>> WELCOME EVERYONE TO THE
SECOND DAY OF OUR SYMPOSIUM.
WE'RE VERY EXCITED WITH ALL THE
WONDERFUL PRESENTATIONS AND
DISCUSSION FROM YESTERDAY SO WE
KNOW TODAY WILL BE EQUALLY AS
EXCITING.
SO I WANTED TO INTRODUCE THE
MODERATOR FOR THE PART THREE AND
THAT'S DR. MAY MALICDAN AND SHE
IS QUITE AN EXPERT REGARDING
PERIPHERAL NERVOUS SYSTEM AND
NEURO MUSCULAR DISEASES AND AN
EXPERT ON A RARE DISEASE CALLED
SPG3A AND HAPPY TO HAVE HER AS A
SCIENTIST STUDYING RARE
DISEASES.
I'LL LET HER TAKE OVER.
THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH.
IT'S A VERY NICE INTRODUCTION.
THIS MORNING WE HAVE SIX VERY
EXCITE BEING TOPICS GOING FROM
PATIENT-DERIVED CELLS TO MOUSE
MODELS YOU'LL HEAR LATER AND THE
GOALS OF UNDERSTANDING THE
MECHANISM OF EFFECTS AND THE
OVERALL GOAL AND AIM OF
IDENTIFYING AVENUES FOR FUTURE
TREATMENT.
OUR FIRST TWO SPEAKERS WOULD
PRESENT AS ARIANE SAID AND A
BRIEF QUESTION AND ANSWER AND
THE FIRST IS DR. TRAYNOR AT THE
NATIONAL INSTITUTES ON AGING.
A MEMBER OF THE NIH GENE THERAPY
TASK FORCE.
HE LED THE CONSORTIUM THAT
IDENTIFIED THE NUCLEO PEPTIDES
IN THE GENE AND RECEIVED HIS MTD
FROM THE UNIVERSITY OF COLLEGE
LONDON AND HE CON COMPLETED A
NEUROLOGY RESIDENCY AT THE
CHILDREN'S HOSPITAL AT BRIGHAM
AND WOMEN'S HOSPITAL IN BOSTON.
AFTER DR. BLACKSTONE WILL BE
PRESENTING.
HE RECEIVED HIS Ph.D. FROM JOHNS
HOPKINS UNIVERSITY AND HE
COMPLETED A FELLOWSHIP IN
CLINICAL MOVEMENT DISORDER AT
THE MASSACHUSETTS GENERAL
HOSPITAL.
DURING THIS TIME HE ALSO
CONDUCTED POST-DOCTORAL RESEARCH
AT HARVARD MEDICAL SCHOOL
INVESTIGATING THE FUNCTIONS OF
PROTEINS IMPLICATED IN
HEREDITARY DEPLOYMENTS AN JOINED
AS AN INVESTIGATOR AND HIS
LABORATORY INVESTIGATED CELLULAR
MECHANISMS UNDERLYING
INHEREDITARY MOVEMENT DISORDER
AND HE LOOKS AT HEREDITARY PERI
>>I WANT TO SAY UP
FRONT THANK YOU SO MUCH FOR THE
INVITATION TO PRESENT TO YOU
THIS MORNING AND THANK YOU FOR
YOUR TIME LISTENING.
NIA AND NCATS LINE FOR RARE
DISEASE THERAPEUTICS.
IF YOU THINK ABOUT IT, IT'S
REALLY WHAT I WANT TO TALK ABOUT
TODAY IS OUR WORK IN THE GENE
THERAPY SPACE.
AND OUR DEVELOPMENT TRYING TO
HELP PLATFORMS FOR TREATMENTS
FOR RARE AND ULTRA RARE
DISEASES.
I LIKE TO START BY GIVING A
SUMMARY UP FRONT WHAT I'M GOING
TO TALK ABOUT BECAUSE I THINK
THAT SERVES TO ORIENTATE
EVERYBODY BECAUSE IT'S NOT GOING
TO BE A TALK FOCUSSED ON SPG4
IT'S BROADER AND APPLIES TO THE
DISEASE OF INTEREST AT THIS
PARTICULAR CONFERENCE.
REALLY, THE MESSAGE WANT TO
CONVEY IS THAT WE HAVE SET UP A
NEW LABORATORY OVER AT NCATS THE
NAME IS THE RNA THERAPEUTICS
LABORATORY AND AS THE NAME
SUGGESTS THE REAL AIM HERE AND
OVER ARCHING PURPOSE OF THIS
LABORATORY IS TO DEVELOP ASO FOR
RARE AND ULTRA RARE DISEASES.
THERE'S MANY FACET TO THIS
PARTICULAR PROGRAM IN TERMS OF
DELIVERY AND MANUFACTURING BUT
THE ONE I WANT TO TALK IS IN
VITRO CELL-BASED MODELS TO
PREVENT THE TOXICOLOGY WITH THIS
NEW CLASS OF THERAPIES.
IT'S TOXICOLOGY THAT PREVENTED
THE WIDER USE OF ASOs IN THE
GENERAL POPULATION.
IF WE CAN LICK THAT, I THINK WE
CAN START TO USE THESE MORE
BROADLY.
THE OTHER POINT AND I KNOW MANY
ON THE CALL YOU ARE ALL VERY
USED TO ME TALKING ABOUT LOU
GHERIG'S DISEASE ALL THE TIME.
THOUGH ALS IS STILL CLOSE TO MY
HEART AND WE'RE STILL USING ALS
AS A TEST BED FOR TREATMENT OF
ACUTE NEUROLOGICAL OR CHRONIC
NEURODEGENERATIVE DISEASES, THIS
HAS A BROADER SCOPE, THIS WHOLE
PROGRAM.
IT'S MORE FOCUSSED ON RARE AND
ULTRA RARE DISEASES NOT JUST
ALS.
SO WITH THAT IN MIND, I JUST
WANT TO START OFF BY TALKING A
LITTLE BIT ABOUT WHAT IS -- WHY
IS IT IMPORTANT TO GO AFTER AND
TRY TO TREAT THESE RARE AND
ULTRA RARE DISEASES.
I THINK THE NEXT COUPLE OF
STARTS WE'LL TRY TO GET ACROSS
HOW IMPORTANT THESE ARE TO THE
COMMUNITY.
YOU SEE HERE ON THE RIGHT-HAND
SIDE A SCREEN SHOT FROM THE
WEBSITE THAT TRACKS THE
OCCURRENCE OF THE DEFINITION OF
RARE AND ULTRA RARE DISEASES
GLOBALLY AND THEY REPORT THERE'S
NEARLY 10,000 TYPES OF RARE
DISEASES FOR WHICH WE KNOW THE
UNDERLYING GENETIC DEFECT IN
ABOUT 7,000 TO 8,000.
WHILE THE NUMBERS ARE HIGH, I
DON'T THINK THEY CONVEY THE
MASSIVE SCALE OF THE PROBLEM.
WHEN YOU THINK OF IT IN ABSOLUTE
NUMBERS IT TURNS OUT ACCORDING
TO THE BEST ESTIMATES THERE'S
HALF A BILLION PEOPLE WORLDWIDE
WHO SUFFER FROM RARE DISEASES
AND THAT'S RARE ULTRA RARE BUT
I'M TALKING ABOUT THE ULTRA
RARE, THE RAREST OF THE RARE
TYPES OF DISEASES, THAT NUMBER
SHRINKS TO ABOUT 4 MILLION.
I STILL THINK IS QUITE A BIG
NUMBER BECAUSE IT'S ABOUT THE
POPULATION OF IRELAND AND OF
COURSE I'M IRISH SO I THINK
IT'S A BIG NUMBER AND ASSOCIATED
WITH THAT AS THE MASSIVE HEALTH
CARE COSTS TO THE COMMUNITY.
I THINK THE NIH AND IN
PARTICULAR THE INTRAMURAL
PROGRAM IS A REALLY GOOD PLACE
TO GO AFTER THESE TYPES OF
DISEASES BECAUSE THE LOW NUMBER
OF THEM, THE LOW NUMBER OF
OCCURRENCE OF PATIENTS FOR EACH
PARTICULAR RARE DISEASES MEANS
THEY'RE NOT GOING ATTRACTIVE ANY
COMMERCIAL INTEREST AT LEAST NOT
IN THE NEAR TERM.
MAYBE 10 YEARS FROM NOW BUT NOT
IN THE NEAR TERM.
I THINK BECAUSE OF THAT THE NIH
CAN FILL IN THAT PARTICULAR
VACUUM.
THE OTHER POINT IS BECAUSE WARE
TALKING ABOUT SO MANY DITCH
TYPES OF DISEASES, 10,000, IT
LENDS TO SELF TO THIS NOTION OF
A PLATFORM DEVELOPMENT SO WE'RE
NOT GOING AFTER TRYING TO DO ONE
DISEASE AT A TIME BUT RATHER DO
IT ACROSS THE GAMUT OF RARE AND
ULTRA RARE DISEASES.
NOW ONE OF THE KEY POINTS ABOUT
THE RARE DISEASES IS IF YOU GO
DOWN AND LOOK AT IT, THE VAST
MAJORITY OF RARE AND ULTRA RARE
DISEASES, THEY AFFECT THE
CENTRAL NERVOUS SYSTEM IN ONE
FORM OR ANOTHER.
THE REASON WHY THAT'S IMPORTANT
IS IS BECAUSE IN ORDER TO TREAT
THEM WITH ANTISENSE OLIGOS WE
HAVE TO TREAT THEM THROUGH THE
LUMBAR SPINE AND THE NEUROTOX
SIDE EFFECTS ONE SEES WITH THIS
TYPE OF MEDICATION IS SOMETHING
WE HAVE TO CONSIDER AND CAN
BECOME A LIMITING FACTOR IN
TERMS OF WHAT WE CAN ADMINISTER.
THE OTHER KEY FACT AND
COMMONALITY THE RARE AND YOU
WILL RA RARE DISEASE HAVE IN
COMMON IS FOR THE VAST MAJORITY
NO EFFECT OF TREATMENT FOR MANY
OF THEM.
WE'RE TALKING PREDOMINANTLY
SYMPTOMATIC TREATMENT FOR THIS
POPULATION.
THAT BEING SAID, THERE ARE
ACTUAL GLIMMERS OF HOPE.
THIS IS A PICTURE YOU SEE ON THE
LEFT OF YOUR SCREEN WHO IS A
NEUROLOGIST AT BOSTON CHILDREN'S
HOSPITAL AND SAW THIS YOUNG GIRL
IN HIS CLINIC WITH A PROFOUND
EPILEPSY DISORDER.
HE SEQUENCED MILA'S GENOME,
FOUND THE UNDERLYING MUTATION
AND THEN TURNED HIS LABORATORY
AROUND AND SPENT ABOUT 9 TO 18
MONTHS DEVELOPING A TREATMENT
FOR THIS YOUNGER GIRL AND WAS
ELEGANTLY SHOW HIS TREATMENT WAS
ABLE TO DECREASE THE SEIZURE
RATE UNFORTUNATELY SHE SUCCUMBED
TO HER DISEASE LAST YEAR BUT HE
SHOWED ELEGANTLY THE SCIENCE IS
POSSIBLE.
THE SCIENCE OF DEVELOPING AN ASO
THERAPY PERSONALIZED TO ONE
PATIENT IS POSSIBLE.
THE PROBLEM FACING US NOW IS HOW
DO WE OPERATIONALIZE THIS AND
MOVE IT FROM A ONE-OFF FOR ONE
PATIENT TO BE ABLE TO ACTUALLY
DEVELOP IT FOR VIRTUALLY EVERY
PATIENT WOULD PRESENTS TO US
WITH A KNOWN RARE DISEASE AND
KNOWN UNDERLYING GENETIC
MUTATION?
AGAIN, WHAT WE'RE TALKING ABOUT
HERE IS REALLY DEVELOPING
PLATFORMS TO REALLY TREAT ACROSS
THE GAMUT OF RARE AND ULTRA RARE
DISEASES.
NOW, WHEN YOU LOOK AT WHAT TIM
DID, IT CAUSED HIM ABOUT $2
MILLION AND TO BE HONEST THAT
WAS THE BARGAIN BASEMENT LEVEL
OF DEVELOPMENT AND IT TOOK HIM
AS I SAY NINE AND 12 MONTHS TO
DO THAT.
NOW, IF YOU DELVE DOWN INTO
THIS, A LOT OF WHAT HAS TO
HAPPEN BETWEEN THE DISCOVERY OF
THE ACTUAL MUTATION AND GETTING
YOUR TREATMENT INTO THE PATIENTS
FOR THEIR FIRST IN-HUMAN STUDIES
AND A LOT HAS TO HAPPEN BUT WHEN
YOU DRILL DOWN THERE ARE TWO
PARTS TO IT.
THEY ACT AS LINCHPINS THAT DRIVE
THE COST AND TAKE TIME TO
ACTUALLY COMPLETE.
THEY ARE GMP MANUFACTURING AND
EXPLORATORY ANIMAL TOXICOLOGY
WHICH IS MANDATED BY THE FDA
BEFORE YOU CAN ACTUALLY PUT
THESE THERAPIES INTO HUMANS.
AS I SAY, NOT ONLY ARE THEY COST
SENSE BUT TIME SENSE.
WE WANT TO NARROW THAT DOWN AS
MUCH POSSIBLE BECAUSE WE HAVE
THE SENSE OF URGENCY TO TRY AND
GET THE TREATMENT INTO THE
PATIENT AS QUICKLY AS POSSIBLE.
SO OF COURSE THIS IS ACTUALLY
WHERE NCATS ENTERS INTO THE
STORY.
SO NCATS, AS MANY OF YOU KNOW,
THE NATIONAL CENTER FOR
ADVANCING TRANSLATIONAL SCIENCES
IS AN INSTITUTE AND THE CORE
MISSION IS TO DRIVE TREATMENTS
FROM THE LABORATORY INTO THE
PATIENTS AS QUICKLY AS POSSIBLE.
OF COURSE WE SAW AN OPPORTUNITY
HERE IN OUR CRAZY WAY OF
THINKING ABOUT IT, WHAT COULD WE
DO TO INSTEAD OF COST -- TAKE 18
MONTHS AND $2 MILLION, WHAT
COULD WE DO TO DRIVE IT DOWN TO
6 MONTHS AND $100,000?
SOMETHING THAT COULD BE RAISED
BY A LOCAL KICK STARTER
CAMPAIGN.
OF COURSE, THIS IS A NAIVE WAY
OF THINKING ABOUT IT AND THIS IS
HIGH-RISK SCIENCE.
WE DO NOT KNOW IF WE'RE GOING
SUCCESS BUT IF WE SUCCESS EVEN
PARTIALLY I THINK WE'LL CHANGE
THE LANDSCAPE FOR TREATMENT OF
RARE AND ULTRA RARE DISEASES AND
THE REAL FOCUS WAS TO DECREASE
THE COST OF THE DEVELOPMENT TIME
ASSOCIATED WITH THIS AND THIS IS
ONE THING I LOVE ABOUT WORKING
WITH THE NIH I GET TO COMBINE MY
SKILLS AS A PHYSICIAN AND
SCIENTIST AND WORK
TRANSLATIONALLY AND COMBINE TO
BRING THE STRENGTHS OF BOTH
PROGRAMS TO BEAR ON THIS REAL
CHALLENGE FOR HEALTH CARE.
I WAS ABLE TO WORK WITH DON LOWE
AT NCATS AND WE ESTABLISHED THIS
RNA THERAPEUTICS LABORATORY
WHICH HAS A REAL GOAL TO MAKE
THESE ASOs ACCESSIBLE TO
EVERYBODY REGARDLESS OF THEIR
INCOME AND STATUS.
