENOTYPING WITH THEM.
NOW WE HAVE WILL 621
PARTICIPANTS IN THE REGISTRY.
THERE'S A CLOUD-BASED DATA
HOLDING AND IF YOU LOOK HAT
GENES 1-20 PER GROUP IN THE GENE
AND ENROLLMENT STILL HAPPENING
BUT AT A TRICKLE LEVEL BECAUSE
WE'RE IN THE STAGES OF
REFUNDING -- HOPING TO BE
REFUNDED.
YOU CAN SEE MORE HERE.
THERE'S A QR CODE TO TAKE US TO
OUR WEBSITE.
IT IS A REG IS GEARED TO BE A
RESOURCE SO THERE'S A WAY TO GET
ACCESS TO THE DATA.
YOU CAN FIND IT HERE.
WE RECENTLY PUBLISHED A PAPER TO
TELL YOU MORE ABOUT THE
DEMOGRAPHIC OF THE PATIENTS IN
THE DATABASE.
THIS WAS PUBLISHED THIS YEAR BUT
CAN'T REMEMBER HOW MANY SUBJECTS
WERE IN IT BUT IT'S NOT ALL THE
SUBJECTS THAT WERE STATED BUT
GIVES A PRETTY GOOD SNAPSHOT OF
THE DEMOGRAPHICS.
I'M GOING TO TALK ABOUT WHAT I
LOVE WHICH IS THE PHENOTYPING.
THIS IS AIM 1.
I WANTED TO LET YOU HEAR A
LITTLE BIT ABOUT THE DEVELOPMENT
OF THE PHENOTYPING BATTERY.
WE CREATED THIS BATLY THE RAPID
NEUROBEHAVIORAL ASSESSMENT
PROTOCOL AND JOHN CONSTANTINO
WAS THE OTHER P.I. AND HAD BIG
IDEAS ON WHAT NEEDED TO HAPPEN
WITH THE BATTERY AND PROTOCOL
AND WANTED IT TO BE STANDARDIZED
AND LOOKED AT DOMAINS IMPORTANT
TO INTELLECTUAL DISABILITY AND
ACROSS A BROAD AGE RANGE AND
WANTED TO BE ABLE TO SEE
ANYBODY.
HE WANTED IT TO BE FREE WHICH I
HAD TO SAY, LOOK, I DON'T KNOW
THAT'S POSSIBLE BUT WE'LL MAKE
IT AS CHEAP AS POSSIBLE AND LOOK
FOR NORMED OR THINGS AVAILABLE
AT LOW COST.
HE WANTED IT TO BE SOMETHING
THAT COULD BE EASILY
ADMINISTERED BY WILL CLAIMS
PEOPLE BUT NOT WILL Ph.D. LEVEL
PERSON AND WHEN COVID HAPPENED
THAT ALL ADDED TO THE MIX OF
REMOTE.
SO REMOTE ADMINISTRATION FOR ALL
THIS.
THAT WAS A BIG ASK.
THEE ARE DOMAINS WE WERE HOPING
TO TAP.
IT'S AN ABBREVIATED BATTERY.
IT'S NOT SUPPOSED TO BE THE
BIGGEST MOST ROBUST PICTURE OF
PATIENTS.
IT'S A SNAPSHOT ACROSS THESE
DOMAINS.
THE IDEA WILL WOULD SERVE AS A
JUMPING OFF PLACE FOR STUDY AND
INVESTIGATIONS.
THESE ARE THE TOOLS AND MEASURES
THAT ARE INCLUDED IN THE BATTERY
AND YOU CAN SEE HERE THE THINGS
YOU RECOGNIZE BUT A COMBINATION
OF QUESTIONNAIRES, OFF THE SHELF
THINGS AND A FEW ADAPTED OR
ADMINISTERED VIA
TELEOBSERVATELE
OBSERVAHEALTH
OBSERVATIONS AND WE USED IT WILL
AND ADAPTED AND GOT PERMISSION
FROM THE PUBLISHER TO ADAPT ONE
SUB SCALE OF THE SHIPLEY A
NON-VERBAL REASONING TASK TO
ADMINISTER THROUGH TELEHEALTH
WITH A SHARED SCREEN.
WE GOT PERMISSION BUT IT'S NOT
GOING TO WORK FOR EVERYBODY.
WE ALSO USED A PARENT REPORT
PROFILE FOR THOSE SITUATIONS.
SO WE TRIED FOR A DIRECT
OBSERVATION BUT COULDN'T WENT
WITH ALTERNATIVES AND THIS IS A
LAUNDRY LIST OF THINGS WE WERE
COLLECTING.
IT'S KIND OF BROKEN DOWN INTO
TWO SECTIONS.
A SECTION WHERE WE HAVE
QUESTIONNAIRES AND REPORTS.
WE HAVE CONVERTED ALL OF THOSE
INSTRUMENTS WHERE WE NEEDED TO
WITH PUBLISHER PERMISSION TO RED
CAP FORM TO E-MAIL TO FAMILIES.
SO WE HAD TO CODE THAT AND DID
AND ON THE BACK END WE HAD TO
CODE THE SCORING FOR THOSE
FORMS.
SO FORMS GET SCORED.
WE HAD TO DO BOTH OF THOSE
THINGS BUT THOSE HAVE BEEN DONE
AND THEN HAVE A TELEHEALTH
VISIT.
IT DEPENDS ON HOW MUCH TIME WE
NEED BUT INCLUDES THIS
ACCOUNTING SCREEN IF WE NEED TO
DO IT.
AN AUTISM OBSERVATIONAL SCREEN
AND SOME SCREENERS WE CREATED TO
LOOK FOR MORPHOLOGY AND
NEUROLOGICAL SCREEN.
IT'S ABOUT 30 TO 60 MINUTE
BATTERY OF TELEHEALTH AND THE
REST IS REMOTELY ADMINISTERED
QUESTIONNAIRES.
WE ALSO ON THE SLIDE I USUALLY
HAVE A PICTURE OF A PLANE AS
WE'RE TRYING TO BUILD IT AND
IT'S IMPORTANT BECAUSE THE OFF
THE SHELF THINGS WEREN'T USED IN
THE WAYS AND WANTED TO MAKE SURE
WE WOULD VALIDATE WHAT WE WERE
COLLECTING TO MATCH UP IT WITH
GOLD STANDARD DIAGNOSTIC DATA.
WE DID IT IN AN ACTIVE WAY AND
WHAT WE REALIZED WE NEEDED WAS
MAPPING TOOLS.
AND SO WE TOOK THE -- THIS IS
PARTLY BECAUSE THE GENOME -- THE
GENE CURATION SAID WE NEED
EVERYTHING IN TERMINOLOGY AND
THAT WILL HELP WITH THE GENE
CREATION.
WE HAD TO TAKE THE PHENOTYPING
DATA AND MAP IT TO HPO TERMS AND
HELPS WITH THE VALIDATION
PURPOSE.
SO WE DID NOT DO ALL 13,000
TERMS.
THERE'S A LOT OF HPO TERMS.
WE SAID YOU HAVE TO GIVE US YOUR
LAUNDRY LIST.
SO THEY DID.
I DON'T EXPECT YOU TO READ THIS
BUT THEY PICKED OUT THE TERMS
AND SAID PLEASE LOOK FOR THESE.
THEY'RE PRIMARILY ASSOCIATED
WITH INTELLECTUAL DISABILITY AND
DEVELOPMENT DELAY AND ADHD AND
THEY SAID HERE'S WHAT WE'D LIKE
YOU TO DO.