NOW, ONE OF THE KEY ADVANTAGES
THAT WE HAVE AT NCATS AND THE
NIH IS WE'RE ACTUALLY A
GOVERNMENT ENTITY, RIGHT.
BECAUSE WE'RE A GOVERNMENT
ENTITY WE CAN WORK MORE CLOSELY
WITH THE FDA OUR SISTER
GOVERNMENT ENTITY AND DISCUSS
WITH THEM AT AN EARLY STAGE THE
REGULATORY ASPECTS WITH THIS.
AND WE SHARE A FELLOW WHO YOU'LL
SEE A PICTURE OF LATER ON, SHE'S
A SHARED FELLOW BETWEEN THE FDA
AND NCATS AND THE FDA WHEN TALK
TO THEM THEY'RE REALLY SMART
SCIENTISTS AND PHYSICIANS AND
KNOW THEY'RE FACING THIS TITLE
WAVE, THIS TSUNAMI OF INDs AND
APPROVAL APPLICATIONS COMING IN
FOR ASOs.
SO THEY REALLY WANT TO GET TO
THE BOTTOM OF THIS AND THEY'RE
VERY SMART AND VERY INTERESTED
AND MOTIVATED TO TRY AND
UNDERSTAND THE TOXICOLOGY OF
THIS NEW CLASS OF MEDICATIONS.
NOW, NCATS IS KNOWN FOR THE
SCREENING AND WE WANT TO PLAY TO
THAT AND A LARGE PART OF WHAT WE
DO FOCUSES ON THE DEVELOPMENT OF
WHAT IS A SUITE OF ASSESSES TO
UNDERSTAND TOXICOLOGY ASSOCIATED
WITH ASOs MORE FULLY.
IN THE INTEREST OF TIME I'M
GOING TO GIVE YOU ONE SUCH
EXAMPLE OF IT.
I THINK IT'S AN IMPORTANT ONE.
IT'S THE ACUTE NEUROTOXICITY
ASSOCIATED WITH ASSOS.
AT THE
ASOs AND MANY RARE DISEASES ARE
ASSOCIATED WITH CNS EFFECTS AND
BECAUSE OF THAT WE'LL HAVE TO
INJECT THOSE ASOs INTRAFECALLY.
THE PROBLEM IS YOU GET THIS
ACUTE NEUROTOXICITY.
LET ME DESCRIBE THIS.
IF YOU INJECT A BAD OR TOXIC ASO
INTO A MOUSE YOU GET A
STEREOTYPED PHENOTYPE WHICH
CONSISTS OF PARALYSIS THAT COMES
ON WITHIN MINUTES AND LASTS FOR
A NUMBER OF HOURS AND THEN WANES
OFF.
AND IT'S A VERY STEREOTYPED ONE.
SO REGARDLESS OF WHICH GENE
YOU'RE ASO IS TARGETING IT
HAPPENS THE SAME WAY EVERY TIME
YOU INJECT A BAD ASO.
YOU DON'T WANT TO INJECT IT INTO
A HUMAN, YOU'RE TRYING TO AVOID
THAT BUT I'M TALKING ABOUT
INJECTING THESE INTO MICE AND
THE REASON WHY THIS HAPPENS OR
WHAT WE THINK IS HAPPENING IS
THE ASO BINDS TO THE SURFACE OF
THE NEURON AND WHEN IT BINDS IT
CAUSES ELECTRICAL SILENCING OF
THAT NEURON BECAUSE OF THE
MEMBRANE AND AS THE ASO GETS
ABSORBED INTO THE NEURON BY
ENDOCYTOSIS THE ELECTRICAL
SILENCING GOES WAY AND THE
NEURON CORRECTS ITSELF AND ABLE
TO START OVER.
THE REASONY EMPHASIZE THIS IS
BECAUSE THIS PARTICULAR SIDE
EFFECT LIMITS OUR SELECTION OF
ASOs BROADLY LOOKING ACROSS THE
GENOME AND ONCE HAVE YOU THE ASO
IN HAND AND INJECT TO HUMANS IT
LIMITS THE DOSE YOU CAN
ADMINISTER.
THIS IS THE KEY LINCHPIN IN
TERMS OF TOXICITIES ASSOCIATED
WITH THESE DISEASES AND TREATING
THEM WITH ASOs.
THE GOOD NEWS IS THIS IS
SEQUENCE CONTENT AND CHEMISTRY
SPECIFIC.
AND BECAUSE OF THAT WE ACTUALLY
THINK WE CAN PREDICT WITH THIS
PARTICULAR TYPE OF TOXICITY
USING IF WE GENERATE ENOUGH IN
VITRO DATA AND APPLY THAT IN
TERMS OF MACHINE LEARNING WE MAY
BE ABLE TO PREDICT AHEAD OF TIME
WHICH ASOs ARE BAD AND THE
ABILITY TO PREDICT THIS MEANS
THE ASOs CAN GET WEEDED OUT
EARLY IN THE PROCESS.
IT WILL SPEED UP OUR PROCESS AS
WE GO ALONG AND INCREASE THE
COST SOCIETIED WITH THE
DEVELOPMENT -- ASSOCIATED WITH
THIS DEVELOPMENT OF ASO.
WE HAVE BEEN FORTUNATE TO WORK
WITH A GROUP AT THE HEAD OF THE
STEM CELL LABORATORY AT NCATS
AND HAS AN ORGANOID ASSAY WE'VE
ADAPTED TO SCREEN FOR THIS ACUTE
TOXICITY.
AND EACH OF THESE IS A LITTLE
BALL ABOUT 300 MICRONS IN
DIAMETER CONTAINING ABOUT 10,000
NEURONS AND 1,000 ASTROCYTES AND
IN EACH WELL YOU CAN SEE A
SPHEROID.
AND THE REAL BEAUTY OF WHAT HIS
TEAM HAS ACCOMPLISHED IS THEY'RE
REMARKABLY CONSISTENT LITERALLY
CARBON COPIES TO EACH OTHER AND
HERE HE SEEMED TO HAVE LICKED
THE PROBLEM AND FORMED IT FROM
WELL TO WELL.
THE OTHER COOL ASPECT IS BECAUSE
IT'S A BALL OF NEURONS YOU GET
SPONTANEOUS AND SYNCHRONIZED
ELECTRICAL ACTIVITY FROM THEOID
THE SPHEROID AND YOU CAN SEE THE
SPIKES THAT COME OUT
SYNCHRONIZED ACTIVITY ASSOCIATED
WITH THIS NEURO ORGANOID OR
SPHEROID AND WHEN YOU HAVE THIS
ASO5 OF 3 MICROMOLES YOU SEE
ELECTRICAL FLATTENING WITHIN
THREE MINUTES OF ADMINISTERING
THE ASO IF YOU FOLLOW IT OUT YOU
SEE IT GO BACK TO BASELINE IN
HOURS AND WE REALLY IDENTIFY
THOSE TOXICITY ASO TO THEN
PREDICT AHEAD OF TIME OR SCREEN
FROM OUR FILTERING PROCESS.
AND WE'RE TRYING TO DEVELOP IT
FOR THE FIELD BECAUSE YOU WANT
TO TAKE IT OPEN AND SOURCED SO
EVERY OTHER ACADEMIC HOSPITAL
CAN USE THE METHOD TO SCREEN
THEIR ASOs WHEN I THEY SEE A
PATIENT.
IS A PICTURE OF OUTSTANDING
POST-DOCS LEADING THIS EFFORT
OVER AT NCATS AND WE HAVE A NEW
LABORATORY WITH A PARTICULAR
FOCUS ON RARE AND ULTRA RARE
DISEASES AND DEVELOPING ASOs IN
A RAPID AND CHEAP MANNER SO THEY
CAN GET INTO PATIENTS AND OPEN
UP THE FIELD IN TERMS OF
INCLUSIVITY AND ACCESS.
REALLY A FOCUS ON DECREASING
COST AND OPERATIONALIZING THIS
TYPE OF TREATMENT.
OF COURSE, THERE'S LOTS OF
ACKNOWLEDGE MAMENTS HERE ALL OF
WHOM HAVE BEEN WORKING HARD
DURING THE PANDEMIC.
IT'S BEEN A HARD TIME TO BE
HONEST IN TERMS OF GETTING THIS
SORTED OUT.
WE'VE COME A LONG WAY ALREADY IN
A RELATIVELY SHORT PERIOD OF
TIME.
AND I DO WANT TO GIVE MENTION TO
THE CONSORTIA.
I THINK THIS IS A VERY IMPORTANT
AND I SEE REBECCA SCHULE IN THE
AUDIENCE WHO IS ALSO A MEMBER OF
THIS N EQUALS 1 COLLABORATIVE
NETWORK AND ONE THING I LIKE
ABOUT THE ASO FIELD RATHER THAN
TRYING TO COMPETE AGAINST EACH
OTHER WE'RE COMING TOGETHER AND
RECOGNIZING NO ONE GROUP WILL
HAVE SUFFICIENT BANDWIDTH TO
ADDRESS ALL OF THIS SO WE'RE
REALLY PUTTING OUR MINDS
TOGETHER AND TRYING TO THINK
ABOUT HOW WE CAN ACTUALLY MOVE
THIS FORWARD FOR OUR PATIENTS AS
WELL.
AND OF COURSE I WANT TO TALK
ABOUT -- I MENTIONED THE VARIOUS
PHARMACEUTICAL COMPANIES WE
COLLABORATE WITH AND PATIENTS
AND FAMILIES WITHOUT WHOM THIS
WOULD NOT ACTUALLY WORK.
ONE LAST HOUSEKEEPING ITEM, WE
RUN A MONTHLY GENE THERAPY
SPECIAL INTEREST GROUP AND I
JUST WANT TO PUT IT ON YOUR
CALENDARS THAT THE NEXT MEETING
IS GOING TO BE GIVEN BY CHRIS
BOSSOFF TALKING ABOUT THE URGENT
NETWORK INITIATIVE THAT HE HAS
BEEN SPEARHEADING AND THAT'S
GOING TO TAKE PLACE MAY 12 AT
12:00 NOON FOR ANYONE WHO WANTS
TO JOIN.
I'M HAPPY TO PAUSE THERE AND
TAKE QUESTIONS.
>> WE'LL TAKE QUESTIONS AFTER
DR. BLACKSTONE'S PRESENTATION.
IT'S A PLEASURE TO SPEAK TO THIS
GROUP TODAY AND THANK YOU TO
ARIANE AND BRINGING US TOGETHER
AND WE HAVEN'T HAD MANY
OPPORTUNITIES THE LAST COUPLE
YEARS AND IT'S GREAT WE GET A
CHANCE TO BE TOGETHER.
LI
LIKE BRYAN, I'M GOING DRILL DOWN
INTO SPG4 DE NOVO CASES WHICH I
KNOW IS THE TOPIC OF THIS
MEETING BUT I ALSO WANT TO TALK
A LITTLE BIT ABOUT DE NOVO
SPG3A.
YOU MAY BE LESS FAMILIAR WITH
THAT BUT I WANTED TO EMPHASIZE
THERE'S SOME COMMONALITIES I
THINK WILL BE HELPFUL IN MAKING
PROGRESS IN SPG4.
I'LL START TALKING ABOUT SPASTIC
PARAPLEGIA AND THERE'S IMPORTANT
DISTINCTIONS WE HAVE TO THINK
ABOUT WHEN WE THINK ABOUT THE
PATIENTS WITH DE NOVO FORMS.
THE HISTORIC PARAPLEGIAS AFFECT
THE LEGS AND THERE ARE PATIENT
WHO'S HAVE COMPLICATED ONES WITH
OTHER NEUROLOGICAL SYMPTOMS BUT
FOR THE MOST PART WE THINK OF
SPGs AS AFFECTING WALKING AND
FOR DE NOVO FORMS IT'S MORE
EXTENSIVE AND IT'S IMPORTANT TO
THINK OF THEM AS POTENTIALLY
RELATED TO SPASTIC PARAPLEGIA
AND THERE'S OTHER TYPES OF
DISORDERS AND WE HAVE TO THINK
ABOUT DIFFERENT MECHANISMS AND
THE DIFFERENT WAYS THE MUTATIONS
MAY BE AFFECTING PEOPLE.
ONE OF THE DRAMATIC THINGS I
THINK GREAT THINGS ABOUT THE
HEREDITARY SPASTIC PARAPLEGIAS
THERE'S DIFFERENT GENES.
THERE'S 90 DIFFERENT GENETIC
LOCI AND THAT ALLOWS US TO
IDENTIFY PROTEINS AND MAKE
RELATIONS AND I HAVE A PICTURE
OF A SCHEMATIC PERSON AND
CORTICOSPINAL TRACT AND NEURONS
FROM YOUR CORTEX TO THE SPINAL
CORD AND MAKE CONNECTIONS OR
SYNAPSES THAT MOVE YOUR MUSCLES
AND THE LONGEST ONES ARE THE
ONES THAT CONTROL YOUR LEGS AND
WE THOUGHT OF THESE AS
LEG-DEPENDENT DISORDERS.
OTHER FORMS MAY NOT SHOW THAT
QUITE AS MUCH AND WE NEED TO
KEEP THAT IN MIND.
SO AGAIN, IT'S IMPORTANT TO
THINK ABOUT THESE DE NOVO FORMS
BOTH AS HEREDITARY SPASTIC
PARAPLEGIAS AND THINK OF THE
DIFFERENT MECHANISMS AND
TREATMENTS.
ONE THINGS WE HAVE HISTORICALLY
DONE BECAUSE OF ALL THE GENES
WE'VE IDENTIFIED IS TO GROUP
THEM INTO CLUSTERS AS PARTS OF
THE CELL AND CELLULAR DISORDER
AND LONG CELLS ARE AFFECT THE
MOST AND IT'S IMPORTANT TO
REMEMBER JUST BECAUSE WE'RE
THINKING ABOUT A LONG NEURON
DOESN'T MEAN THE PATHOLOGY IS IN
THE NEURON AND WE LOOK AT OLIGO
DENDROCYTES AND OTHER NEURONS
CAN IMPACT THE FUNCTION OF
NEURONS SO WE HAVE TO KEEP AN
OPEN MIND WHEN WE THINK OF MODEL
SYSTEMS TO THINK HOW THE OTHER
CELLS ARE AFFECTING LONG NEURONS
THAT GIVE RISE TO THE SYMPTOMS
WE SEE.
NOW, OF COURSE THE ONES WE'RE
GOING TO TALK ABOUT TODAY, SPG3A
AND SPG4 HAVE A RELATIONSHIP
WITH ONE ANOTHER.
AS YOU CAN SEE IN MY SESSION
THEY'RE BOTH LISTED THERE BUT
YOU'LL NOTICE IT'S LISTED OTHER
PLACES AND THIS UNDERLYING SPG4
AND SPG3A.
THE COMMONALITIES AND
DIFFERENCES AND THEY CAN BE
IMPORTANT AS WE COMPARE AND
CONTRAST HOW WE MIGHT APPROACH
THEM THERAPEUTICALLY.
ONE THING THAT IS CLEAR IS THAT
SEVERAL OF THESE SPASTIC
PARAPLEGIC GENES ALL WORK
TOGETHER TO FORM COMMON CELLULAR
FUNCTIONS.
AND I THINK WE GOT A REALLY
INTERESTING SERIES OF TALKS
YESTERDAY ABOUT DRAMATIC
ADVANCES IN GENETICS OF THE
SPAST IIC PARAPLEGIAS IN TERMS OF
UNDERSTANDING HOW DIFFERENT
MUTATIONS CORRELATE WITH
DIFFERENT TYPES OF CLINIC
SYNDROMES.
I THINK IT'S AN IMPORTANT THEME
TO BUILD OFF OF AS WE CREATE
MODEL SYSTEMS AND GET CLOSER TO
UNDERSTANDING WHAT OUR TARGETS
SHOULD BE FOR THERAPY.
AGAIN, BRYAN OUTLINED NICELY ONE
FORM OF GENE THERAPY ASOs AND WE
HEARD YESTERDAY ABOUT OTHER
TYPES OF GENE THERAPY AND
DELIVER GENES TO REPLACE A
MISSING PROTEIN AND I'LL TALK
ABOUT A THIRD.
THERE'S MANY TYPES OF GENE
THERAPIES AND MANY TYPES OF
PHARMACOLOGIC THERAPIES.
ALL THESE THINGS TO CONSIDER.
BECAUSE IT'S A RARE DISEASE WE
DON'T HAVE THE LUXURY OF TRYING
A WHOLE BUNCH OF THEM.
I THINK IT'S ONE OF THOSE WHERE
WE WANT TO USE OUR MODEL
SYSTEMS, WHICH IS A BIG PART OF
MY TALK TO NARROW DOWN THE
POSSIBILITIES OR THE MOST LIKELY
POSSIBILITIES FOR SUCCESS AND BE
ABLE TO PURSUE THOSE.
NOW, ONE THING AND BRYAN SHOWED
ONE TOO AND A LOT OF US TALK
ABOUT MODEL SYSTEMS BUT A LOT OF
PEOPLE ON THE CALL MAY NOT HAVE
SEEN WHAT THE MODEL SYSTEMS AND
WHAT DO WE MEAN.
IN THE CASE OF THIS MOUSE, THIS
IS A MOUSE WE MADE TO MIMIC
HEREDITARY SPASTIC PARAPLEGIA
AND WE HEARD YESTERDAY SOMETIMES
THE GENES MIGHT COMBINE TO CAUSE
A MORE SEVERE SYNDROME AND WE
USED THAT TO THIS DISEASE AND
TRIED TO CREATE A MORE SEVERE
MODEL WHERE THE MICE GET
SYMPTOMS EARLIER TO START
TESTING QUICKER RATHER THAN
WAITING FOR THE MOUSE TO GET TO
A CERTAIN AGE TO SPEED THE
PROCESS UP.
TO GIVE YOU AN IDEA WHAT WE LOOK
FOR IN THE MODEL SYSTEM, THE
MOUSE IS WALKING, HOPEFULLY YOU
CAN SEE THE VIDEO AND HE'S
MOVING FINE AND YOU'LL NOTICE
THE MOUSE AT THE BOTTOM HAS
MUTATIONS IN THE SPG GENES AND
THIS MOUSE HAS MORE STRUGGLE
MOVING.
IN FACT THE TREADMILL IS MOVING
SEVEN TIMES SLOWER AND YOU STILL
SEE ALL THE STRUGGLES.
THOSE TYPE OF PHENOTYPES OR
BEHAVIORAL ABNORMALITIES WE LOOK
FOR AND TRY TO SUPPRESS LIKE IN
PEOPLE WE SEE A WALKING
DIFFICULTY AND WANT TO MAKE IT
BETTER.
IN MICE AND OTHER ORGANISMS WE
HAVE THE ABILITY TO DELVE DEEPER
AND DO STUDIES TO UNDERSTAND
WHAT'S HAPPENING AT DIFFERENT
LEVELS.
AT THE LEVELS OF INDIVIDUAL
CELLS AND DIFFERENT ORGANS AND
YOU CAN SEE THIS IS JUST A
QUANTIFICATION BEFORE I MOVE ON
IN THE SAME WAY WE HAVE AND WE
HEARD ABOUT THESE YESTERDAY,
SPECIFIC ASSESSMENT TOOLS FOR
PEOPLE THAT WE WANT TO
ULTIMATELY SEE IF THOSE
IMPROVEMENTS IN THOSE IN
RESPONSE TO THERAPY WE DO THE
SAME FOR OUR MODEL SYSTEMS IN
THIS CASE A MOUSE.
YOU'LL SEE WE CAN HAVE SPEED
TEST OR ROTOR ROD A SPINNING
DRUM TO SEE HOW LONG THEY CAN
STAY ON IT.
A LEDGE TEST TO WALK ALONG AN
EDGE AND CAN COMPARE THEM TO
NORMAL MICE AND MUTANT MICE AND
THE BIGGER THE EFFECT THE EASIER
TO SEE WHETHER A DRUG OR THERAPY
IS HELPING.
SO THESE ARE JUST THE TYPES OF
THINGS.
I WON'T GO THROUGH THE DETAILS
OF THIS BUT THIS IS THE TYPE OF
MODEL AND READOUT THAT IS
VALUABLE FOR US AS WE TRY NEW
THERAPIES.
THIS IS ANOTHER THING WE CAN DO
IN AN ANIMAL MODEL WE CAN'T DO
IN PEOPLE WE CONDITION ACTUALLY
RECONSTRUCT PART OF THE SPINAL ACTUALLY
RECONSTRUCT PART OF THE SPINAL
CO
SPINALCOCORACORD AND YOU'LL NOTICE ON
THE LEFT IS JUST THE WHAT THE
WHOLE TRACT LOOKS LIKE AND THE
ORANGE IS THE ENDOPLASMIC
RETICULUM AND THE BLUE IS
MITOCHONDRIA AND YOU NOTICE THE
STRANDS GOING UP AND DOWN AND IN
THE MUTANT FORM IN PANEL B,
THERE'S ALL THESE LATERAL-LIKE
STRUCTURES.
THIS IS REMARKABLE.
WE CAN SEE THE ABNORMALITY THAT
CAUSES THIS DISEASE IN THE
ACTUAL NEURONS INVOLVED MOST.
THAT ALLOWS US TO START WHEN WE
START THINKING ABOUT THERAPY, IT
ALLOWS US TO HAVE A READ-OUT
THAT IS NOT JUST BEHAVIORAL, NOT
JUST SYMPTOMS WE SEE BUT ALSO
SORT OF MORE MEC NIFTILY
MECHANISTICALLY AND WHAT WAS
USED AS MARKERS BEFORE AND THE
BOTTOM COMPARES WILD TYPE TO A
MUTANT FORM AND THERE'S DRAMATIC
DIFFERENCES AND THEY'RE SO EASY
TO SEE THAT IF WE HAVE A
THERAPY, WE REALLY HAVE THE
RELATIVE
RELATIVELY STRAIGHTFORWARD
ABILITY TO ASSESS WHETHER THE
THERAPY IS IMPROVING THESE
CHANGES AS WELL AS THE
BEHAVIORAL CHANGES AND THINK
ABOUT IN THE HUMAN AS BIOMARKERS
AND THINGS WE CAN FOLLOW AS
CLINICAL OUTCOMES AND WE DO THAT
ALSO IN MODEL SYMPTOMS.
HERE'S A YOUNG GIRL WITH DE NOVO
MUTATION AND SPG3A.
YOU CAN SEE SHE'S WALKING IN A
THEY'RE MARATHON AND MILDLY
AFFECTS COMPARED TO SOME WE
TALKED ABOUT AND UNDERSTAND
EVERYTHING THE MUTATION IN TERMS
OF HOW IT WORKS AND WE CAN MODEL
THIS DISEASE ALSO IN USING CELLS
FROM PATIENTS LIKE THIS YOUNG
GIRL.
THIS WAS DONE BY JUNE LI LATER
ABOUT TAKING CELLS FROM A PERSON
AFFECTED AND MAKE THEM INTO STEM
CELLS AND THEN MAKE THEM INTO
NERVE CELLS SO IT ALLOWS US TO
GET ACCESS TO THE NERVOUS SYSTEM
WITHOUT HAVING TO DO ANYTHING
INVASIVE AND THERE'S THIS YOUNG
GIRL'S CELLS MADE INTO A CELL
AND UP TOP IS A HEALTHY
VOLUNTEER.
ON THE BOTTOM THE PROCESSES FROM
THE NERVE SMALL AND THOSE CAN BE
REVERSED WITH DIFFERENT DRUG
THERAPIES.
THIS IS ANOTHER WAY TO SCREEN
FOR COMPOUNDS FOR THERAPIES THAT
MIGHT ACTUALLY HELP REVERSE SOME
OF THE ABNORMALITIES WE SEE.
AND AGAIN IT'S A MODEL.
OF COURSE THE CELLS DON'T HAVE
HSP.
IT'S NOT IMPORTANT TO THINK
ABOUT IT THEY WAY BUT THE TOOLS
THAT ALLOW TO US TEST IDEAS THAT
CAN ULTIMATELY LEAD TO
THERAPIES.
NOW, JUST LIKE IN THE CASE OF
SPG4 THE FOCUS OF THIS MEETING
THERE'S BEEN A GROUP OF PATIENTS
WITH VERY SEVERE PHENOTYPES WITH
PREDOMINANTLY MISSED SENSES AND
YOU CAN SEE FROM THE ARTICLE
THIS WAS DONE 15 YEARS AGO.
I THINK THERE'S AN INCREASING
REALIZATION NOW THAT THESE
SEVERE PHENOTYPES CAN BE THOUGHT
OF DIFFERENT DISEASES.
WE SHOULDN'T THINK OF THEM AS ON
THE SAME SPECTRUM BUT FROM THE
THERAPEUTIC POINT OF VIEW AS
INTERESTING DISORDERS.
AND DARIUS DIDN'T TALK ABOUT IT
YESTERDAY BUT HE AND HIS
COLLEAGUES HAVE DONE A
REMARKABLE JOB WITH SPG3A
LOOKING AT ABOUT 500 DIFFERENT
PATIENTS AND IDENTIFYING THOSE
WITH SEVERE FORMS AND BE ABLE TO
NARROW THE AREAS OR TYPES OF
MUTATIONS DOWN TO SPECIFIC PARTS
OF THE PROTEIN THAT REALLY GIVES
INSIGHTS INTO HOW WE MIGHT
ADDRESS THERAPY FOR THIS
COMPARED TO THE MORE COMMON
FORMS WHICH ARE LESS SEVERE.
ONE OF THE THINGS WE'VE BEEN
DOING AS PART OF THIS SPG3A DE
NOVO EFFORT IS WORKING WITH A
FOUNDATION CALLED THE CARTER
FOUNDATION AND I'M AN ADVISER
FOR THAT FOUNDATION AND THINKING
MUCH THE SAME WAY YOU ARE IN THE
MEETING HOW WE CAN COME UP WITH
WAYS TO DO RESEARCH, IMPROVE
OPTIONS FOR THERAPIES FOR THE
MORE SEVERE DE NOVO PATIENTS IN
PARTICULAR.
ONE OF THE THINGS WE'VE DONE AS
PART OF THIS AGAIN IT COULD BE
COMPARED AND CONTRAST TO WHAT
YOU'RE DOING IS DEVELOPING
SEVERAL MODEL SYSTEMS INCLUDING
A FLY MODEL AND WE MADE AN
INTERESTING MOUSE MODEL AND I'LL
TELL YOU ABOUT THAT BECAUSE IT'S
A UNIQUE WAY TO THINK OF GENE
THERAPY.
THE PROMISING THERAPEUTICS IS
WHAT WE LEARNED FROM PLASTIC
PARAPLEGIA AND JUNE IS NOW
SCREENING FOR A LOT OF THESE
TYPES OF PATHWAYS TO SEE IF THEY
WORK IN CELLS FROM PATIENTS WITH
THIS MORE SEVERE DE NOVO FORM.
AND I WANTED TO EMPHASIZE AT THE
BOTTOM AND I TALKED AT THE
BOTTOM ABOUT DARIUS' GREAT WORK
IN TERMS OF LIKE WE HEARD
YESTERDAY FOR SPG4 AS WELL.
UNDERSTANDING BROADLY THE TYPES
OF SYMPTOMS THAT PATIENTS GET IN
TRYING TO CORRELATE THAT WITH
THE TYPES OF GENETIC CHANGES AND
LOOK AT STUDY THIS FURTHER.
I WANTED TO EMPHASIZE ONE
INTERESTING NEW TYPE OF GENE
THERAPY AND AGAIN BRYAN TALKED
ABOUT ASOs AND SOME THAT ARE
PROMISING FOR CERTAIN DISORDERS
BUT WE HAVE TO UNDERSTAND WHAT
OUR GOALS ARE.
ONE THING ABOUT THESE DISORDERS,
SPG3A AND SPG4 AND WE HAVE
MUTATION OFTEN AND THOSE ARE
AMENABLE TO JUST AT A BASIC
LEVEL WHAT IF WE COULD GO IN AND
JUST CHANGE THE ABNORMALITY AND
MAKE IT BETTER.
WE WANT TO DO THAT AS MUCH
POSSIBLE BUT IF WE CAN DO THAT
AND THE TECHNOLOGY EXISTS TO DO
THAT.
WE'RE FORTUNATE TO WORK WITH AN
INVESTIGATOR AT THE BRODE --
BROAD INSTITUTE AND WE MADE THIS
MOUSE MODEL AND JACKSON
LABORATORY WERE NICE ENOUGH TO
MAKE IT FOR US INSTEAD OF
CHARGING US AND INSTEAD OF
MAKING THE MUTATION IN THE MOUSE
WE ACTUALLY PUT A CHUNK OF THE
HUMAN GENE INTO THE MOUSE SO WE
CAN TEST THE EXACT SORT OF
CHEMICAL BIOLOGY RE-AGENTS AS IN
THE MOUSE WITH DAVID LU'S LAB.
THIS IS AN AREA WHERE THERE'S A
LOT OF INTEREST IN TERMS OF
TRANSLATING THESE CHANGES INTO
BENEFITS FOR PEOPLE.
AN UNUSUAL APPROACH HERE BUT
IT'S ONE THAT COULD DEFINITELY
FIT IN AS WELL TO SPG4 WHERE A
LOT OF THE CHANGES ARE SORT OF
THESE SINGLE CHANGES THAT GIVE
RISE TO AMINO ACID CHANGE AND IN
MY LAST FEW SLIDES I WANTED TO
FOCUS ON SO THAT'S WHAT I'VE
DONE WITH SPG3A AND CREATED
DIFFERENT MODEL SYSTEMS AND
ORGANISMS AND TRIED TO
UNDERSTAND THE AFFECTS OF THEM
ON THE BIOLOGY OF THE PROTEIN
AND THE PROTEIN IS AN ENZYME.
AND IN ONE OF THE DISCUSSIONS
YESTERDAY IS THIS GAIN OF
FUNCTION, LOSS OF FUNCTION, IT'S
IMPORTANT TO REMEMBER WITH
ENZYMES IS YOU CAN EITHER HAVE
TOO MUCH ACTIVITY OR TOO LITTLE.
YOU MAY NOT GET THE SAME
SYMPTOMS.
FOR SPG3A THERE'S SOME
SPECULATION THE DE NOVO PATIENTS
MAY HAVE TOO MUCH ACTIVITY AND
THE TRADITIONAL ONES MAY HAVE
TOO LITTLE.
YOU CAN SEE THAT AS BOTH TOXIC
GAIN OF FUNCTION BUT IT'S
DIFFERENT BECAUSE ONE IS LOSS OF
ENZYME ACTIVITY AND ONE IS TOO
MUCH.
BUT THEY'RE BOTH TOXIC IN
DIFFERENT WAYS.
THE SPG4 PROTEIN HAS AN
IMPORTANT DISTINCTION.
AS I WAS LISTENING TO THE TALKS
YESTERDAY I WAS STRUCK ABOUT
TALK ABOUT HOW THERE'S VARIATION
OR WHY THESE CERTAIN MUTATIONS
SHOULD GIVE RISE TO A MORE
SEVERE FORM OR OTHERS DON'T.
IS IT AS SIMPLE AS CHANGES IN A
CERTAIN AREA OR IS THERE
SOMETHING MORE TO IT AND AGAIN
WE'RE TALKING ABOUT GENETIC
MODIFIE
MODIFIERS.