SO WE MAPPED OUT THE 30 OR SO
HPO TERMS AND TOOK OUR
PHENOTYPING DATA AND CONVERTED
THEM WITH AN ALGORITHM INTO THE
TERMS.
I DON'T HAVE IT HERE BUT WE DID
A LOT OF QC WITH IT AND HAVE
100% MAPPING SUCCESS.
THAT WE WERE PLEASED ABOUT AFTER
THE QC AND NOW WHEN WE GO INTO
OUR DATABASE YOU CAN GENERATE A
REPORT THAT SAYS TELL ME FROM
THE PATIENTS WHAT ARE THE HPO
TERMS.
IT DIDN'T TELL YOU WHAT THEY'RE
ASSOCIATED WITH AND IT'S
PROBABLY THERE.
SO THEN WE USED THOSE TERMS TO
THINK ABOUT OUR VALIDATION FOR
THE PHENOTYPING.
AND WHAT WE NEEDED FOR THAT WAS
GOLD STANDARD CLINICAL REPORT
AND SAY THE CHILD HAS A
COGNITIVE MEASURE.
THEY GOT A CLINICAL DIAGNOSIS OF
AUTISM AND IDD.
GOOD OUR RNAP DATA FALL IN LINE
WITH THEIR CLINICALLY OBSERVED
GOLD STANDARD REPORTING?
WE'VE HAD TO DO A LOT OF DATA
CLEANING.
THE 13 CENTERS THAT WERE
COLLECTING DATA FOR US, THEIR
MISSION WAS TO COLLECT THE DATA
FOR THE PROJECT AND GOLD
STANDARD REPORTS.
WHEN YOU DIG INTO THE GOLD
STANDARD REPORT SOMETIMES IT WAS
THE SCHOOL IP THAT DIDN'T REALLY
MENTION ANYTHING ABOUT THE
CLINICAL DIAGNOSIS OR HOW IT GOT
THERE.
JUST HAD MORE ACADEMIC MATERIAL
OR SOMETIMES JUST A CLINIC NOTE
AND DIDN'T REALLY DESCRIBE WHAT
WAS USED AND SOME DATA WE HAD TO
CLEAN OR REMOVE AND IT'S BEEN A
LENGTHY PROCESS AND HAVE DONE
EXTRACTION FROM THE E.H.R. AND
CLINICAL RECORDS AND DATA
CLEANING AND WE JUST FINISHED
THIS SPRING.
I LOOKED AT THE DATA AND LOOK
LIKE IT GOOD CONCURRENT VALIDITY
WITH MORE SEVERE CASES YOU MAY
CONSIDER STRAIGHTFORWARD AND LOW
FUNCTIONING.
WHEN THE DATA SAID THERE'S AN
INTELLECTUAL DISABILITY THE
SUBJECT AND CLINICAL REPORT HAS
A CLEAR CASE OF INTELLECTUAL
DISABILITY.
IT WORKED PRETTY WELL FOR THOSE.
IT DID NOT WORK PRETTY WELL AND
AGAIN THIS IS PRELIMINARY BUT
WE'LL NEED TO GET AN ADDITIONAL
REPORTER BECAUSE THE
SELF-REPORTING DIDN'T WORK WELL
AND IF PEOPLE DIDN'T COMPLETE
THINGS OR COMPLETE THEIR
INFORMATION AND THE MISSING DATA
PROBLEM LOOKING TO SEE IF THE.
RNA
RNAPA AGREES WITH THE DIAGNOSTIC
REPORT AND WANT TO DO WITH
ADDITIONAL HPO TERMS AND STARTED
WITH THE WILL AUTISM RELATED
TERMS AND WHAT THE COLLABORATORS
WERE SO EAGER TO SEE AND HAVE
ADHD AND THINGS OF HIGH INTEREST
AND THAT IS ALSO GOING TO BE ON
OUR LIST.
AND SOME USE A MACHINE LEARNING
ARLING -- ALGORITHM AND WHAT
I'LL DESCRIBE WHEN YOU LOOK IN
THE E.H.R. YOU CAN GO OFF ON AN
ERRONEOUS PATH AND SEE A PERSON
MAY HAVE A DIAGNOSIS OF AUTISM
BUT WHEN YOU DIG IN THE RECORD
IT'S BECAUSE THEY WENT TO A
CLINIC AND PEOPLE THOUGHT THEY
HAD AUTISM AND NEVER GOT A
DIAGNOSIS BUT IT STUCK IN THE
E.H.R. AND WHEN YOU DO AN
EXTRACTION IT PULLS UP AS
AUTISM.
WE'RE TRYING TO GET MORE DATA
THAT'S RELIABLE.
I DIDN'T TALK A LOT ABOUT
SPANISH BUT WE'RE DOING ALL THE
SAME THING FOR OUR
SPANISH-SPEAKING PARTICIPANTS.
ALONG THE WAY WE HAD
INVESTIGATORS SAY WHAT ABOUT
SPANISH?
WE HIRED PEOPLE TO DO THE
TELEHEALTH IN SPANISH AND
COLLECTED THE DATA.
THAT'S ALSO ON OUR LAUNDRY LIST.
SO THERE'S PROS AND CONS WITH
THESE PHENOTYPING AND WE CAN
ANTICIPATE THE PROS.
IT'S COST EFFICIENT AND CAN DO
BIG NUMBERS.
YOU CAN SEE PATIENTS IN THE
COMFORT OF THEIR HOMES AND THERE
ARE SOME CONS AND THEY'RE NOT
SMALL.
TELEHEALTH REQUIRES IT DEVICES
AND MANY FAMILIES WHEN YOU SAY
CAN YOU DO A TELEHEA HEAHEALTH
THEY LOOK AT THEIR PHONE AND SAY
YES.
SOME TOOLS REQUIRE A BIG SCREEN
SO WHEN YOU ASK IF THEY HAVE THE
TECHNOLOGY MAYBE THEY DO AND
MAYBE THEY DON'T.
I HAVE COLLEAGUES THAT SHIP A
LAPTOP TO FAMILIES TO DO THE
ASSESSMENT AND THEN SHIP IT
BACK.
THE INTERNET CONNECTIVITY IS
ALSO A PROBLEM FOR THE
TELEVISIT.
NOT SO MUCH THE QUESTIONNAIRES
BUT THE TELEHEALTH VISIT THE
INTERNET CAN BE CHOPPY AND YOU
NEED A PRETTY GOOD INTERNET
CONNECTION.
A PAPER TALKS ABOUT THE COMPUTER
ADMINISTERED BATTERY AND A PAPER
TALKED ABOUT MEASURE ON UNSU
UNSUPERADVISED.
IF YOU CAN IMAGINE WHEN YOU'RE
AT HOME MAYBE YOU'RE FEELING
UNDER THE GUN TO DO IT QUICKLY
AND UNCONTROLLED.
WE HAVE MANY VIDEOS OF SIBLING
RUNNING IN THE BACKGROUND AND
DON'T KNOW WHAT WILL HAPPEN IN
THE BACKGROUND THAT MAY AFFECT
THE TELEHEALTH ASSESSMENT.
THOSE ARE THE CONS BUT
TELEHEALTH IS HERE TO STAY.
AND THE NIH IS WORKING IN THIS
EFFORT AND THERE'S NEW THINGS
AND NEW THINGS ARE BEING
VALIDATED AS WE SPEAK IN TERMS
OF ASSESSMENTS CONDUCTED AND
EVALUATED VIA TELEHEALTH.