IT'S IMPORTANT TO REMEMBER SPG4
HAS ITS OWN MODIFIER AND ONE
mRNA AND WE CALL M1 AND M87.
WE THINK OF THEM AS USING
DIFFERENT TRANSLATION START
SITES BUT WHAT WE'VE DONE
RECENTLY IS COME UP WITH WAYS TO
GENETICALLY CHANGE A CELL TO
TAKE ON M1 AND M87 SEPARATELY
AND YOU CAN'T DO WITH SRNA
APPROACH BECAUSE THEY HAVE THE
SAME BUT YOU CAN IF YOU EDIT THE
GENOME.
I WANT TO SHOW YOU PICTURES AT
THE BOTTOM AND YOU SEE THIS TINY
BAND AND M87 IS REALLY BIG.
WHEN WE KNOCKOUT M1 WE SEE A
HUGE DIFFERENCE IN ENDOPLASMIC
RETICULUM AND IF YOU KNOCKOUT
M87 IT HAS NO EFFECT.
THEY'RE TWO DIFFERENT PROTEINS
MADE OFF THE SAME GENE AND THEY
HAVE DIFFERENT FUNCTIONS.
SO IF YOU THINK ABOUT THAT AND
ANOTHER THING WE FOUND IS THE
EFFECT OF M1 ON ER DOESN'T
DEPEND ON THE ACTIVITY AND OTHER
FUNCTIONS OF M87 DO.
THAT'S A WAY TO IMAGINE AN
EXPLANATION.
IF YOU THINK ABOUT IT YOU HAVE
AN MUTATION THAT IS AFFECTING
TWO DIFFERENT PROTEINS IN TWO
DIFFERENT WAYS.
YOU CAN IMAGINE DIFFERENT
MUTATIONS CAN AFFECT ONE MORE
THAN THE OTHER OR BOTH AT THE
SAME RATE AND YOU COULD GET
DIFFERENT LEVELS OF SEVERITY AND
DIFFERENT TYPES OF SYMPTOMS.
I WANTED TO EMPHASIZE TO A LOT
OF THE PEOPLE ON THE CALL TODAY
THAT THERE'S SEVERAL VERY
DEDICATED PEOPLE WORKING ON
SPASTIC PARAPLEGIA AND DOING
THIS ALL THEIR LIFE BUT THERE'S
ALSO A LOT OF SUPPORT WE GET
FROM PEOPLE WHO AREN'T WORKING
ON SPGs AND DON'T NEUROLOGIC
DISEASE BUT PROVIDE EXPERTISE
THAT IS CRITICAL YOU WON'T SEE
THEM AT THESE TYPES OF MEETINGS
BECAUSE THEY'RE OFTEN ENGINEERS
OR INFORMATICIANS.
A LOT OF DIFFERENT ROLES AND I
WANT TO HIGHLIGHT A GROUP THAT'S
BEEN CRUCIAL TO ME EN ADVANCING
RESEARCH AND SEVERAL PEOPLE AT
HOWARD HUGHES MEDICAL INSTITUTE
AND A STUDENT SPEARHEADED A LOT
OF THESE COLLABORATIONS AND HE
WAS IN THE GROUP AS WELL.
BUT THOUGH IT'S IT'S A RARE
DISEASE WE HAVE SOME OF THE
GREATEST MINDS ON EARTH WORKING
ON THIS AND WE HAVE A NOBEL
PRIZE WINNER AND ONE OF THE BEST
CELL BIOLOGISTS ON EARTH AND
SOME ARE CREATED ADVANCED
IMAGING TECHNOLOGIES INCLUDING
THE ONE I SHOWED FOR
RECONSTRUCTING THE SPINAL CORD.
THESE ARE PEOPLE WHO AREN'T AT
THE CLINICAL MEETINGS BUT
PROVIDE EXPERTISE AS THAT WILL
CRITICAL AS WE ANALYZE THE MODEL
SYSTEMS.
I WANTED TO GIVE THEM A SHOUT
OUT AND PEOPLE BEHIND THE SCENES
THAT ARE REALLY TALENTED.
THOUGH IT'S A REALLY RARE
DISEASE WE'RE TALKING ABOUT WE
HAVE SOME OF THE GREATEST MINDS
ON EARTH HELPING OUT WITH IT.
HERE'S AGE -- AN EXAMPLE OF WHAT
WE CAN DO NOW LOOKING AT A
PROTEIN MOVING AND THE DOTS ARE
INDIVIDUAL PROTEINS MOVING ON
THE ER.
ONE THING WE THINK ABOUT WHEN WE
THINK OF MODEL SYSTEMS IS HOW WE
ASSESS THEM.
WE LOOK A LOT PERSON AND WE THEM
WALK AND TEST THEIR MOTION AND
CELLS SHOW A STATIC PICTURE.
I DOESN'T HAVE TO BE LIKE THAT.
WE HAVE THE ABILITY NOW TO LOOK
AT PROTEINS DYNAMICALLY AND IN
THE LAST SLIDE OR TWO I'LL SHOW
WHAT A SPAST MUTATION LOOKS LIKE
AND THAT'S THE INDIVIDUAL
MOLECULE MOVING, ON THE LEFT IS
A NORMAL ONE.
THE ONE ON THE RIGHT IS MUTANT
FORM AND THE ONE ON THE LEFT IS
WILD TYPE, NORMAL.
LOOK AT THE DRAMATIC DIFFERENCE.
THE ONE ON THE RIGHT IS MOVING
IT'S JUST NOT GOING WHERE AND
THE ONE ON THE LEFT IS GOING ALL
OVER THE PLACE.
IT GIVES ANOTHER WAY TO LOOK AT
SPAST IN FUNCTION.
IT'S ANOTHER WAY TO EMPHASIZE
WE'VE HAD GREAT COLLABORATORS
WHO CONTRIBUTED REALLY THE MOST
CUTTING-EDGE TECHNOLOGY TO OUR
ABILITY TO STUDY SPG4 AND OF
COURSE THIS RELATES TO THE DE
NOVO PATIENTS AS WELL.
WE CAN COMPARE DE NOVO MUTATIONS
TO THE TRADITIONAL ONES IN NEW
WAYS.
I THINK THAT WILL ALLOW US TO
AGAIN UNDERSTAND WHAT THE
DIFFERENCE MORE AND THAT
UNDERSTANDING WILL DIRECTLY
APPLY TO HOW WE ULTIMATELY TREAT
THIS.
I WANTED TO END WITH THOSE.
A FINAL SLIDE, I THINK ONE OF
THE IMPORTANT SLIDE AND TAKE
HOME MESS AG -- MESSAGE OF MY
SLIDE AS WE NEED TO LOOK AT THIS
AS TRADITIONAL DISEASE WE NEED
TO LOOK AT M1 AND M87 AS TWO
DIFFERENT PROTEINS AND WHEN YOU
LOOK AT ONE GENE MAKING TWO
DIFFERENT PROTEINS IT GETS
EASIER TO UNDERSTAND HOW THE
MUTATION WILL AFFECT THE PROTEIN
IN DIFFERENT WAYS AND THOSE CAN
ALSO IF WE DON'T STUDY THEM
SEPARATELY IT CAN GET MORE
CONFUSING IN TERMS OF
UNDERSTANDING THE BASIC BIOLOGY
THAT UNDER LIES THE SPG4.
I WANT TO THANK THE PEOPLE I
WORK WITH.
I WANT TO EMPHASIZE SOME OF THE
GROUPS THAT REALLY PROVIDE
CUTTING-EDGE TECHNOLOGY THAT
WOULD BE AVAILABLE NOWHERE ELSE
AND I WANTED TO EMPHASIZE FOR
THOSE LISTENING ON THE CALL HOW
IMPORTANT THE NIH UDP,
UNDIAGNOSED DISEASE PROGRAM HAS
BEEN.
I REMEMBER WHEN CAMILA AND I
WERE TALKING ABOUT THE FIRST
PATIENTS WITH THE DE NOVO FORMS
THE UNDIAGNOSED DISEASES PROGRAM
HAS ALWAYS BEEN THERE IN TERMS
OF PROVIDING THE ABILITY TO LOOK
AT NEW DISEASES IN VERY DETAILED
AND NEW WAYS AND I THINK HAS
ALLOWED US TO THINK OF THE
CONCEPT OF SOME OF THESE TYPES
OF DISORDERS AND THE NEW
MECHANISMS AND IT'S BECAUSE OF
THEIR LEADERSHIP I DON'T KNOW BY
HOW MANY YEARS BUT AT SOMEONE AS
NIH FOR 20 YEARS, I WANTED TO
EMPHASIZE THE IMPORTANCE OF THAT
PROGRAM IN RARE DISEASE RESEARCH
AND IN TERMS OF JUMP STARTING
RESEARCH INTO RARE DISEASES LIKE
THIS DE NOVO FORM OF SPG4 IN
PARTICULAR.
AGAIN, THANK YOU AND I KNOW AT
SOME POINT I'LL BE ABLE TO
ANSWER QUESTIONS.
>> THANK YOU VERY MUCH.
VERY EXCITING TALK.
THERE'S A FEW QUESTIONS FOR
BRYAN IN THE CHAT AND I'LL START
READING ONE OF THEM.
BRYAN, ARE THE BRAIN SPEAROIDS
GENERATE FROM CELLS OR NEURONS
FROM THE RARE DISEASED PATIENTS
AND NEURONS OR CELLS THAT
GENERATE IN THEIR DISEASES?
>> THAT'S EXACTLY WHAT YOU DON'T
WANT TO DO BECAUSE WE'RE TALKING
ABOUT 10,000 RARE DISEASES.
WHAT YOU ABSOLUTELY DO NOT WANT
TO DO IN THIS INSTANCE IS START
MAKING DISEASE-SPECIFIC ASSAYS.
THIS HAS TO WORK ACROSS THE
GAMUT OF NEUROLOGICAL AND RARE
DISEASES.
SO THEY'RE NOT DISEASE SPECIFIC.
THEY'RE ACTUALLY TAKEN FROM --
THEY'RE TAKEN FROM A NORMAL
HEALTHY INDIVIDUAL AND TO JUMP
FORWARD BECAUSE I SAW A QUESTION
IN THE CHAT BOX THERE, ONE OF
THE KEY FEATURES WE'RE TRYING TO
DEVELOP IS WE'LL MAKE ALL THE
PROTOCOLS AND ALL THE DATA
PUBLICLY AVAILABLE AS QUICKLY AS
POSSIBLE BECAUSE WE WANT THESE
PROTOCOLS TO BE OPEN AND SHARED
WIDELY BECAUSE IT BASICALLY
MEANS THAT IF YOU'RE WORKING IN
AN ACADEMIC HOSPITAL IN OHIO OWE
YOU CAN PICK UP THE BALL AND RUN
DOWN THE FIELD FURTHER WITH IT
WHEN YOUR PATIENT PRESENTS IN
CLINIC.
ANOTHER ASPECT OF THE GENE
THERAPY ONGOING AT NCATS IS
CALLED PAVED GP AND THE IDEA
THERE IS THIS IS TO DEVELOP AAB
VIRAL VECTORS FOR DISEASES.
AND EVERYTHING HAS BEEN MADE
PUBLICLY AVAILABLE EVEN FOR ONE
OF THE FIRST TIMES THE FEEDBACK
FROM THE FDA WHEN THEY SUBMITTED
THEIR IND APPLICATION.
THE FDA VERY KINDLY ALLOWED US
TO PUT THEIR COMMENTS UP ONLINE
SO PEOPLE COULD SEE IN REAL TIME
WHAT THE COMMENTS COMING BACK
FROM THE FDA WERE AND HOW WE
WOULD ACTUALLY RESPOND TO THEM
IN ORDER TO ADDRESS THEIR
CONCERNS.
I THINK THAT OPENNESS IS REAL
IMPORTANT HERE AND ALSO HAVING A
COMPATIBLE ACROSS THE GAMUT OF
RARE DISEASES.
>> AND I GUESS THERE'S A SIMILAR
QUESTION FROM PETER.
ARE THE ASO'S SPECIFIC TO THE
MUTANT GENE SO EXPRESSION OCCURS
FROM THE WILD TYPE GENE AND IS
TO THE ASO LIMITED BY PROTEINS
AGGREGATE AND BECOME LONG LIVED.
>> THAT'S A SLIGHTLY SEPARATE
QUESTION BECAUSE THAT'S MORE
TALKING ABOUT THE EFFICACY AND
WHAT DO YOU WANT TO TARGET.
AND I THINK THAT IS ESSENTIALLY
THAT'S AN UNANSWERED QUESTIONS
WITHIN THE FIELD.
AND THERE IT PROBABLY IS A
LITTLE BIT MORE DISEASE SPECIFIC
IN HOW YOU WANT TO APPROACH IT.
THERE ARE GOING TO BE INSTANTES
WHERE YOU WANT TO TAKE IT --
INSTANCES WHERE YOU WANT TO TAKE
OUT THE WILD TYPE AND MUTANT
ALLELES AND THERE'S TIMES YOU
WANT TO TAKE BOTH OUT AND
INSTANCE WHERE'S YOU'LL WANT TO
BE MORE SELECTIVE AND EVEN
INSTANCES TO INCREASE UP
EXPRESSION BY TARGETING WHAT IS
KNOWN AS NATURAL ANTI-SENSE
TRANSCRIPTS.
IT'S ALMOST LIKE NATURAL
PREDICTED AHEAD OF TIME WHAT
ASOs WOULD BE LIKE AND ACTUALLY
PUT A LITTLE ASO IN FRONT OF OR
ADJACENT TO ABOUT 30% OF THE
GENES.
AND WHAT IS ACTUALLY INTERESTING
IS WHAT'S EMERGING NOW IS
ACTUALLY A LOT OF THE GENES THAT
ARE IMPORTANT IN NEUROLOGICAL
DISEASES AND THEIR EXPRESSED IN
THE CNS, THEY'RE THE VERY ONES
THAT ACTUALLY HAVE THESE NATURAL
ANTI-SENSE TRANSCRIPTS.
VIROLOGY AND EVOLUTION MAY BE
TRYING TO TELL US SOMETHING
ABOUT IMPORTANCE OF THESE.
TO SPEAK TO PETER'S QUESTION
ABOUT INCLUSIONS, I ACTUALLY
DON'T KNOW THE ANSWER TO THAT
AND I DON'T THINK ANYBODY DOES.
LET'S WAIT AND SEE WHAT HAPPENS
THERE.
I WILL SAY JUST COMING FROM THE
NS FIELD WE KNOW THERE'S
INCLUSIONS THOUGH WE THINK OF
THEMES BOWLS OF PROTEIN.
THEY'RE QUITE ACTIVE.
THERE'S STUFF GOING IN AND STUFF
COMING OUT.
ONE HOPES IF YOU CAN CHANGE THE
UNDERLYING PROCESS MAYBE THE
PROTEIN CLUMPS WILL GO AWAY.
I DON'T KNOW.
MAYBE IT'S AN OPEN QUESTION.
>> THE NEXT QUESTION IS IN TERMS
OF LIKE SHARING SAMPLES AND
PROVIDING FEE FOR SERVICE AND
THE SECOND SECOND IS A
FOLLOW-UP.
DO YOU THINK YOUR IN VITRO TOX
ASSAYS AT SOME POINT REPLACE IN
VIVO APPLICATION AND DO YOU SEE
FDA MOVING THAT WAY IN THE
FORESEEABLE FUTURE.
>> I'LL ADDRESS THE FIRST
QUESTION BECAUSE THE SECOND HAS
BEEN ANSWERED ALREADY AND
DR. SCHULE IS BASED IN GERMANY
AND THE RULES ARE SLIGHTLY
DIFFERENT OVER THERE.
THEY DON'T REQUIRE IND APPROVAL
TO PUT DRUGS INTO HUMANS WHICH
IS A STEP THE FDA REQUIRES.
REBECCA AND MYSELF HAVE TALKED
ABOUT THIS A LOT AND THIS IS
WHAT WE'RE HOPING.
WE HOPE AT SOME STAGE IN THE
FUTURE WE CAN CONVINCE THE FDA
OUR CELL-BASED ASSAYS ARE JUST
AS GOOD AS THE ANIMAL TOX.
THAT'S THE PLATONIC IDEAL WE'RE
AIMING FOR BUT IT'S HIGH RISK
RESEARCH AND I DON'T KNOW WE'LL
SUCCEED BUT IF WE DO WE'LL
CERTAINLY CHANGE THE LANDSCAPE
SOMEWHAT.
>> AND DO THINK ABOUT WHEN
YOU'RE READY TO DESIGN AN ASO IS
IT ABLE TO DESIGN IT AGAINST THE
M87 ISOFORM AGAINST THE OTHER.
>> YOU'RE SHAKE YOUR HEAD BUT I
THINK IT'S POSSIBLE.
MAYBE YOU CAN HIT THE PROMOTER.
IF YOU KNOW WHICH ONE DRIVES THE
M1 VERSUS M87 YOU MAY BE ABLE TO
SWITCH THAT RATIO A LITTLE BIT,
CRAIG.
>> YOU MIGHT BE ABLE TO BUT HOW
CONSISTENTLY CAN YOU DO THAT?
IT'S MORE COMPLICATED BECAUSE
IT'S MORE THAN ONE TRANSCRIPT.
IT'S NOT IMPOSSIBLE.
ONE ADDITIONAL POINT IS ONE
THING AND WITH YOU ARE
EMPHASIZING PLATFORMS TO BE USED
WITH HSPs WE HAVE LOTS OF
DIFFERENT MUTATIONS.
BUT IF YOU COULD USE AN
ASO-BASED APPROACH, YOU DON'T
HAVE TO TARGET THE MUTANT
MUTATION.
YOU CAN TARGET -- THERE'S
CERTAIN POLYMORPHISMS YOU CAN
OCCASIONALLY TARGET WITH A
CERTAIN PREVALENCE AND IF
THEY'RE ON THAT ALLELE YOU CAN
HAVE A SMALLER NUMBER OF PERHAPS
ASOs YOU COULD USE WITHOUT
HAVING TO HAVE A DIFFERENT ONE
FOR EVERY DIFFERENT FORM.
WE DON'T WANT TO MAYBE GET RID
OF THE WHOLE PROTEIN JUST GET
RID OF MUTANT ALLELE.
>> THIS IS -- TO BE FAIR WE
CHANGE THE NAME OF OUR
LABORATORY.
INITIALLY WAS THE RAPID ASO
DEVELOPMENT AND CHANGED IT TO
THE RNA THERAPEUTICS LABORATORY
BECAUSE I THINK THERE'S OTHER
APPROACHES OTHER THAN ASOs TO
BRING IN AND WE'RE ESSENTIALLY
ON THE SAME PAGE.
I SEE A QUESTION ABOUT USING
MONKEYS, THE FDA REQUIRING
MONKEYS.
IF I CAN ADDRESS THAT QUICKLY.
THEY REQUIRED MONKEY STUDIES FOR
WHEN YOU ARE ADMINISTERING ASOs
TO RELATIVELY COMMON DISEASES.
SO IF YOU WANTED TO DO STUDIES
FOR THERE'S A NEW ASO COMING OUT
TO TREAT HYPERLIPIDEMIA THE U.K.
AND THEY JUST BOUGHT 100,000
ZEROS -- DOSES AND MONKEY
DISORDERS ARE REQUIRED FOR THAT
AND THE FDA ONLY REQUIRES A
MOUSE OR SOME SORT OF RODENT
STUDY.
THEY DON'T REQUIRE ANY MORE AS
LONG AS IT'S A RARE AND ULTRA
RARE DISEASES A NON-HUMAN
PRIMATE STUDY.
>> FOR CRAIG THERE'S A QUESTION
FROM DARIUS.
IS THERE ANYTHING KNOWN ABOUT
THE CELL TYPE SPECIFIC
EXPRESSION.
FOR INSTANCE, NEURONAL
SUBPOPULATIONS OF M1 AND M87 IN
THE CONTEXT OF BRAIN
DEVELOPMENT?
>> VERY GOOD QUESTION.
BASICALLY BECAUSE M1 HAS BEEN SO
HARD TO SEE USING TRADITIONAL
APPROACHES, WE DON'T REALLY
KNOW.
BECAUSE AS I SHOWED YOU, YOU
ALMOST HAVE TO OVER EXPOSE ANY
GELS TO BE ABLE TO SEE IT.
THERE'S NO SPECIFIC ANTIBODIES
THAT ALLOW TO YOU TELL THEM
APART AND I CAN TELL YOU WE CAN
SEE PHENOTYPIC DIFFERENCES EVEN
WHEN WE CAN'T DETECT THE PROTEIN
ANY OTHER WAY.
WE KNOW IT'S THERE.
IT'S JUST SUCH LOW COPY NUMBERS
OR LOW NUMBERS OF MOLECULES WE
CAN'T SEE IT.
BUT IT DOES EMPHASIZE THE FACT
THAT WE DO NEED TO BE COGNIZANT
OF THE FACT IT EXISTS AND THINK
THE M1 IS THE MOST IMPORTANT
FORM FOR THE DISEASE.
WE DON'T KNOW THAT FOR SURE BUT
WE HAVE THE ABILITY NOW TO
SEPARATE THE TWO FORMS TO THINK
OF THEM AS TWO DIFFERENT
PROTEINS AND ASK QUESTIONS HOW
MUTATIONS AFFECT DIFFERENT FORMS
AND THEIR FUNCTIONS ARE
DIFFERENT.
IT'S A GOOD POINT.
WE WOULD LIKE TO KNOW THAT.
IT'S JUST BEEN HARD BECAUSE THE
M1 FORM IS SO LOW ABUNDANCE AND
THE M87 FORM IS SO HIGH.
IT'S JUST EXPERIMENTALLY
DIFFICULT TO DO BUT IT'S A VERY
IMPORTANT QUESTION.
>> AND AS A FOLLOW-UP YOU CAN
SEE IN THE CHAT, CAN YOU CLARIFY
THE MECHANISM BETWEEN M1 AND
M87.
ARE THERE TWO DIFFERENT
PROMOTERS.
>> BY STRENGTHENING THE COZAK
CONSEQUENCE WE CAN INCREASE THE
AMOUNT OF M1 PRODUCED.
I THINK THE DIFFERENTIAL
TRANSLATION START SITES AND PART
IS THE STRENGTH OF THE COZAK
SEQUENCE AT LEAST THAT'S ONE
THING WE'VE SEEN SO FAR BUT IT'S
NOT LIKE WE ALWAYS HEAR ABOUT
SPLICE VARIANTS AND SO ON.
THIS IS THE SAME TRANSCRIPT JUST
THE DIFFERENT TRANSLATION START
SITES AND ONE WAY WE'VE BEEN
ABLE TO ADJUST THAT IS ADJUSTING
THE COZAK SEQUENCE THAT PLAYS AN
IMPORTANT ROLE FOR TRANSLATION
INITIATION.
>> I MISSED A QUESTION.
>> I ANSWERED THAT EARLIER.
>> THERE'S ONE MORE QUESTION
FROM THE AUDIENCE.
>> I WANTED TO ASK A QUESTION.
KIM WHO IS THE MOM OF OWEN THE
YOUNG ADULT AFFECTED SPG4.
SHE SAID HER SON WAS SELECTED
FOR A TRIAL REGARDING AN ASO BUT
PUT ON HOLD BECAUSE THERE WAS
CONCERN THE ASO WOULD NOT HAVE
THE MUTANT GENE AND THE
NON-MUTATED COPY OF SPAST.
CAN YOU COMMENT FROM A FAMILY
PERSPECTIVE WHICH PATIENTS MAY
BE ELIGIBLE FOR ASOs AND WHAT
THE CONSIDERATIONS ARE.
GENERAL TERMS THIS IS THE ISSUE
THAT FACES THE FIELD.
CAN YOU BE SPECIFIC TO KNOCKING
DOWN MUTANT VERSUS WILD TYPE.
THERE'LL BE TIMES WHERE THAT'S
WHAT YOU NEED TO DO AND OTHER
TIMES WHEN IT DOESN'T MATTER AND
YOU CAN JUST KNOCK DOWN
INDISCRIMINATELY THE TRANSCRIPT.
IT'S THE ISSUE THAT FACE THE
FIELD.
AND THEY GO HAND IN HAND.
WHEN YOU WANT TO -- WE KNOW WE
CAN KNOCK DOWN TRANSCRIPTS
SELECTIVELY.
THE PROBLEM IS WHEN YOU GO AND
DO THAT WITH THOSE PARTICULAR
TRANSCRIPTS THEY'RE ALSO TOXIC.
SO IF WE COULD FIND SOME WAY TO
MITIGATE THAT TOXICOLOGY
ASSOCIATED WITH IT, IT WOULD
OPEN UP THE SCOPE OF ASOs WE CAN
ADMINISTER TO OUR PATIENTS.
IT'S REALLY THE AREA AND PROBLEM
THAT FACES THE FIELD.
JUST TO PUT IT IN PERSPECTIVE,
WE IN SILICO MADE EVERY SINGLE
ASO YOU CAN POSSIBLY MAKE
AGAINST EVERY SINGLE GENE YOU
CAN POSSIBLY THINK OF.
THEN WE HAD CAN PRE CALCULATE
AND ONLY 0.07% WERE SAFE AND
SHOWS IS THE NARROWNESS OF THE
GENE AND THAT'S STOPPING THE NEW
CLASS OF THERAPIES.% WERE SAFE AND
SHOWS IS THE NARROWNESS OF THE
GENE AND THAT'S STOPPING THE NEW
CLASS OF THERAPIES.2% WERE SAFE AND
SHOWS IS THE NARROWNESS OF THE
GENE AND THAT'S STOPPING THE NEW
CLASS OF THERAPIES.
AND IF I CAN HAVE ONE MORE
MINUTE TO MAKE THE POINT.
IN SMALL MOLECULES WE KNOW WE
CAN GET THEM TO THE TISSUE AND
KNOW THE TOXICOLOGY.
WE JUST DON'T KNOW WHETHER THE
SMALL MOLECULE HAS AN EFFECT ON
SOMETHING INSIDE THE CELL AND
THAT'S FACED THE PHARMACOLOGIC
INDUSTRY FOR YEARS AND IN GENE
THERAPY IT TURNS IT ON ITS HEAD.
20,000 GENES WE CAN DELIVER BUT
WE CAN'T DELIVER WITHOUT
TOXICOLOGY AND IT'S TURNED IT ON
ITS HEAD.
>> THANK YOU SO MUCH.
THAT WRAPS THE FIRST TWO
SPEAKERS SO WE CAN CATCH UP ON
TIME IF THERE'S NO FINAL
QUESTIONS.
WE HAVE FOUR MORE SPEAKERS FOR
THE SESSION.
THE NEXT SPEAKER IS DR. JUNE LI
WHO HAS POST-DOC TRAINING IN
STEM CELL RESEARCH.
SHE'S CURRENTLY AN ASSOCIATE
PROFESSOR AT THE DEPARTMENT OF
BIOMEDICAL SCIENCES AT THE
COLLEGE OF MEDICINE RUTFORD.
HER LEE FOCUSES ON NEURONAL SUB
TIMES OF STEM CELLS AND USING
THE STEM CELLS TO STUDY AXONAL
DEGENERATION.
IN PARTICULAR HER LAB IS
INTERESTED IN MODELS OF
HEREDITARY SPASTIC PARAPLEGIAS.
THE FOURTH SPEAKER IS
DR. CHI-LUN CHANG WHO EARNED HIS
Ph.D. FROM THE UNIVERSITY OF
TEXAS STUDYING THE
INTER-ORGANELLE INTER FAFAC FACFAC FACFACE S AND
STUDIED PROTEIN TRAFFICKING AND
JOINED THE DEPARTMENT OF CELL
AND MOLECULAR BIOLOGY AND HIS
RESEARCH INTERESTS INCLUDE
SPATIAL TEMPORAL REGULATION OF
INTERORGANOIDS AND THE FIFTH
SPEAKER IS DR. PETER BAAS A
PROFESSOR AT DREXEL DEVELOP ALSO
THE DIRECTOR OF THE PROGRAM IN
NEUROSCIENCE AND THE DIRECTOR A
NIH-FUNDED TRAINING PROGRAM IN
SPINAL CORD INJURY.
HE HAS STUDIED SPG4 FOR THE PAST
YEARS AND FOCUSSED MAINLY ON THE
UNDERLYING MECHANISM OF THE
DISEASE AND DEVELOPED THE FIRST
ANIMAL MOUSE MODEL WITH LOSS OF
FUNCTION AND GAIN OF FUNCTION
PERFORMANCE AND HE'LL BE
PRESENTING HIS TALK ABOUT THE
MODELS TODAY.
LASTLY, DR. ERIC SAMARUT HAS TAY
DOCTORATE FROM THE UNIVERSITY OF
STRASBURG.
AND HE IS NOW THE CO-FOUNDER AND
CHIEF SCIENTIFIC OFFICER OF A
COMPANY FOR TREATMENT OF RARE
DISEASES.
HIS RESEARCH INTERESTS AIM TO
BETTER UNDERSTAND THE MECHANISMS
AND UNDERLYING NEUROLOGICAL
DISEASES AND TO DEVELOP
PRECISION MEDICINE STRATEGIES.
I'D LIKE TO CALL ON DR. JUNE LI
TO PRESENT HER TALK.
>> THANK YOU.
>> CAN YOU HEAR ME WELL?
>> YES.
>> I'M HONORED TO BE HERE.
I'M NEW TO THE TEAM.
I'D LIKE TO THANK DR. BLACKSTONE
AND THE ORGANIZERS OF THE
MEETING FOR THE OPPORTUNITY TO
PRESENT AT THIS WONDERFUL
SYMPOSIUM.
I'LL DISCUSS WITH YOU ABOUT OUR
WORK ON DIFFERENTIATING PLURI
PLURIPOTENT STEM CELLS FOR
COMPOUND SCREENING.
CHARACTERISTIC OF STEM CELLS IS
THEY HAVE THE CAPACITY TO
DIFFERENTIATE INTO DIFFERENT
TYPES OF CELL TISSUES.
BASED ON THEIR CAPACITY TO
GENERATE OTHER TYPE OF CELLS,
HERE ARE THREE TYPES.
AND THE RESEARCH IN MY LAB IS
FOCUSSED ON USING THE STEM CELL
BASED MODELS.
THE PLURIPOTENT STEM CELLS CAN
GENERATE ANY CELL TYPE IN OUR
BODY.
THESE OTHER CELL TYPES ARE
DERIVED FROM THE LAYERS AND THEY
CAN GENERATE THIS PROJECTION OF
NEURONS DEGENERATED AND CAN
CAUSE NEUROLOGICAL DISEASE AND
OTHER TYPES OF CELLS.
THERE'S TWO TYPES AND ONE IS
INDUCED.
THESE CELLS CAN BE ASSOCIATED ON
THE FEEDER CELLS FOR
SELF-RENEWAL AND FORCED THE
HUMAN EMBRYONIC STEM CELLS WERE
ESTABLISHED BY JIM JOHNSON FROM
UW MADISON PUBLISHED IN 1998.
THIS IS A UNIQUE SYSTEM TO
GENERATE THE DIFFERENT TYPE OF
CELLS INCLUDING THE CELLS THIS
EMBRYONIC STEM CELL LIMITED TO
AVAILABILITY.