I THINK IT'S THE WAY OF THIS
FUTURE AND CLINICAL TRIALS IS
WELL SUITED TO THINK OF HOW TO
IMPLEMENT MEASURES TO DECREASE
THE BURDEN OF COMING IN MULTIPLE
TIMES TO A SITE.
I'M GOING TO JUST STOP HERE AND
ACKNOWLEDGE THE FUNDING FOR OUR
BRIDGING REGISTRY TEAM.
AND I WANT TO THANK OUR FUNDERS.
THANK YOU.
>> THANK YOU.
I DON'T KNOW.
>> QUESTION.
>> WHY CAN'T YOU DO PATIENT
RETURN OUTCOME RESULTS?
>> WHAT DO WE DO OR WHAT DO I
THINK WE SHOULD DO.
>> WHAT ARE YOU DOING?
>> SO WE DID FEEL IT WAS
IMPORTANT TO GIVE BACK FEEDBACK
RESULTS BUT DIDN'T WANT TO GIVE
BACK THE INFORMATION FROM ALL
THE EXPERIMENTAL MEASURES.
WE HAD A BIG DEBATE AND INCLUDED
DATA INCLUDED IN OUR BATTERY AND
DATA FROM THE DEVELOPMENT
ASSESSMENT.
WHETHER THE SHIPLEY BECAUSE
THOSE ARE STANDARDIZED SCORES WE
THOUGHT MANY FAMILIES MIGHT LIKE
TO GIVE TO THEIR SCHOOL SYSTEM
FOR EXAMPLE OR THEIR CLINICIANS.
THOSE WERE THE PRIMARY -- ALSO
THE CBPL OF THINGS WE ADMINISTER
SO WE GIVE THAT OUTPUT AS WELL.
IT'S A VERY ABBREVIATED FEEDBACK
REPORT WE GIVE.
>> I APPRECIATE THE PRESENTATION
AS WELL AS EMPHASIZING AS PART
OF THE PROGRAM BECAUSE TO ME
IT'S BEEN A MAJOR OBSTACLE IN
OUR ABILITY TO DO LARGE SCALE
EPILEPSY CLINICAL WORK AND
OBSERVATIONAL TRIALS I'M SURE
YOU'RE AWARE AND HAVEN'T TALKED
ABOUT THE MORE COMMON EPILEPSY
AND IT WILL REQUIRE THE CAREFUL
PHENOTYPING OF MANY PATIENTS AND
I'VE BEEN IN THAT WORLD A BIT
AND HAVE MY OWN EXPERIENCE.
I CAN'T IMAGINE HOW HARD TO THE
WORK HAS BEEN FOR YOU.
WE TALKED ABOUT THE CHALLENGES.
CAN YOU EXPAND ON TWO AREAS.
ONE, WHAT IS YOUR EXPECTED
ENROLLMENT BY THIS POINT AND DID
YOU COME ACROSS DIFFICULTIES AND
HOW DO YOU THINK OF THE ABILITY
TO USE THE METHODS FOR FOLLOWING
PATIENTS OVER TIME?
IN OTHER WORDS ONCE THEY GET
ENGAGED WE SEE A FALL OFF IN THE
PROTOCOL.
WHAT DO YOU THINK WILL BE THE
FUTURE IN THAT REGARD?
>> SO TWO QUESTIONS.
WHAT WAS THE EXPECTED ENROLLMENT
WE HAD TO READJUST OUR
ENROLLMENT GOAL AND IN THE
ORIGINAL IT WAS LIKE 1,000
SUBJECTS AND WHEN COVID HAPPENED
THEY READJUSTED THE GOAL.
THE NEW GOAL IS LIKE LIKE 670
INDIVIDUALS.
I'M NOT SURE THEY CAME UP WITH
THE NUMBER BUT WE WERE HAPPY.
WE GOT CLOSE TO OUR GOAL AND
HAVE THE TRIPLE ENROLLMENT NOW.
WE WEENDED OUR FUNDING PSYCH AN
THE GOAL OF RESUBMISSION IS NOT
TO DO FOLLOW-UP BUT TO EXPAND TO
OTHER PATIENT OR CLINICAL
GROUPS.
FIRST PROJECT WAS IT A GROUP OF
IBBRCs.
IN THE COURSE OF THIS STUDY WE
HAVE HAD GROUP OUTREACH TO US
CAN WE SEND YOU ALL OF OUR
SUBJECTS AND PATIENTS?
SOME OF THE RARE DISEASE GROUPS
HAVE ASKED IF WE CAN SUPPORT
THEM BY ENROLLING THEM IN THE
REGISTRY TO BECOME A DATA HUB
AND DO THE PHENOTYPING AND
COLLECT THEIR RECORDS.
THAT'S THE SPIRIT OF THE RENEWAL
IS EXPANSION NOT JUST TO THE
IBBRCs NOT NECESSARILY
LONGITUDINAL.
THE REGISTRY PURPOSE IS TO HELP
INVESTIGATORS HAVE A PLACE TO
LOOK FOR SUBJECTS AND PATIENTS
AND DO ADDITIONAL STUDIES AND
RECOMPACT THEM.
I DON'T HAVE A GOOD ANSWER TO
HOW INVESTED THEY'LL REMAIN.
THEY'RE ALSO ENROLLED IN CLIN
GEN.
THEY DO PERIODIC UPDATES AS
WELL.
I DON'T HAVE A GOOD ANSWER FOR
THAT QUESTION.
>> DO ANY SEQUENCING COMPANIES
COME TO YOU LOOK FOR ADVICE HOW
TO IMPROVE THEIR DATA?
>>
>> I DON'T THINK SO, NO.
I HAVE NOT PERSONALLY TALKED TO
THEM.
>> OUR NEXT SPEAKER IS LANIE IS
ROSS FROM UNIVERSITY OF
ROCHESTER ADDRESSING ETHICAL
ISSUES.
>> THANK YOU.
I WANT TO THANK YOU VICKI AND
THE ORGANIZERS.
I'M A GENERAL PEDIATRICIAN.
I HAVE A Ph.D. IN PHILOSOPHY AND
HERE AS AN ETHICISTS.
MY OWN WORK HAS BEEN IN
MONOGENICS.
I'VE LOOKED AT MONOGENIC
DIABETES AS WELL AS PARKINSON'S.
I'LL ACKNOWLEDGE MY IGNORANCE
AND THERE'S A LOT I DON'T KNOW
AND A LOT A LOT US DON'T KNOW
AND USE THAT TO FRAME.
I'LL BEGIN WITH A QUOTE, THOSE
WHO CANNOT REMEMBER THE PAST ARE
CONDEMNED TO REPEAT IT AND SOME
OF THIS IS ON ISSUES THAT WERE
RAISED AND THERE WERE A LOT OF
ETHICAL ISSUES RAISED AND MANY
COMMENTS WERE MADE BY OTHER
SPEAKERS BUT SOME I WANT TO
EMPHASIZE.
I WANT TO BEGIN WITH THIS QUOTE
ABOUT REMEMBERING OUR HISTORY.
AS WE TALKED ABOUT GENETIC
STRATEGIES.
WE HAVE TO REMEMBER THE GENE
TRANSFER TRIAL HAS RISK AND WE
MENTIONED AN 18-YEAR-OLD WHO HAD
AN OTC DEFICIENCY WHICH CAN BE
TREAT ED AND THERE WAS AN AD
VIRUS AND HE SUFFERED AN IMMUNE
RESPONSE LEADING TO ORGAN
FAILURE AND BRAIN DEATH.