THESE COME TO THE OTHER TYPE OF
PLURIPOTENT STEM CELLS WE CALL
INDUCED PLURIPOTENT PLURIPOTENT
STEM CELLS.
BUT IF THE CELLS ARE
DIFFERENTIATED AND THE STEM
CELLS AND THESE CELLS IT WOULD
BE HARD FOR THE CELLS TO GO BACK
TO BECOME STEM CELLS.
SO THIS DOGMA HAS BEEN
CHALLENGED.
IN 2006 A GROUP SHOWED FROM THE
MOUSE DIFFERENTIATED FIBROBLAST
CELLS CAN REPROGRAM BACK TO
PLURIPOTENT STEM CELLS AND A
2007 ANOTHER GROUP SHOWED IF YOU
CAN TAKE THIS HUMAN FIBROBLAST
CELLS WHICH ARE ALREADY
DIFFERENTIATED CELLS FROM TAKEN
FROM SKIN BIOPSY AND INDUCE
PLURIPOTENT FACTORS AND THEN
CULTURE IN A STEM CELL MEDIUM
THE CELLS WILL CHANGE THEIROLOGY
AND NOW LOOK SIMILAR TO
EMBRYONIC STEM CELLS AND HAVE
THE SAME GENE EXPRESSION PROFILE
AND GENETIC STATUS AND ARE
PLURIPOTENT AND CAN BECOME THIS
CELLS IN VIVO AND CAN START A
NEURO DEGENERATIVE DISEASE.
BECAUSE OF THIS THEY'VE
GENERATED HUMAN IPA CELLS AND
OTHERS WHO BROUGHT UP THE
PROGRAMMING CONCEPT THEY
TOGETHER WON A NOBEL PRIZE IN
MEDICINE IN 2012.
AS ILLUSTRATED HERE AND IN OUR
LAB WE COULD TAKE THIS PATIENT
CELLS AND USUALLY WE HAVE THE
FIBROBLAST CELLS WHICH CAN BE
DERIVED BY SKIN BIOPSY AND USE
BLADDER CELLS AND WE COULD
TRANSDUCE A SET ON THE PLURI-POE
PLURIPOTENCY FACTOR AND THEN
THEY CAN PROVIDE A SOURCE TO
GENERATE THE PATIENT-SPECIFIC
CELLS AND IN OUR LAB WHERE WE
DIFFERENTIATE THE CELLS INTO THE
NERVE CELLS AND USE THEM TO TEST
THIS DIFFERENT COMPOUNDS AND TO
ALSO IDENTIFY THE THERAPEUTIC
TARGET.
SO TO USE THIS IPSC MODELS THE
FIRST TIME IS TO EFFICIENTLY
GENERATE THE NERVE CELLS THAT
ARE SPECIFIC A FACTOR IN THE
DISEASE.
SO AS WE KNOW YOU HAVE A NERVOUS
SYSTEM AND DIFFERENT TYPES OF
NEURONS.
FOR EXAMPLE, LIKE DOPAMINE
NEURONS AND ONE IMPORTANT
QUESTION IN APPLYING THE STEM
CELL DERIVED MODEL TO START THE
DISEASE IS HOW WE'RE ABLE TO
HAVE NAIVE PLURIPOTENT STEM
CELLS AND AFTER APPLYING THEM TO
THE STEM CELLS CAN THEY BE
FURTHER DIFFERENTIATED INTO THE
DIFFERENT TYPE OF NEURONS.
FOR EXAMPLE, THERE'S HAS BEEN
REFERRED TO AS THE CORTICO
PROJECT NEURON DEGENERATED IN
THIS IPSC.
WE NEED TO LOOK AT WHAT ARE THE
KEY FACTORS REGULATING THIS
PROCESS DURING DEVELOPMENT.
AND WE HAVE ON THE KEY STEPS WE
CAN USE THIS AND GENERATE THIS
FINAL MOTOR NEURONS AND BY
REGULATING THE SIGNALS WE COULD
LOOK AT THE PROJECTION NEURONS
AND OTHER CELLS DEGENERATED IN
THE SPG3A AND SPG4.
I'LL TALK MORE ABOUT IT LATER.
AFTER WE ESTABLISHED THE SYSTEM
TO GENERATE THE NERVE CELLS A
FACTOR IN THE DISEASE WE CAN
FURTHER START THE DISEASE MODELS
TO TEST THE DRUGS.
PARTICULARLY IN COLLABORATION WE
STARTED SPG3A AS DR. BLACKSTONE
HAS INTRODUCED AND GAVE AN
INFORMATIVE AND INCLUSIVE
INTRODUCTION ABOUT IPSC IT'S THE
MOST ONSET FORM.
AND ONE CHARACTERISTIC CHANGE IS
THE AXONS WHICH CONTROL THE
SPINAL MOTOR NEURON FOR THE
MUSCLES.
THE SPG3A GENE ENCODES THE
PROTEIN AND THIS IS A MEMBER OF
THIS ER GTP PROTEIN AND BECAUSE
THIS IS IMPORTANT FOR THE LIPID
SYNTHESIS AND METABOLISM, SO I
THINK THE AND YOU CAN SEE THIS
OTHER FIBROBLAST CELLS WHICH
HAVE AN ELONGATED MORPHOLOGY.
WE USED THE METHOD AND WE USE
THE VIRUS MEASURED.
BY EXPRESSING THE FACTORS AND
THE CLONES AFTER ONE MONTH WE
START TO SEE THE STEM CELL
CLONES.
ARE STEM CELL CLONES AND THE
FIRST TIME WAS TO VALIDATE AND
CHARACTERIZE THE IPSC CELLS AND
THE CRITERIA TO CHARACTERIZE THE
CELLS IS THE PLURIPOTENCY AND WE
LOOK AT THE EXPRESS OF THE
PLURIPOTENT GENES AND PROTEINS.
I SHOW HERE SO WE CAN SEE THE
IPSC CLONES FORMULATE AND
EXPRESS THIS PLURIPOTENT
PROTEINS.
WE ALSO TESTED THE PLURIPOTENCY
USING THE FORMATION AND SHOW
THEY CAN FORM THE THREE GERM
LAYERS IN VIVO.
WE'LL CONFIRM THE CELLS ARE
PLURIPOTENT.
THE OTHER IMPORTANT THING IS TO
SEE WHETHER AFTER REPROGRAMMING
WHETHER THE CELLS STILL MAINTAIN
THE PATIENT SPAST MUTATION.
FOR THIS MALE PATIENT THE FIRST
ONE AS DR. BLACKSTONE ALSO
MENTIONED THIS IS A MUTATION A
DE NOVO MUTATION AND YOU CAN SEE
HERE IT HAS IPSC CELLS WE CAN
FURTHER GENERATE THE NEURONS
FROM THE CELLS TO FURTHER LOOK
AT WHAT ARE THE DISEASE SPECIFIC
PHENOTYPES IN THIS
PATIENT-DERIVED CELLS AND WE
HAVE SEEN THEY CAN REDUCE THIS
AT THE EARLY STAGE.
AND THIS WILL BE EXPRESSED FROM
THE AXONAL CONTROL GROUP TO
DIFFERENT CLONES FROM IS THE
PATIENT'S IPSC CELLS.
AND REDUCE THE CELLS.
ONE QUESTION USING IPSC CELLS TO
MODEL DISEASE IS WHETHER THE
PHENOTYPE WE SEE IS STILL
RELATED TO THIS MUTATION.
SO TO DO THAT WE USE THE CRISPR
GENE EDITING TO CORRECT THE
MUTATION.
IF YOU LOOK AT THE TWO PANELS
HERE SO THIS SHOWS LIKE THERE
CLONES AND THE PROTEIN AND THIS
MUTATION.
BY USING THE MEDIATED GENE AFTER
LIKE A GENE CORRECTION I SEE THE
CRITER CELLS AND THIS SHOWS THE
MUTANT CELLS.
OF THE CORRECTION THIS IS
RESTORED.
THIS SUGGESTS IMPAIRED CELLS ARE
DERIVED BY THE MUTATION.
WE ALSO KNOCK IN THE DIFFERENT
MUTATION TO THE PROTEIN FOR 161
AND WE CAN ALSO SEE THE CELLS
HAS A SIGNIFICANT REDUCE LENS
AND THE SUGGESTS THE MUTATIONS
CAN RESULT IN THE REDUCED AXON
OUTGROWTH.
ONE REASON FOR PATHOLOGICAL
CHANGE IS ACCUMULATIVE PARTICLES
CAUSED BY THE IMPAIRED AXON.
SO INTERESTINGLY IF YOU CULTURE
THIS CORTICAL NERVE CELLS WE CAN
SEE IN THE PATIENT-DERIVED CELLS
YOU CAN SEE IT FORMED THIS AND
CAN SEE THE BREAKDOWN OF THIS
AXON.
AND GET A SIGNIFICANT INCREASE
AND THEY'RE RESCUED IN THE
CORRECT CELLS.
THIS SUGGESTS THE MUTATION CAN
RESULT IN ACCUMULATED SWALLOWING
AND CAN SEE THE SWALLOWING OF
OTHER MUTATION.
AND THOUGH THIS AXONAL POUCH WE
LOOKED AT THE FUNCTIONAL CHANGE
BY USING THE IPSC DERIVED NERVE
CELLS WE CAN LOOK AT THE
FUNCTION IN IMAGING.
AN STEM CELLS WE DO A LIVE CELL
IMAGE FIVE MINUTES.
THIS X AXIS IN A DIFFERENT
POSITION AND IF THE MITOCHONDRIA
MOVES IT WILL CHANGE THE
POSITION ALONG THE X AXIS.
YOU CAN SEE IMMEDIATELY IN THE
CONTROL CELLS THERE'S A LOT OF
MITOCHONDRIA MOVES BUT IN THESE
PATIENTS MOST MOVE VERY LITTLE
OR DO NOT MOVE.
SO THERE'S A SIGNIFICANT
REDUCTION OF THIS MITOCHONDRIA
AND THE EVENTS OF MITOCHONDRIA.
WE CAN SEE MUTATION OF THESE HR1
RESULTS IN REDUCED OUTGROWTH
RESULTS AND THE IMPAIRED POUCH
WHICH RECAPITULATE THESE
SPECIFIC PHENOTYPES.
WE CAN USE THE MODEL TO TEST THE
THERAPEUTIC COMPOUNDS.
I'LL NOW GIVE AN EXAMPLE HOW WE
USE THIS ONE TO TEST THIS
COMPOUNDS AND WHAT ARE THE
CHALLENGES AND WHAT ARE THE
FUTURE PLANS WE'RE GOING TO DO
WHICH CAN SCREEN COMPOUNDS TO
RESCUE THE AXONAL DEGENERATION.
SO WE CAN SEE WE HAVE A PATIENT
WITH THIS MUTATION WITH THE
PROTEIN AND RECEIVE AND GENERATE
IPSC CELLS FROM ANOTHER
MUTATION.
CRAIG HAS MENTIONED THE
MUTATION.
THESE ARE SEVERE IPSC PATIENTS
AND ACTUALLY THIS MUTATION HAS
ALSO BEEN LOOKED AT BEFORE AND
THIS STARTED IN 2007.
THEY HAVE BEEN SCREENED OVER 100
PATIENTS WHICH DO NOT HAVE A
CLEAR MUTATION OF SPG4.
THE SCREEN FOUND THEY HAVE
MUTATION SPG3A.
AND THREE ARE DE NOVO MUTATIONS.
AND YOU CAN SEE THESE ARE THE
THREE DE NOVO AND THERE'S TWO IN
THE DTP AND THIS ONE IN THE ONE
MENTIONED AND WE HAVE ALSO HAVE
THIS PATIENT HAD SEVERE EARLY
ONSET AND SEVERE PHENOTYPES.
AND THESE PATIENTS HAVE A SEVERE
PHENOTYPE AND EARLY ONSET AND
AND WE SEE REDUCED THIS IN THE
PATIENT WITH OTHER DE NOVO
MUTATIONS.
AND ALSO LIKE WITH DIFFERENT
CLONES.
SO AS I TURN TO THIS FIGURE
SHOWED WE HAVE ALREADY TESTED AS
A PROOF OF CONTEST MACRO TUBULE
TARGETING COMPOUNDS AND THE
CELLS IN THE SPG3A IPSC-DERIVED
NEURONS AND WE SEE A SIGNIFICANT
OUTGROWTH OF THE PATIENT CELLS
AND WE SEE THE DEFECTS.
SO THIS SUGGESTS IT'S A
MICROTUBULE TARGETING CAN
MITIGATE THE GROWTH AND SUGGEST
THE PATIENT'S STEM CELLS IN CAN
HELP SCREEN THE DRUG AND WE CAN
USE A SYSTEM LIKE THIS COMPUTER
ALGORITHM TO ANALYZE THE
EXTENSION.
IN THIS WAY WE COULD TEST LIKE A
LARGE NUMBER OF COMPOUNDS IN THE
FUTURE.
SO I SHOW HERE LIKE NOT ONLY IN
ADDITION TO HAVING THE SYSTEM WE
WANT TO ALSO WANT TO DEVELOP
SOME SENSITIVE HIGH THROUGHPUT
METHOD.
WE HAVE SHOWN A SIGNIFICANT
ALTERATION OF THIS IN THE
MEDIUM.
SO WE WANT TO SEE LIKE WHETHER
WE COULD HAVE A MORE SENSITIVE
MEASURE AND WE'RE LOOKING AT A
TEST CASE IN THE CELLS.
IN THIS MORE SENSITIVE HIGH
THROUGHPUT MEASURE WE WILL BE
ABLE TO TEST A LARGE NUMBER OF
DIFFERENT COMPOUNDS AND COMPARE
THE COMPOUNDS TARGETED AT
DIFFERENT PATHWAYS AND
POTENTIALLY ALSO TEST THIS IN
THE FUTURE.
FOR EXAMPLE DR. BLACKSTONE
SHOWED THE TARGET DRUG WE CAN
TEST OTHER DRUGS.
AND WE CAN IDENTIFY THIS AND USE
ANALYSIS FOR THE CELLS.
AND WE CAN TEST THIS STEM CELL
DERIVED NEURONS.
ONE THING INTERESTINGLY IS ONE
ADVANTAGE FOR THE MODEL IS THE
CELLS CAN GENERATE OTHER TYPE OF
NERVE CELLS.
CLEAR CELLS AND ASTROCYTE AND
THE MUTATION THIS MUTATION CAN
IMPAIR THESE DROPLET IN
ASTROCYTES.
I'LL NOT TALK TOO MUCH DETAIL
BUT YOU SEE THE STEM CELL
DERIVED ASTROCYTE AND SEE THE
DROPLET IN THE CELLS.
AND THERE'S VERY FEW OF THESE
DROPLET AND FOR THE STUDY SHOW
IN THIS MUTANT CELLS THE DE NOVO
MUTANT CELLS WE SHOW THE SIZE OF
THE DROP LETSS -- DROPLETS ARE
REDUCED IN THE GLIAL CELLS.
WE KNOW AS WE SHOW HERE WITH THE
OTHER SCHEMATIC SHOWS THE GLIAL
CELLS AND THE NEURONS WITH LATER
DEVELOPMENT WHEN THEY ARE
MATURE, THEY ARE DEPENDENT ON
THIS ASTROCYTE AND GLIAL CELLS
SO THERE'S TRANSFER FROM THE
CELL TO THE NEURON AND THE
NEURONS HAVE A DEFICIENCY WHICH
LEAD TO THE DEFECTS.
THEREFORE BY USING THE MODELS AS
SUMMARIZED HERE WE CAN TRY TO
DEVELOP SOME SENSITIVITY METHOD
TO TEST COMPOUNDS TARGETED IN
DIFFERENT PATHWAYS AND IF THE
FUTURE TEST SOME LABORATORIES.
AND WE CAN FURTHER LOOK AT THE
ANALYSIS IN THE IPSC MODEL MORE
IMPORTANTLY WE CAN LOOK AT THE
GLIAL IN ACTION AND IN THE
FUTURE IT CAN BE TESTED IN
ANIMAL STUDIES.
SO WE CAN SEE THIS IS IPSC CELL
DERIVED MODELS CAN PROVIDE A
VERY POWERFUL TOOLS BY COMBINING
WITH DIFFERENT APPROACHES AND
OTHER MODELS IN THE FUTURE WILL
PROVIDE A SYSTEM TO IDENTIFY
SOME POTENTIAL AGENTS TO RESCUE
THE AXONAL DEFECTS IN THE SPG3A
PATIENTS.
I'D LIKE TO THANK THE PEOPLE IN
MY LAB AND I WANT THANK
DR. BLACKSTONE AND HIS TEAM.
AND UP PARTICULAR I WANT TO
THANK THE FUNDING AGENCIES
SPORING OUR WORK.
I'LL BE HAPPY TO ANSWER ANY
QUESTION US HAVE IN LATER
DISCUSSION.
THANK YOU.
>> THANK YOU, DR. LI.
WE CAN PROCEED WITH THE TALK
FROM DR. PETER BAAS.
IT'S A GREAT PLEASURE TO BE
HERE.
SO WONDERFUL OF THEM AND
TERRIFIC TO INTERACT WITH
PHYSICIANS AND PARENTS OF
CHILDREN SUFFERING FROM THIS
DISEASE AND SCIENTIST.
I'LL TALK ABOUT TODAY IS MOUSE
MODEL FOR SPG4.
IN DOING SO I THINK IT'S
IMPORTANT I TALK ABOUT
MECHANISMS UNDERLYING THE
DISEASE AND I ALSO WHERE THIS
GOES WITH REGARD TO POTENTIAL
THERAPIES.
I WAND TO REMIND THINGS WE HEARD
AND HEREDITARY SPASTIC
PARAPLEGIA HAS THINGS IN COMMON
AND HOW WE CATEGORIZE THESE ARE
GAIT DEFECTS AND WE'RE STARTING
TO UNDERSTAND OTHER
ABNORMALITIES.
USUALLY THE DISEASE IS ADULT
ONSET BUT NOT ALWAYS AND THAT'S
THE POINT OF THE MEETING TODAY.
THERE'S ALSO A GREAT DEAL OF
VARIABILITY EVEN WITHIN THE SAME
FAMILY.
THE MAIN THING THAT HAPPENS IS
DEFEND RATION OF THE SPINAL
MOTOR NEURONS AND THESE AXONS
DIE BACK FROM THE SYNAPSES AND
WHAT WE SEE CLASSICALLY IN
POSTMORTEM TISSUES IS
PATHOLOGICAL SWELLINGS.
IF YOU LOOK AT THE CAUSES FOR
THE SYMPTOMS THE NUMBER OF GENES
IS GROWING.
IT USED TO BE THOUGHT THERE WERE
NINE -- 12 AND NOW UP TO 92 AND
THE LIST GOES ON AND ON.
CODES FOR A PROTEIN CALLED
SPASTIN WHICH IS A PROTEIN BUT
IN THE CASE CRAIG POINTED OUT
WE'RE LEARNING MORE ABOUT THE
MULTIPLE FUNCTIONS OF THE
SPASTIN PROTEIN.
WE HEARD LOSS OF FUNCTION AND
GAIN OF FUNCTION IN THE
SYMPOSIUM AND IT'S RELEVANT TO
MAKE APPROPRIATE MOUSE MODEL FOR
THE DISEASE.
HERE'S AN EASY WAY I THINK ABOUT
IT.
IF IT'S A LOSS OF FUNCTION, THE
KID JUST DIDN'T SHOW UP FOR
CLASS, HE'S JUST NOT THERE.
BUT IF IT'S GAIN OF FUNCTION
HE'S THERE BUT MAKING TROUBLE.
SO DON'T THINK GAIN OF FUNCTION
MEANS IT'S SOMETHING GOOD.
GAIN OF FUNCTION USUALLY IN THE
DISEASE CONTEXT MEANS IT'S
MAKING SOME KIND OF TROUBLE.
SOMETIMES THE TROUBLE THE MUTANT
PROTEIN MAKES CAN BE PREDICTED
BY ITS NORMAL FUNCTION.
OTHER TIMES IT'S NOT SO EASY.
HAVE THIS MUTANT PROTEIN AND IT
DOES UNPREDICTED THINGS LIKE
HYPERACTIVATE KINASES OR OTHER
THINGS YOU'D NEVER PREDICT ON
THE OF ITS NORMAL FUNCTION.
IN THIS CASE IT GETS
PROGRESSIVELY WORSE AND USUALLY
BECAUSE MISFOLDED PROTEINS HAVE
A TENDENCY TO ABROGATE AND ONCE
THEY ABROGATE THEY ACCUMULATE
AND THEN THE STICK AROUND FOR A
LONG TIME.
THEY CAN GET WORSE.
AS CRAIG POINTED OUT EARLIER,
THE SPAST GENE ENCODES TO
PROTEIN.
ONE WE CALL THE M1, THE LONGER
OF THE TWO.
THE OTHER IS M87 JUST SLIGHTLY
SHORTER AND M87 PREDOMINANCE.
SO M87 IS IN VIRTUALLY EVERY
CELL OF THE BODY AND ENRICHED IN
THE SYSTEM AND LIVER AND SKIN
AND WIDELY EXPRESSED AND AN
IMPORTANT MICROTUBULE SEVERIN
PROTEIN AND THERE'S THE WHY
PERFECT ONE CRAIG MENTIONED.
IT'S EXPRESSED AT MUCH LOWER
LEVELS AND AS CRAIG POINTED OUT
YOU REALLY DON'T SEE IT BECAUSE
THERE'S SO LITTLE OF IT BUT WE
DO SEE IT IN CERTAIN INSTANCES
I'LL GET TO IN A MOMENT.
SO HERE'S A WESTERN BLOT AND AS
YOU CAN SEE IF YOU LOOK AT
CEREBRAL CORTEX, THIS IS FROM
RODENT, E18, P0, P12, THE BAND
YOU SEE THIS BAND IS ALL M87.
BUT HERE'S THE SPINAL CORD AND
REMEMBER THE SPINAL CORD
SOMEWHERE THE CORTICAL SPINAL
TRACKS LIE AND WHERE YOU START
TO SEE A BIT OF THE M1 BECOME
VISIBLE IN THE ADULT SPINAL CORD
AND WE THINK THERE'S SOMETHING
ABOUT THE SPINAL TRACTS THAT LIE
IN THE SPINAL CORD THAT HAVE THE
TENDENCY TO M1 AND THAT COULD BE
CRITICAL TO UNDERSTANDING THE
DISEASE AND WHY THE DISEASE HITS
THE CORTICAL SPINAL TRACKS.
WE PONDERED ON THE GAIN OF
FUNCTION AND LOSS OF FUNCTION
AND THE COMMUNITY IS GETTING
FRIENDLY ABOUT THE CONTROVERSY.
WHEN WE FIRST GOT INTO IT WAS A
CONTROVERSY AND THE PATIENT HAS
ONE GOOD GENE AND ONE NOW
FUNCTIONING GENE.
AND IT'S AS IF THE
MALFUNCTIONING GENE IS SIMPLY
NOT THERE AND SO THE PHENOTYPE
IN THIS MECHANISTIC SCENARIO IS
INTERPRETED IN TERMS OF NOT
ENOUGH FUNCTIONAL SPASTIN.
THAT COULD BE NOT ENOUGH
FUNCTIONAL M1 OR COULD BE NOT
ENOUGH FUNCTIONAL M87, WHATEVER
THE CASE IT'S NOT ENOUGH
FUNCTIONAL SPASTIN THEREFORE THE
SPINAL CORD PHENOTYPES SUFFER
AND TROUBLE ENSUES.
THERE'S NOT A LOT ABOUT THE
PHENOTYPE OVER THE YEARS WE
OBSERVED THAT WE DON'T THINK
FITS A LOSS OF FUNCTION SCENARIO
AT LEAST NOT EXCLUSIVELY.
ONE EXAMPLE IS THE KNOCKOUT
MOUSE.
SO MOST PEOPLE IN THE FIELD
PRIOR TO WHAT WE DEVELOPED USED
A SPASTIN KNOCKOUT MOUSE IN
ORDER TO MODEL THE DISEASE.
THE PROBLEM IS IT DOESN'T MIMIC
THE PHENOTYPE, THE SYMPTOMS OF
THE HUMAN DISEASE.
IT'S NOT A PERFECT MOUSE.
YOU CAN EITHER KNOCKOUT ONE OR
TWO GENES AND IT DOES HAVE SOME
NERVOUS SYSTEM DEFECTS BUT IT
REALLY DOESN'T MIMIC THE GAIT
DEFICIENCIES OF THE HUMAN
PATIENT.
WE COME AROUND TO THINKING
THOUGH IN RECENT YEARS THAT THE
LOSS OF FUNCTION IS A COMPONENT
OF THE DISEASE.
I'LL GIVE YOU MORE INFORMATION
AS TO WHY WE THINK THAT USING
OUR MOUSE MODELS BUT THESE DAYS
WE THINK THE GAIN OF FUNCTION
AND TOXIC PROPERTIES OF THE
MUTANT PROTEINS CAUSE THE
PHENOTYPE.
BUT THE LOSS OF FUNCTION, THE
FACT THAT HALF THE SPASTIN IS
NOT FUNCTIONING PROPERLY IS ALSO
A CONTRIBUTING FACTOR.
SO WE'RE BEGINNING TO SORT THIS
OUT AND WE'RE LOOKING AT LOSS OF
FUNCTION PATHWAYS AND LOOKING AT
LOSS OF FUNCTION FOR THE EXXON
--
AXONAL FUNCTION AND THIS SLIDE
SHOWS A FEW OF THE MECHANISTIC
I'D THAT WE'RE PURSUING AS TO
WHY EACH OF THESE PATHWAYS
BECOMES CONSEQUENTIAL TO THE
DISEASE.
THE COLLABORATOR USED SQUID
AXALPLASM AND WE INFUSED MUTANT
M1 VERSUS MUTANT M8 7 AND FOUND
THE MUTANT M1 THAT PRODUCED
PROBLEMS WITH AXONAL TRANSPORT
AND THE MUTANT M87 WAS INCONS
INCONSEQUENTIAL AND NO
TRANSPORT.
WE USED A FLY MODEL AND
SIMILARLY IF WE KNOCKED IN THE
HUMAN MUTANT M87 THERE WAS
VIRTUALLY NO PHENOTYPE BUT IF WE
KNOCKED IN THE HUMAN MUTANT M1
THEN THE FLIES COULD NOT HOLD
THEIR WINGS PROPERLY OR FLY OR
FLIP OVER WHEN PUT ON THEIR
BACKS.
IT SEEMS THAT SPASTIN PROTEINS
IS TOXIC WHEN IT'S M1 BUT NOT
WHEN IT'S M87.
AND IT KIND OF MAKES SENSE
BECAUSE THE REGION OF M1 THAT IS
SPECIFIC TO M1 HAS THE
CHARACTERISTICS OF A PROTEIN
THAT WOULD BE PRONE TO
MISFOLDING AND TAKING ON TOXIC
PROPERTIES.
AND EVOLUTIONARILY TOO MUCH OF
IT IS NOT A GOOD THING.
SO WE SET FORTH TO CREATE A
KNOCK-IN ANIMAL.
WE WANTED TO MAKE A MOUSE THAT
WOULD KNOCK IN HUMAN MUTANT
SPASTIN.
THESE DAYS AS CRAIG MENTIONED,
THERE ARE SOPHISTICATED WAYS OF
GETTING INTO THE GENE OF THE
ANIMAL TO THE SPASTIN GENES AND
WHAT WE WANTED TO DO WAS LEAVE
THE ENDOGENOUS GENES ALONE AND
JUST KNOCK IN AND WE USE THIS
SYSTEM TO KNOCK IN HUMAN-MUTANT
SPASTIN.
WE WANTED TO START BY CREATE A
MOUSE THAT HAD ALL THE NORMAL
SPASTIN, MOUSE SPASTIN, BUT ON
TOP OF THAT HAS THE HUMAN MUTANT
SPASTIN.
SO WE CREATED A MOUSE NOT LOSS
OF FUNCTION.
IT'S ONLY GAIN OF FUNCTION.
HERE'S THE WILD TYPE MOUSE
WALKING ON A ROD AND IF I WANTED
TO FOOL YOU, I CAN SHOW YOU THE
SAME MOVIE WITH A KNOCKOUT MOUSE
AND IT WOULD LOOK THE SAME.
THERE'S NO WALKING DEFECT WITH
THE KNOCKOUT MOUSE.
LET ME SHOW YOU THE KNOCK-IN
MOUSE.
HERE'S THE KNOCK-IN MOUSE AND
NOTICE IT REALLY STRUGGLES TO
WALK.
ITS BODY IS SCRUNCHED UP BECAUSE
OF DIFFICULTY WALKING AND
STRUGGLES.
THIS IS AN ADULT EARLY ADULT HAS
THESE CHARACTERISTICS AND HAS A
TREMOR SOMEWHAT LIKE SPACTICITY.
WHAT I THINK THIS SHOWS IS YOU
CANNOT ACHIEVE THE HSP PHENOTYPE
WITH KNOCKOUT ALONE BUT YOU CAN
ACHIEVE THE HSP PHENOTYPE WITH
KNOCK-IN ALONE.
SO I THINK THIS IS THE STRONGEST
YET EVIDENCE IN FAVOR OF GAIN OF
FUNCTION BEING THE UNDERLYING
MECHANISM OF DISEASE.
I'M NOT GOING TO PUT A LOT OF
TIME INTO SHOWING DETAILS.
THESE THE SORTS OF THINGS WE
OBSERVE, ADULT ONSET, GAIT
DEFICIENCY AND HOMO ZYGOTES
WORSE HAND HETEROZYGOTES AND WE
DID TRACER STUDIES AND YOU
DETECT WHETHER THERE ARE FEWER
AXONS IN THE DISTAL REGION OF
THE SPINAL CORD AND WE SAW FEWER
AXONS IN THE DISTAL REGION
INDICATING THE AXONS ARE DYING
BACK FROM THEIR SYNAPSES AND
PULLING BACK.
HOW ABOUT THE AXONAL SWELLINGS I
MENTIONED?
CURIOUSLY WE DON'T SEE THEM IN
THE KNOCKOUT MOUSE BUT WE DO IN
THE KNOCK-IN MOUSE.
THE KNOCKOUT MOUSE SHARES THAT
FEATURE WITH THE HUMAN PATIENTS
WHEREAS THE KNOCKIN MOUSE DOES
N
NOT.
I THINK IT FORTIFIES THE LOV THIS THAT
IT FORTIFIES A ROLE AND WE SEE
THAT THE INSUFFICIENT LEVELS OF
SPASTIN IS NOT SUFFICIENT TO
CAUSE THE PHENOTYPE OF DISEASE
BUT WHEN YOU ADD THE MUTANT
SPASTIC PROTEIN THAT IS.
AND TO BELABOR THE DETAILS BUT
WE CROSSED THEM AND WE AN ANIMAL
INSUFFICIENT AND THE PROTEIN AND
EVERYTHING IS WORSE.
THE BEHAVIOR IS WORSE, EARLIER
ONSET, STRONGER BEHAVIORAL
DEFICITS AND CORTICAL SPINAL DIE
BACK IS MORE EXTREME AND THE
AXONS HAVE SWELLING.