WHAT WAS IMPORTANT WAS THE
PROBLEMS WITH THE ETHICS.
THERE WERE A LOT OF ONLY CAL
LAPSES AT THE FEDERAL AND WILL
ADVISORY COMMITTEE.
FIRST THE APPROVED PROTOCOL SAID
IT WAS IN THE BLOODSTREAM BUT IT
WENT TO THE LIVER AND EXCLUSION
CRITERIA WERE IGNORED.
HE HAD A HAMBURGER THE DAY
BEFORE HE WAS SUPPOSED TO GET
THE INFUSION AND HIS LACKS WERE
OFF THE CHART AND DIDN'T MEET
THE CRITERIA BUT DECIDED TO GO
AHEAD ANYWAY.
SO ADVERSE EVENTS AND THIS WAS A
PHASE I SO THE FIRST HAD ADVERT
EVENTS AND IT WAS NOT DONE AND
HE WAS NOT GIVEN THE UPDATE AND
THE CONSENT FORM HAD OTHER
OMISSIONS AND IT THERE WERE
CONFLICTS OF INTERESTS NOT
DISCLOSED AND THEY WOULD HAVE
EARNED QUITE A BIT OF MONEY IT
WAS SUCCESSFUL.
THIS IS 1999.
YOU HAVE TO GO OVER A DECADE TO
LOOK AT THE RATION TO RESEARCH
DEVELOP AND COMMERCIALIZE OTHER
CAR T CELLS AND THEN OVER 2600
GENE THERAPY CLINICAL TRIALS
WERE ONGOING, COMPLETED
WORLDWIDE AND LISTED IN
CLINICALTRIALS.gov AND SOME
TREATMENTS ALREADY APPROVED.
DESPITE THEY'LL BE APPROVED SOME
RISKS KEPT COMING OUT AND THERE
WAS A TREATMENT IN CANCERS AND
CEREBRAL EDEMA IT. WASN'T
RECORDED EARLY ON THOUGH THEY
SAW NEUROLOGICAL TOXICITY WITH
DELIRIUM AND CONFUSION AND IN
PIGLETS ADMINISTERED THEY SAW
TOXICITY AS IT GOT TO THE HIGHER
DOSES.
AND THERE WAS APPROVAL OF THE
TREATMENT FOR WILL.
SMA AND WHILE WE CELEBRATE SOME
OF THE CRITICAL ADVANCES WE ALSO
REMEMBER DELAYS RISK AND NEED TO
ACKNOWLEDGE AS WE TALK ABOUT
TRANE TRANSFER STUDIES IN THE
PEDIATRIC COMMUNITY.
AND THERE WAS CHRIS PER
TECHNOLOGY LOOKING AT IT IT T
THALAS
THALASSEMIA AND AT THIS TIME
IT'S BEEN REPORTED THERE'S BEEN
NO SIGNS OF AFFECTING OTHER
GENES TO END THE CRISPR BUT 3
BILLION BASE PAIRS MAY HAVE
IMPACT BECAUSE OF THEIR
INFLUENCE IN REGULATORY GENES
WE'LL HAVE TO FOLLOW FOR YEARS
IF NOT ED AS TO COME.
SO WHAT CAN GO WRONG WITH CHRIS
PER?
IT MAY THEY CAN THE PATIENT
WORSE OFF AND MAY CAUSE OTHER
PROBLEMS OFF TARGET BEEN GREAT
CRISPR TO ALLOW FOR TRANSPLANTS
AND SO FAR IT'S LOOKING GOOD
THOUGH THERE WERE UNANTICIPATED
DIFFICULTIES IT'S HARD TO KNOW
AND IT'S HARD TO DIRECTLY ASSESS
THESE GIVEN THEY CAN OCCUR YEARS
TO DECADES AFTER TREATED THE
CRISPR TREATED THERAPIES.
SO I DO CLINICAL ETHICS AT MY
RESEARCH INSTITUTION.
THE TRADITIONAL RESEARCH ETHICS
WE ALL NEED TO DO ANY TYPE OF
RESEARCH IS BASED ON THE BELMONT
REPORT FROM 1978 WHICH HAD A
STRICT SEPARATION FROM
RESEARCHER AND CLINICIAN AND
HUMAN SUBJECTS AND RESEARCH
PARTICIPANTS.
OKAY.
I'M GOING TO STAND OVER HERE.
SORRY.
SO RESEARCH ETHICS OR RARE
DISEASES HAVE TO LOOK AT HUMAN
SUBJECT PROTECTION AND THE
CLINICIAN IS OFTEN THE SAME
PERSON AS THE RESEARCHER AND THE
IS OFTEN THE SAME PERSON AS THE
RESEARCH PARTICIPANT OR EVEN THE
PATIENT IS A PARTNER IN THE
RESEARCH AS WE'VE HEARD WITH THE
PATIENT ADVOCACY GROUPS.
IT WAS 1978 RULES WERE MEANT FOR
STRICT CLINICAL TRIALS AND SOME
CLINICAL RESEARCH CENTER MAY NOT
BE THE BEST.
ONE THING I'VE BEEN WORKING ON
IN ONE OF THE GRANTS IS THE
SUPPLEMENT LOOKING AT WHAT WE
CALL TRANSLATIONAL BIOETHICS
WHICH EMBRACES DUALITY AND THE
PATIENT IS RESEARCHER AND THE
PATIENT IS ALSO A RESEARCH
PARTICIPANT EVEN POSSIBLY AN
ADVOCATE FOR THE FAMILY IS THE
ADVOCATE.
SO RATHER THAN SEPARATING THESE
WE NEED TO LOOK AT MORE OF A
LEARNING HEALTH SYSTEM WHERE THE
ELECTRONIC HEALTH RECORD CAN
INCLUDE DATA, PATIENT CARE DATA
AS WELL AS CLINICAL RESEARCH.
THAT IS SOMETHING THAT TO GIVE
WITH THE COMMUNITY I'VE BEEN
HEARING SO FAR TODAY.
THE ISSUES IN EPILEPSY GIVEN
WHAT I'VE LEARNED IS HOW TO
IDENTIFY CHURCH AND WHO SHOULD
BE THE FIRST HUMAN PARTICIPANT
AND WHAT RESEARCH METHODS AND
DATA COLLECTED AND JUSTICE
ISSUES.
FIRST, HOW TO IDENTIFY THOSE
WITH A MONO AUAUTO.
AND AT TIMES THE PERSON HAS A
RARE DISEASE AND YOU DON'T WANT
YOUR CLINICIAN EVERY TIME YOU GO
IN WITH A HEADACHE YOU DON'T
WANT THE DOCTOR TO ORDER A FULL
SCALE WILL OF BLOOD TESTS AS
WELL AS AN MRI BECAUSE OTHERWISE
AND THEN WE'LL FIND INCIDENTAL
FINDINGS AND GO DOWN A RABBIT
HOLE AND SO WE HAVE TO FIGURE
OUT HOW TO REALIZE SOMETIMES
IT'S A ZEBRA AND THAT WILL BE A
REAL PROBLEM BECAUSE.
AND WE'RE LOOKING FOR RARE
EPILEPSIES 93% OF THE TIME THEY
CAN PROBABLY GO ON A STANDARD
TREATMENT BUT HERE IN THESE
CASES THEY CAN'T AND HOW DO WE
TRAIN PEOPLE TO BE AWARE AND
READY TO CHANGE THE WHOLE
APPROACH WHEN IN A SENSE IT'S
WHAT THEY'VE BEEN TAUGHT IN
MEDICAL SCHOOL.
IT WILL REQUIRE A GENE CHIP AND
A TENDENCY AND I'LL JUST POINT
AT YOU.
AND MANY WILL WANT TO DO GENOMIC
SEQUENCE AND IT WON'T BE COVERED
BY MANY INSURANCE AND WILL NEED
TO EDUCATE THE PEDIATRICIANS AND
PRIMARY CARE NEUROLOGIST WHAT TO
LOOK FOR AND WHY IT MAY BE A
RARE DISEASE AND RIGHT NOW MOST
TREATMENTS ARE EXPERIMENTAL AND
IT'S NOT CLEAR WHO WILL PAY FOR
IT AND THE CLINICIAN HAS LESS
MOLE MOTIVATION TO DO THE
TESTING.
YOU CAN SEE HOW IT SNOWBALLS IN
TRYING TO GET PEOPLE TO DO THE
RIGHT THING.
THE RESULT IS ONLY CHILDREN OF
HIGHLY EDUCATED HIGHLY RESOURCED
PARENTS WILL GET THE DIAGNOSIS.
ONLY AFTER WILL DIAGNOSTIC
ODYSSEY AND WE HEARD MANY
STORIES ALREADY.
THERE'S TO IT WAS A TO TRY TO
AVOID THE DIAGNOSTIC ODYSSEY.
THE FIRST ONE IS IT THINK OF
ADDING IT WITH AND WE HAVE 4
MILLION DONE ANNUALLY AND EVERY
TITLE WOULD BE TEST FOR ALL
KINDS OF MONOGENIC EPILEPSY THE
PROBLEM IS IT DOESN'T MEET THE
WORLD HEALTH ORGANIZATION
CRITERIA FOR NEWBORN SCREENING.
IT WOULD SOLVE THE EQUITY ISSUE.
IT WOULD BE FAIR.
THE PROBLEM IS GENOTYPE DOESN'T
EQUAL GENOTYPE.
WE'LL HAVE PEOPLE COMING IN FOR
SPECIALIST CARE AND IT'S
DIFFICULT TO OBTAIN PARTICULARLY
IF YOU LIVE IN A RURAL AREA AND
MANY GENETIC VARIANTS WE KNOW
OFTEN COME FROM EUROPEAN
ANCESTRY AND THEY PARTICIPATE IN
RESEARCH AND IT WILL LEAD TO
FURTHER DISPARITIES EARLY ON.
THE OTHER PROBLEMS ARE THAT
UNTIL WE KNOW THE PHENOTYPE IT
DOESN'T MEET THE CRITERIA FOR
NEWBORN SCREEN WHICH CAN'T BE
DONE WITHOUT PARENTAL CONSENT
AND IF WE STARTED TO OFFER
CONDITIONS FOR WHICH WE COULDN'T
OFFER TREATMENT WE WOULD THEN
REQUIRE PARENTAL CONSENT AND
WOULD BE UNACCEPTABLE BECAUSE WE
DON'T WANT TO MISS THE DISEASES
ALREADY ON THE PANEL TO PREVENT
MORBIDITY AND MORTALITY.
SHOULD WE THINK OF ALL
SEQUENCING OF ALL PEOPLE WHO
PRESENT WITH THE FIRST SEIZURE?
THIS WOULD SOLVE THE EQUITY
ISSUE.
THE PROBLEM IS SCREENING IS NOT
NECESSARILY COVERED BY INSURANCE
AND THE SCREENING WOULD BE HARD
TO JUSTIFY WITHOUT A TREATMENT
AND WE NEED TO MAKE SURE ALL
INDIVIDUALS WHO COULD BENEFIT
WILL HAVE ACCESS TO IT.
SO WHO SHOULD BE THE FIRST HUMAN
PARTICIPANT?
WE HEARD ABOUT THIS IN THE PAST
FEW DAYS.
WE HAVE CONVERSATION POINTS.
FIRST WE'VE SEEN THE VARIABILITY
IN THE NATURAL HISTORY MAKES IT
HARD TO KNOW WHEN WOULD BE THE
IDEAL TIME WILL AND WE TALKED
ABOUT THE FRONTAL TEMPORAL
DEMENTIA UNLESS YOU UNDERSTAND
THE NATURAL HISTORY OF THERAPY
AND TO WHAT EXTENT WE WANT TO
DEAL WITH THOSE ALREADY
SYMPTOMATIC OR PRESYMPTOMATIC
INVOLVING THOSE PRESYMPTOMATIC
CAN BE PROBLEMATIC AND HAVE TO
DECIDE THE END POINTS TO CHOOSE
AND TO BE IN NEGOTIATION WITH
THE PATIENTS AND FAMILIES
THEMSELVES ABOUT ABOUT WHAT
MATTERED FOR THEM AND HOW WILL
THIS IMPACT EQUITY I THINK WE'LL
NEED TO CONSIDER.
IT WILL BE A SCIENTIFIC AND
ETHICAL STAKEHOLDERS AND
ADVOCACY GROUPS AND FAMILIES AS
WELL AS THE CLINICIANS AS WELL
AS THE FUNDERS.
AND THEN WE HAVE ETHICAL OR
SCIENTIFIC ISSUES AND THEY'RE
ONLY CAL ISSUES.
DO WE HAVE TO LOOK AT THE
INCLUSION CRITERIA AND THE MORE
DIFFICULT YOU MAKE IT THE MORE
DEGREE OF SIGNIFICANCE UNLESS WE
HAVE A GOOD CURVE TO SAY WHEN
WE'LL GET NATURAL HISTORY AND IT
WILL BE IMPORTANT TO DETERMINE
THE END POINTS AND IT MAY NOT BE
JUST REDUCING THE NUMBER OF
SEIZURES BUT COMMUNICATION IS
MORE IMPORTANT FOR THE FAMILY
AND THE ACCESSIBILITY OF RISK
FROM THE FAMILIES.
FOR SOME THE RISK OF PUTTING
THEIR CHILD TO BET EVERY NIGHT
IS SO GREAT THEY'RE WILLING TO
ENROLL IN ANY TRIAL FOR OTHERS
THE RISK MAY NOT BE ACCESSIBLE.
AND FREQUENCY OF DATA COLLECTION
AND HOW DATA ARE COLLECTED AND
THE EXTENT TO WHICH WE CAN USE
PATIENT REPORTED OUTCOMES AND
WHAT DO WE THINK OUTSIDE OF THE
CLINIC AND THINGS OF THAT SORT.
SO AND WHEN WE THINK OF AN AAV A
VIRAL SECTOR SOMETIMES YOU ONLY
HAVE ONE CHANCE AND USUALLY
THERE HAS TO BE A TYPE OF STUDY.
AND A PARENT TRIES TO DECIDE
WHEN TO ENROLL THEIR CHILD GETS
INTO THIS PROBLEM OF WHAT IN
PHILOSOPHY WE CALL THE BETTER
BOTTLE OF WINE INTRODUCED BY JOP
POLYP IT MEANS EVERY DAY IT GETS
BETTER.
SO DO YOU HAVE TO TAKE TAKE THE
PREVENTION AND WHEN SOMEBODY
WILL LIVE PREFER WILL DRINK THE
WINE AND BETTER TOMORROW BUT IF
YOU KEEP WAITING IN A SENSE
THEY'LL NEVER DRINK THE BOTTOM
OF WINE BUT YEAR NOT IMMORTAL
AND THEY'RE NEUROLOGICALLY
PROGRESS AND THE PARENTS HAVE TO
DECIDE WHEN TO ENROLL.
IN THE FIRST TRIAL?
AND WE SAW THIS IN WAITING FOR A
BETTER THERAPY AND YOU MAY HAVE
A ONE AND DONE AND NOT BE ABLE
TO GET A SECOND CHANCE.
A SEPARATE ISSUE I WANT TO RAISE
ALSO THIS RAISES ISSUES AND THE
PARTICIPANT CAN ALWAYS HAVE THE
RIGHT TO IF WILL ENROLL IN THE
RESEARCH AND IT'S NOT LIKE A
CLINICAL TRIAL LIKE YOU CAN STOP
A DRUG BUT ONCE YOU'RE THERE
YOU'RE THERE FOR THE DURATION
AND HERE THE PATIENT CAN
WITHDRAW AND SO THEN WE'RE NOT
GETTING THE DATA.
UNSUCCESSFUL THERAPY YOU STILL
WANT TO KNOW WHAT HAPPENS TO THE
INDIVIDUALS.
SO IS BAD OUTCOME FROM THE
RESEARCH AND THIS GETS BACK TO
THE NEED FOR TRUST AND
PARTNERSHIP THAT HAS BEEN TALKED
ABOUT OFTEN AND WAS BEAUTIFUL TO
GO TO THE EVENT LAST NIGHT AND
SEE ALL THE PARTNERSHIPS WORKING
TO HOPEFULLY AVOID EVENTS LIKE
THAT.
AND WE'LL NEED TO TALK ABOUT
THIS IT WE WANT SUPPORT AND WE
NEED TO COLLECT THE NATURE
HISTORY.
WE WANT TO HAVE AN EMPHASIS ON
STANDARDIZING PATIENT REPORTED
OUTCOME AND THE NEED TO DEVELOP
SPECIFIC TO EPILEPSY AND WE ALSO
WILL LOOK AT THE CROSS S AND
WILL NEED TO RECORD AND MAKE
AVAILABLE SUCCESS AND FAILURE
AND WE'RE ALWAYS TOLD JOURNALS
ONLY WANT TO PUBLIC SUCCESSES
BUT IN ORDER TO NOT REINVENT THE
WHEEL AND MAKE THE SAME MISTAKE
THERE NEEDS TO BE COMMUNICATION.
THE COVID EPIDEMIC TAUGHT US ONE
THING IF YOU GET ENOUGH MONEY
AND GET ALL THE SCIENTISTS IN
THE COUNTRY TO WORK TOGETHER YOU
CAN CREATE A VACCINE IN LESS
THAN A YEAR.
THAT WAS AN INCREDIBLE FEET AND
THE FASTEST BEFORE THAT WAS FOUR
YEARS AND THIS WAS AN INCREDIBLE
FEAT BUT IT WILL REQUIRE A LOT
OF TEAM WORK.
I'M EXCITED BY THE PARTNERSHIPS
I SAW TODAY AND WANT TO
ENCOURAGE THAT TO CONTINUE AND
MAKE IT TO THE AND A HALF
REGISTRIES AND INDIVIDUALS WOULD
AGREE IF IT CAN BE DONE AT HOME,
PATIENT REPORTED OUTCOME I THINK
WOULD BE REALLY USEFUL.
WE CAN HAVE MANY LIFE TIME OF
FOLLOW-UP.
AND MOST IMPORTANTLY OUR EQUITY
AND JUSTICE ISSUES ONE QUESTION
WE'LL HAVE TO ASK IS HOW TO
ENGAGE DIVERSE COMMUNITY AND
ENSURE CHILDREN FROM
UNREPRESENTED COMMUNITIES GET
DIAGNOSED AND MAKE SURE ACCESS
IS FAIR IN THE END OF ONE
THERAPIES WHICH OFTEN REQUIRE
PARENTS WHO ARE INCREDIBLY IT
WILL HIGHLY LITERAL AND MOTIVATE
AND HIGHLY RESOURCED?
GIVEN THE COST OF THE STRATEGIES
WE'LL HAVE TO THINK ABOUT HOW
WE'RE GOING TO DEVISE AN
EQUITABLE STRATEGY AND ALL
STUDIES NEED TO BE IF NOT
PUBLISHED IN JOURNALS PUT INTO A
REPOSITORY AND NOT MAKE THE SAKE
MISTAKES DONE BEFORE AND MOVE
THE SCIENCE FORWARD AS FAST
POSSIBLE IN A SAFE WAY.
WE HAVE TO THINK WHETHER THERE
WILL BE POST STUDY OBLIGATION
AND WHOSE RESPONSIBILITY WILL IT
TAKE TO TL FOR A REGISTRY AND
THEY TAKE TIME AND COST MONEY
AND AFTER APPROVAL WE NEED TO
HAVE THE REGISTRY BECAUSE WE
NEED TO UNDERSTAND ADVERSE
EVENTS AND OPPORTUNITIES TO
ENROLL FOR THE PATIENT
POPULATION WHO MAY BRING UP NEW
SIDE EFFECTS WE MAY NOT HAVE
SEEN FOR THE INCLUSION CRITERIA
FOR CLINICAL TRIALS AND WILL
NEED TO LOOK AT SUCCESSES OR
FAIL AND THE OBLIGATION TO
RE-EVALUATE GENOMIC DATA AND
HAVE NOT MET CRITERIA FROM
EARLIER STUDIES MAY NOW BENEFIT
FROM WILL THERAPIES WE'VE BEEN
DEVELOPING.
LET ME CONCLUDE HUMAN SUBJECT
PROTECTS MUST HAVE
CONSIDERATIONS OF SAFETY.
WE DO NEED EPISTEMIC HUMANITY ON
WHAT WE KNOW AND DON'T KNOW AND
THERE'S A LOT WE DON'T KNOW IN
MANY THE THEMED THERAPIES AND
WE'LL DEVELOP THERAPIES AND I
LOOKED AT POMPEII DISEASE NO ONE
WOULD HAVE DESCRIBED AS HAVING
HEARING LOSS AND WE'RE SEEING
NEW COMPLICATIONS THAT WEREN'T
EXPECTED.
NOT READY TO ADD ANY OF THESE TO
NEWBORN SCREENING BUT MAY BE
READY FOR SCREENING TO PROMOTE
GREATER EQUITY.
AGAIN, THERE'S GOING TO BE
PUSHBACK UNTIL THERAPIES AND
WILL FINALLY FOCUSSING ON A
REDUCTION OF FEATURES MAY NOT BE
THE PRIMARY END POINTS PARENTS
WILL FOCUS ON AND THE LAST LINE
WILL BE WE NEED REGISTRIES AND
SHARING DATA AND THANK YOU FOR
INVITING ME.
I HOPE THIS HAS BEEN HELPFUL AND
BEST OF LUCK AS WE GO AND THE
JOURNEY TOGETHER.
THANK YOU.
>> WE HAVE ONE QUESTION FROM
BRENDA PORTER ASKING HOW DO WE
DEAL WITH ALL THE ELIGIBLE
FAMILIES FOR GENETIC STUDY IN
KNOWING EACH OTHER?
>> HOW DO WE DEAL WITH -- IS AN
AGAIN?
>> ALL THE ELIGIBLE FAMILIES FOR
GENETIC STUDY KNOWING EACH
OTHER?
>> WHAT'S THE PROBLEM WITH THEM
KNOWING EACH OTHER?
I'M ASSUMING THE PROBLEM COMES
WITH A PLACEBO ARM VERSUS DRUG
ARM AND MAYBE TALK AND TALK ON A
PLACEBO ARM AND WILL WANT TO
DROP OUT.
IS THAT WHAT THE ISSUE IS?
THAT'S WHAT I'LL ASSUME.
THAT IS A BIG PROBLEM AND EVEN
IF THEY DON'T KNOW EITHER SOCIAL
MEDIA MADE IT SO EVERYBODY KNOWS
REACH OTHER AND WHERE DATA CAN
BE PUT.
WE'LL NEED FAMILIES TO BE PART
OF THE STAKEHOLDER GROUP AND
DECISION MAKING PROCESS HOW TO
DESIGN THE STUDIES.
IF EVERYONE WERE TO GET THE
TREATMENT IT MAY NOT BE THE BEST
SCIENTIFICALLY SO IT'S GOING TO
TAKE COMPROMISE AND WE'LL TO
WORK WITH THE STAKEHOLDER GROUP
TO DO IT IN A WAY THAT IS
ACCESSIBLE TO THE FAMILIES AND
THAT'S GOING TO BE TOUGH.
>> DOING THE PLACEBO?
THE ANSWER IS PROBABLY YES.
SO THAT'S GOING TO MAKE IT HARD.
THE FACT IS NO ONE WILL SUGGEST
A ONE TO ONE WHETHER A TWO OR
THREE TO ONE BUT INDIVIDUALS
DON'T GET IT.
IN A ONE AND DONE STUDY OF AN
AAV VECTOR ISSUE PEOPLE CAN'T
DROP OUT BUT THE REAL PROBLEM
COMES WHEN YOU TALK ABOUT AN AS
O YOU PLAY WANT TO DO EVERY FEW
MONTHS AND KEEP PEOPLE IN THE
TRIAL.
THAT'S WHY I WAS SO EXCITED TO
BE HERE BECAUSE THERE'S AN
ADVOCACY GROUPS AND WILL
INPERSONALLY AND EXTERNALLY
FUNDED AND TRY TO WORK TOGETHER
AND WE'LL HAVE TO FIGURE OUT A
WAY TO MAKE IT POSSIBLE MAYBE
ONE WAY OF THINKING BIT FOR THE
PEOPLE PUT ON THE PLACEBO IS
WHETHER TO HAVE A CROSSOVER
STUDY SIX OR NINE MONTHS LATER
AND THOUGH UNDERSTANDING THE
TRIAL HAS PROGRESSED.
>> THE QUESTION ABOUT THE
FAMILIES KNOWING EACH OTHER MAY
HAVE TO DO WITH TWO THINGS
RECRUITING AND THE FAMILIES
KNOWING EACH OTHER AND THEY TALK
TO EACH OTHER AND TRY TO FIGURE
OUT WHY ONE PERSON IT HAS
ANOTHER AND THEY AND CAN THEY
TALK ABOUT THIS AND COMMUNICATE
ED ON THE PRIMARY OUTCOME
MEASURE AND THERE'S PEOPLE
AFFECTED BECAUSE OF THAT.
THIS IS A GIANT ISSUE IN TERMS
OF FAMILIES TALKING TO EACH
OTHER AND THINKING THEY'RE
HELPING EACH OTHER BUT ACTUALLY
RUINING THE INTEGRITY OF THE
TRIAL.
>> IF THE FIRST PATIENT DOES
POORLY, I THINK THERE WILL BE NO
FUTURE TRIAL BECAUSE EVEN IF
THERE IS HOPE FOR THE THERAPY
WHO GOES FIRST-WHY ISN'T SO AND
SO GOING FIRST?
THERE'S ALL KIND OF COVERINGS
GOING ON IN THE BACKGROUND.
>> THAT'S WHY I ASKED THE
QUESTION ALSO ABOUT THE PATIENT
REPORTED OUTCOMES BECAUSE ONE
WAY TO TANK THE STUDY IS FOR
EVERYONE TO KNOW AND THE FIRST
PERSON DOESN'T DO WELL NOBODY
ELSE WANTS TO PARTICIPATE.
AND SOME INDIVIDUALS GETTING
BACK PATIENT REPORTED OUTCOME
MAY IMPACT HOW THEY R7D --
RESPOND IN THE FUTURE AND MAY
CHANGE THE DATA.
IT WILL MAKE IT MUCH HARDER TO
HAVE THE PURITY OF THE DATA
NEEDED.
SO IT'S PART OF A LEARNING FOR
ALL OF US AND ALSO FOR THE
PARTICIPANTS.
AND I REALLY UNDERSTAND WHEN
HAVE YOU A SICK CHILD YOU FEEL
LIKE I DON'T HAVE TIME TO WAIT
AND IN' SENSE WHAT THEY'RE DOING
IS HARMING THEIR OWN CHILDREN
AND FUTURE CHILDREN.
SO WE'LL HAVE TO FIGURE OUT A
WAY IN EUROPE AN ETHICAL
PRINCIPLE IS COMMUNITY AND MAYBE
WE ADD THAT TO OUR ETHICAL
FRAMEWORK AND HAPPY TO BRAIN
STORM WITH YOU.
I DON'T HAVE SOLUTIONS TODAY.
THANK YOU VERY MUCH.
>> UNFORTUNATELY, GIVEN THE TIME
WE'LL ROLL ON TO THE WRAP-UP
DISCUSSION AND TURN IT OVER TO
DAN.
>>
>> IN AN IMPOSSIBLE TASK WITH 10
MINUTES OR LEFT BECAUSE WE HAVE
TO STOP PROMPTLY AT 3:00 BECAUSE
PEOPLE HAVE TRAVEL PLANS.
HOW SHOULD WE DO THIS?
TWO POSSIBILITIES IS OPEN FORUM
WITH AN ACTION ORIENTED
CONVERSATION NOT WHAT WAS MOST
EXCITING BUT THOUGHTS ABOUT NEXT
STEPS BECAUSE THAT'S A GOAL TO
TAKE STOP OF EXTRAORDINARY
ADVANCES BUT ALSO THINK ABOUT
NEXT STEPS.
THE OTHER IS QUICK CAUCUSING AND
COME UP WITH ONE IDEA FOR NEXT
STEP AND I'M THROWING THAT OUT
THERE BECAUSE PEOPLE WHO DON'T
WANT TO SPEAK IN A BIGGER GROUP
MAY HAVE A CHANCE TO SPEAK.
ANYBODY HAVE A THIRD OPTION?
OPTION A, OPTION B, SMALLER
GROUP.
THAT DIDN'T WORK.
THOUGHTS ON NEXT STEPS?
>> THE THOUGHT IS TO COME UP
WITH A SET OF COMMON CORE
PRINCIPLES.
BUT THIS IS WHAT WE NEED BEFORE
WE THINK ABOUT A TRIAL.
THESE ARE THE OUTCOMES WE WANT
TO LOOK AT.
WE WANT TO LOOK AT DEVELOPMENT
AND MAYBE THERE'S SOME
CUSTOMIZATION GENE BY GENE BUT
DON'T NECESSARILY NEED A 10 YEAR
STUDY FOR EVERY SINGLE GENETIC
CONDITION BEFORE WE CAN HAVE
GENE SPECIFIC OUTCOME.
HOW CAN WE EFFICIENT SO THE
PROGRESS MADE SO FAR IS TANGIBLE
AND MOVE FORWARD MORE QUICKLY.
>> EFFICIENCY.
>> LONG THE SAME LINES WE HEARD
A LOT ABOUT THE POTENTIAL FOR
COLLABORATION WHICH IS WILL
WONDERFUL.
CURIOUS TO WHAT HOW PEOPLE THINK
ABOUT THAT, WHAT CAN WE ACTIVELY
DO TO BRING GROUPS TOGETHER.
WE MAY NOT KNOW IN THE NEXT
MINUTES BUT PERHAPS CAN PUT
FORWARD A FORUM TO ENGAGE THAT
AND SECOND QUESTION WHAT CAN
NON-PROFIT LENDERS DO TO SUPPORT
MENT IN THIS AREA KNOWING WE
HAVE NON-PROFIT FUNDERS FROM THE
BIGGEST, FROM NINDS TO CURE TO
OTHERS.
HOW DO WE ENGAGE?
>> GREAT.
LET'S KEEP THIS GOING.
WE'RE RECORDING THESE QUESTIONS
SO THERE ARE QUESTIONS THAT ARE
ACTION ORIENTED.
WE NEED TO THINK ABOUT.
OTHER THOUGHTS.
ANYBODY
>> I THINK WE NEED A
STANDARDIZED OUTCOME MEASURE.
I SAID THIS BEFORE AT MANY
MEETINGS BUT I DON'T THINK IT'S
QUITE HAPPENED YET.
I KNOW THERE'S AN AN EFFORT
GOING ON IN THE END OF ONE
CONSORTIUM AND COMBINED BRAIN
AND AN EFFORT IN LORUM BUT THERE
SHOULD NOT BE THREE BUT ONE
EFFORT WHERE EVERYONE GETS
TOGETHER AND MAYBE COORDINATED
BY STNIH, I DON'T KNOW, BUT
COMPARE ALL THE TRIALS OF ALL
THE DISORDERS VERY SIMILAR
THOUGH THEY HAVE DIFFERENT
GENETICS.
I THINK THAT'S A REALLY
IMPORTANT PROJECT AND WE VA TO
BRING IN ALL THOSE GROUPS WHO
THINK THEY'RE DOING THIS ON
THEIR OWN AND MAKE THEM ALL WORK
TOGETHER.
>> IT BUILDING ON WHAT WAS SAID.
>> IF WE WANT TO DEVELOP
EFFECTIVE THERAPIES WE NEED TO
HAVE A PLACE A COMMON PLACE TO
HAVE RESOURCES TO FIND ALL THE
RESOURCES BEGINNING FROM WILL
BASIC SCIENCE LEVEL TO CLINICAL
TRIAL AND USING MANY WHICH ONE
WE'LL USE AND WORK ON THE
EFFORTS
>> HI, EVERYONE.
I'VE BEEN LISTENING TO THE
PRESENTATIONS THE PAST FEW DAYS
THERE WASN'T ENOUGH TIME FOR THE
PANEL BUT WANTED TO GIVE THE
MESSAGE WE'RE EXCITED FOR THE
FIELD AND THE SPIRIT OF
COLLABORATION AND READY TO
COLLABORATE.
THERE'S DIFFERENT AVENUES FOR
HAVING FEEDBACK FROM THE REVIEW
TEAM FOR THE DEVELOPMENT EVEN
BEFORE IT START ED FORMAL AND
INFORMAL WAY TO PARTICIPATE AND
COLLABORATE IN THE DEVELOPMENT.
AND SO MUCH NEEDED THERAPIES
FOR.
JUST WANTED TO MENTION THAT.
>> THANK YOU.
VICKY AND I WERE TALKING ABOUT
THIS YESTERDAY.
WE NEED TO MAKE SURE OUR YOUNG
PEOPLE KNOW NIH IS A VERY
WILLING PARTNER IN THE WORK
WE'RE ALL DOING.
I THINK YOUNG FOLKS SOMETIME
THINK IT'S OFTEN A DISTANCE AND
I BETTER NOT BOTHER MY PROGRAM
OFFICER.
IT'S THE OPPOSITE.
THEY WANT TO BE A MEMBER OF THE
TEAM AND WE SHOULD ENCOURAGE OUR
YOUNG INVESTIGATORS TO RECOGNIZE
THAT AS A RESOURCE SO THANK YOU.
>> AND WILL HOW DO WE DO NATURAL
HISTORY STUDIES ACROSS THESE
DISORDERS AND WHEN DO WE NEED TO
DO THEM IN A GENE SPECIFIC WAY?
SO WE NEED TO THINK ABOUT THAT
AND EVERYTHING HAS BEEN DONE ON
A GENE BY GENE BASIS WHICH IS
HOW IT CAN HAPPEN AND NEED TO
SCALE THIS AND CLASSES OF GENES
AND WHICH THERAPEUTIC STRATEGIES
WORK FOR AND DO IS IN A MORE
MODERATE GROUP WAY AND HAVE TWO
OR THREE POTENTIAL THERAPIES
NEARLY READY TO GO AND DO SOME
PRE CLINICAL WORK AND WHAT
CLINICAL TRIALS MAKE SENSE AND
DO IT RECESSIVE ORDERS AND GAIN
OF FUNCTION MUTATIONS THAT ALL
THE OF US CAN POINT OUT AND WE
CAN DEVELOP THERAPIES NOW NOT
JUST WHEN THE PATIENT WALKS IN
THE DOOR.
IT'S BEEN VERY REACTIVE AND END
OF ONE THERAPY AND WE HAVE A
PATIENT WHO SHOWED UP WHO HAS
MEANS OR WHATEVER AND WE NEED TO
GET AHEAD OF THAT SO WE DON'T
SPEND TWO YEARS DEVELOPING
THERAPIES BUT HAVE SOMETHING OFF
THE SHELF AND THAT'S SOMETHING
FOR NIH AND CURE CAN THINK ABOUT
HOW TO FUND COLLABORATIVE
EFFORTS TO DO THIS EFFICIENTLY.
>> GREAT.
LAST POINT.
>> I THINK THE KEY IS
COLLABORATION AND GUIDANCE AND
USING ALL THE EXPERTISE IN THE
ROOM AND OTHERS WHO COULDN'T
MAKE IT FOR HELPING GUIDE
CLINICAL DEVELOPMENT.
WE ALL KNOW CLINICAL TRIALS WHO
HAVE FAILED BECAUSE OF DESIGN
ISSUES AND I THINK PEOPLE IN THE
ROOM WOULD ALSO BE VERY WELL
POSITIONED TO DEVELOP ADDITIONAL
GUIDANCE HOW WE DEVELOP CLINICAL
TRIALS FOR PATIENTS WITH RARE
GENETIC EPILEPSIES AND FEATURES
THAT WILL IMPACT HOW THE TRIALS
ARE DESIGN AND IF THEY CAN BE
IMPROVED AT ALL.
MORE GUIDANCE AROUND THAT.
>> AND VICKI YOU'LL GET THE LAST
WORD.
>>
>> ONCE AGAIN, THANKS, EVERYONE.
IT'S BEEN A FANTASTIC WORKSHOP.
I LEARNED A TREMENDOUS AMOUNT.
WE'LL DO FOLLOW-UP AND THINK OF
WAYS TO CONTINUE THE
CONVERSATION AND WAYS TO ADDRESS
SOME OF THESE LAST POINTS AND
MOVING FORWARD AS FAST WE CAN
AND SAFE TRAVELS AND BE IN TOUCH
AND ANY THOUGHTS OR IDEAS SEND
THEM OUR WAY.
THANK YOU VERY MUCH.