THIS MOUSE THE CROSS OF TWO IS
THE BEST YET MOUSE FULLY
REPRESENTING THE FEATURES OF THE
DISEASE.
HOWEVER, THE OTHER TWO MICE ARE
REALLY STILL VERY USEFUL IF YOU
WANT TO DO STUDIES SPECIFICALLY
ON GAIN OF FUNCTION OR LOSS OF
FUNCTION FROM THE DISEASE.
WE USED A CAT WALK FOR
BEHAVIORAL TESTING.
THIS IS A HIGHLY SENSITIVE
METHOD.
YOU PUT THE ANIMAL THROUGH A
CHAMBER AND THE PAW PRINTS FROM
THE COMPUTER RECORD IT AND YOU
CAN GET ALL SORTS OF DATA AND
THIS WILL BE USEFUL FOR
ASSESSING THERAPY.
AGAIN, HERE ARE THE DATA THAT I
MENTIONED FROM THE DIE BACK.
I KNOW THIS IS COMPLICATED BUT
THINKING ABOUT WHAT I JUST SAID
RATHER THAN FOCUSSING ON THIS.
SO SCHEMATICALLY SPEAKING THIS
IS HOW WE'RE THINKING, THAT GAIN
OF FUNCTION IS THE MAIN DRIVER
OF THE DISEASE BUT LOSS OF
FUNCTION RENDERS THE AXONS MORE
VULNERABLE TO THE GAIN OF
FUNCTION TOXICITY.
THIS IS WHERE AN INTERESTING
QUESTION COMES IN AND WHAT ABOUT
THE PATIENTS WHO HAVE A FULL
DELETION ONE OF THE SPASTIN
GENES?
THEY ALSO HAVE HEREDITARY SPAST
SPASTIC PARAPLEGIA IS WHY IS
THAT WHEN THEY DON'T HAVE A GAIN
OF FUNCTION COMPONENT OF THE
SPASTIN?
IT GETS COMPLICATED BECAUSE GENE
DELETION NOT ONLY ONE PROTEIN.
THAT'S ONE THING BUT THE MAIN
THING I WANT TO REFER YOU TO IS
WHAT I SAID EARLIER ABOUT THE
LIST OF 92 GENES GROWING LONGER
AND LONGER AND LONGER AS TO WHAT
GENE MUTATIONS CAN CAUSE
HEREDITARY SPASTIC PARAPLEGIA
AND ARGUE THE PATIENTS WITH GENE
DELETION AND HSP PROBABLY HAVE
SOMETHING ELSE GOING ON IN THEIR
GENOME THAT ELICITS THAT
PHENOTYPE WITH THAT GROWING LIST
OF GENES IT WOULD BE SOMETHING
ON ITS OWN CAUSES THE SYSTEMS OR
COMBINATION.
THAT'S ONE OF THOSE COMPLICATED
FACTORS THAT'S GOING TO TAKE
WORK TO RESOLVE.
I'M WORKING WITH MIGUEL ESTEVEZ
ON GENE THERAPY AND A KNOW HE'S
SPEAK IN A LITTLE WHILE SO I
WON'T SPEND A LOT OF TIME ON
THIS AND THE GENE THERAPY WE
HEARD BEFORE IN WONDERFUL
PREVIOUS TALKS IS TO REPLACE THE
MUTANT GENE WITH A WILD TYPE
GENE.
SO WE'RE WORKING ON THAT AND
MIGUEL WILL TALK ABOUT THAT
SHORTLY.
AND I JUST WANT TO CLOSE BY
THANKING ALL OF THE VARIOUS
PEOPLE IN MY LAB OVER THE YEARS
WHO HAVE CONTRIBUTED TO THIS
WORK IN PARTICULAR I WANTED TO
THANK OSCAR AND EMMANUEL WHO DID
A LOT OF THE WORK AND THANK YOU
FOR YOUR KIND ATTENTION.
>> THANK YOU, PETER, FOR KEEPING
ON YOUR TIME AND AN EXCELLENT
TALK.
WE'LL TAKE A BREAK?
SAY THANK YOU FOR THE ORGANIZER
FOR THIS OPPORTUNITY, ESPECIALLY
ARUN FOR INTRODUCING ME TO THIS
COMMUNITY AND I HAVE TO SAY IT'S
A WONDERFUL EXPERIENCE SO FAR TO
LEARN ABOUT THIS FROM THE
PERSPECTIVE OF PATIENTS AND
FAMILY TO THE INITIAL FAMILY.
AS WAS MENTIONED I AM A
BIOLOGIST, SO I JUST SAW MY LAB
ABOUT A YEAR AGO, JUST WANT TO
TELL YOU A LITTLE BIT ABOUT THE
MANY SKILLS BIOLOGISTS HAVE
FOCUSED IN THE LABS WHICH REALLY
TO UNDERSTAND HOW PROTEIN
FUNCTION OR HOW PROTEINS BEHAVE
IN THEIR NATIVE ENVIRONMENT. SO
STRANGER IN THE CELL. SO
HOPEFULLY WE CAN PROVIDE SOME
INFORMATION SPECIAL ABOUT THIS
PROTEINS INVOLVING HSPD HOW THIS
PROTEIN NORMALLY FUNCTIONS
INSIDE THE CELL AND WE CAN START
TO UNDERSTAND HOW THEY'RE
REPAIRED AND HOPEFULLY WE CAN --
THE KNOWLEDGE CAN LATER BE
APPLIED TO DEVELOP SOME
THERAPEUTIC AGENTSME AGENTSMENT. I WANT
TO INTRODUCE YOU HUMAN CELLS ARE
HIGHLY COMPARTMENTALIZED, DATA
INTO THE HUMAN CELLS, LOOKING AT
1.4 CUBIC MICRONS ABOUT 4.1
PERCENT OF CELLS. I HOPE YOU
CAN APPRECIATE THE HUMAN CELLS
ARE REALLY HIGHLY COMPONENT
WHEREAS EACH INDIVIDUALNAL LIS
FROM THE FACTORY THAT HAS HIGHLY
SPECIFIC FUNCTION, AND THIS IS
REALLY THE WHOLE MODEL ALLOW US
FROM SO MANY DIFFERENT OPTIONS,
BUT THIS IS ALSO POSE A VERY
CHALLENGING TO THE CELL HOW
USING A BIT OF RAW MATERIAL AND
HOW DO THEY DISTRIBUTE ALL
DIFFERENT PRODUCTS IN HERE FOR
PERFORMANCE SO THE CELL CAN
FUNCTION AS A UNIT. THIS IS
REALLY -- SO THE QUESTION HOW DO
CELL SOLVE INTER ORGANELLE LODGE
NI
LOGISTIC ISSUES, EVEN IN CELLS
IT'S THE SAME THING IF YOU HAVE
SOME LOGISTICS THAT YOU MIGHT
HAVE SOME DETRIMENTAL TO THE
CELL FUNCTION AND I'M GOING TO
SHARE A STORY INVOLVING THAT YOU
CAN FUNCTION LOGISTIC TO
FACILITATE BETWEEN FACILITY. SO
WHEN I STARTED THIS PROJECT I
WAS VERY VERY INTERESTING THAT
THIS START, BECAUSE IF YOU LOOK
AT TOPOLOGY THIS DOMAIN MEMBER
PROTEIN HAS MEMBRANE ASSOCIATION
TO HAVE HUGE CHUNK OF INTER
GREGS THAT INVOLVE
MICROORGANISM. SO I WAS VERY
NAÏVE IN ASKING THESE QUESTIONS.
TO DO THAT WE ACTUALLY HAVE THIS
PROTE
PROTEIN, AS YOU CAN SEE THE
IMAGE HERE YOU'RE LOOKING AT
M1SPASTIN EXPRESSING, AND THIS
IS AN HELA CELLS, LOCALIZED
MARKERS BOTH IN STEADY STATE AND
IN A STATE TRIGGERED A LITTLE
BIT OF BIOLOGY. SO THE -- SO
REALLY JUST TERMINAL MOTIF
FUNCTIONAL FOR DROPLETS HAVE A
FRAGMENT OF THE PATH THEY ARE
LOCALIZED TO THE FOCALIZED A
LITTLE INTRODUCTION DROPLETS ARE
INSIDE EACH INDIVIDUAL CELLS SO
AS WAS MENTIONED IN THE TALK.
SO AGAIN THIS IS ONLY A
WAREHOUSE SO YOU CAN THINK ABOUT
IT AS A REFRIGERATE NOR YOUR
HOUSE SO YOU KIND OF STORE THE
DROPLETS. SO FOR THE CELLS YOU
USE THIS MATERIAL YOU HAVE
TRAFFIC PROCESSES.
AND WE KNOW THIS TRAFFIC HAS
OCCURRED AT THIS ORGANELLE
COMPACT CITE. ADD 20 NANOS OFF
TO ALLOW THE RECORD AND
EFFICIENT MATERIAL. IT'S BETTER
THAN SITTING BETWEEN THE LIPID
DROPLETS TO FACILITATE THIS
LOGISTICALLY. SO HERE ARE SOME
EVIDENCE: FIRST SO NOW YOU'RE
LOOKING AT A CELL THAT LABELED
LIKE HERE AND HERE AND YOU SEE
THESE ARE THE BASAL INTERACTION
OR BASAL COMPOUND SITUATION
INSIDE THE CELL. AND ONCE WE
OVER EXPRESS YOU CAN START TO
SEE A CLUSTER OF HIGHLY SOC YAW
ACTIVE WITH THE DROPLETS.
SURELY INSIDE OF HERE. I SHOULD
QUANTIFY BY USING, WASN'T
OVERLAPPING, YOU CAN SEE
INCREASE OF THE DROPLETS ACROSS
SOME ASSOCIATION DURING M.
>> CHI-LUN CHANG: SPASTIN.
THIS IS TRADITIONAL IMAGING TO
SHOW THESE TWO ORGANELLES
DROPLET HERE, DROPLET HERE,
FORMING THIS INTER FACE BETWEEN
EACH OTHER SO THIS IS REALLY A
COMPACT WE ALSO MONITOR USING
TIME LAPSE MICROSCOPY TO MONITOR
THE COMPOUND. AS YOU CAN SEE
THIS IS A CONTROL SWACHLTHS SO
YOU CAN SEE THERE ARE COMPOUND
FORMATIONS SHOWN HERE AND HERE.
THIS IS ALSO STABLE COMPOUNDS
LIKE THAT EACH ORGANELLE OVER A
PERIOD OF TIME. AGAIN WE CAN
QUANTIFY THE DURATION HERE AND
THIS IS OVER EXPRESSING CELLS
NOW YOU CAN SEE ALL THIS
ASSOCIATION HIGHLY STABILIZED.
ALSO HOW THEY STAY TOGETHER.
AND WE CAN ALSO USE TO KNOCK
DOWN THIS IMPRESSION AND GET A
REDUCTION. SO THAT FASTING IS A
TYPE FOR LIPID DROPLETS. SO AS
I MENTIONED, SO WE ALSO FURTHER
IDENTIFY A REGION THAT INTERACT
WITH THE PROCESS ON THE
STAFFING, SO WE NAME THIS FOR
INTERA
INTERACTING, SO HERE DUE TO
TIME, TAG THIS PXI REGION,
SIMPLY HELPING A REGION FORM PXI
REGION, THIS IS FAIRLY LOCALIZED
DUE TO THE LIPID DROPLET WHERE
YOU CAN SEE THE ORGANIZATION
HERE IN THIS PROTEIN AND THE
LIPID DROPLET. AND ON LIPID
DROPLET THIS CAN ACTUALLY
ATTRACT OR BIND THROUGH A REGION
NOW YOU CAN SEE THERE'S MANY
MANY ASSOCIATED WITH THE LIPID
DROPLETS. AGAIN THIS IS A -- WE
DO SEE A SIGNIFICANT INDUCTION
OF THIS LIPID DROPLET
OVERLAPPING THIS PXI REGION.
AND WE WONDER ABOUT THE FATTY
ACID IN THESE CELL TWO HIGHLY
RELEVANT FATTY ACIDS BUT TO DO
THAT WE ACTUALLY DIVIDE THE
FATTY ACID WHERE WE JUST LABEL
THE CELL WITH THIS FATTY ACID
AND SHOW MODIFY AND THEN WE
ACTUALLY LOCALIZED TO LIPID
DROPLETS FIRST THEN WASH THIS
INSIDE OUT AND START MONITOR THE
FATE OF THE. THEN HERE IS JUST
WIDESPREAD SHOWING AFTER THE
POST OF THIS MBT FATTY ACID YOU
CAN SEE THE LOCALIZED FATTY ACID
STRUCTURE. AND THIS IS M1
ACTUALLY YOU CAN SEE THERE'S
MANY OF THIS WIDESPREAD HIGHLY
SOC WAITED WITH THIS LIQUID
DROPLETS. SO NOW LOOKING AT ONE
HOUR AFTER THE DIAL STILL YOU
SEE MANY OF THESE STILL REMAIN
INSIDE THE LIPID DROPLETS
LOCALIZED. BUT AFTER TWO HOURS
LATER NOW YOU CAN START TO SEE
THIS FATTY ACID TRAFFIC INSIDE
NOW YOU CAN SEE A LOCALIZATION
OF THE SIGNALS AT THE SAME TIME.
SO WE CAN AGAIN MONITOR OR
QUANTIFY THIS RELATIVELY
INTENSIVELY OF THE FATTY ACID
YOU CAN SEE THE SATURATION YOU
STUDY INCREASE OF THE FATTY ACID
INSIDE BECAUSE COMPARED TO CON
TROLL THERE'S NOT MUCH TRAFFIC.
AND THEN WE -- WE WONDER WHETHER
THIS BEHAVIOR OR THIS LOGISTICS
INVOLVING M1 IS ACTUALLY
RELEVANT TO THE SITUATION. SO I
THINK I'LL INTRODUCE THE MOST
COMMON CAUSE OF THIS MUTANT THE
MUTATION. SO WE ACTUALLY ARE
LOOKING AT A COMPACT FORMATION.
SO YOU CAN SEE THE MUTANT
EXPRESSING CELL MAKING THE
COMPACT, SO THIS IS JUST A
COMMUNICATION HERE YOU SEE THE
SIGNIFICANT DIFFERENCE BETWEEN
THE TWO.
AND ALSO THE FATTY ACID TRAFFIC
IS ALSO YOU CAN SEE THIS JUST
THE DATA IS SHOWN IN THE
PREVIOUS SLIDE AND THE MUTANT IT
COULDN'T REALLY TRAFFIC THE
FATTY ACID FROM THE DROPLETS.
AND HOW IS THIS RELEVANT TO
OTHER THINGS IN THE DEGEN RAGS.
SO WE KNOW FATTY ACID CAN BE
THROUGH ACTIVITIES, SO IT CAN BE
PROACTIVE SO WE'RE LOOK AT WHAT
IS PROJECT TILE FROM THE LIPID
BUILDUP. HERE A FLUORESCENT
ASSAY, SO INVOLVING FATTY OR
CONSTRUCT FROM THE DIVISION YOU
CAN SEE THAT REVIEWS OF THE
BUILDUP OF THE LIPIDS TO A
DEGREE IN THE SAME LINE THAT YOU
CAN ACTUALLY START TO SEE LIPID
DROPLETS COMPACT INCREASE UNDER
THE COMPOSITION SUGGESTING THAT
THIS PLATFORM AND FATTY ACID
TRAFFICKING INVOLVING TO PROTECT
OR ELIMINATE THE LIPID.
AND SO ACTUALLY NOT A SURPRISE
INTRO TUESDAY MUTATION THAT
COULD MAKE THE COMPACT PURSUANT
TO FATTY ACID DROPLETS YOU
UNDERSTAND THEY BUILDUP OF THE
ENVIRONMENT. SO HERE'S WHAT WE
THINK IS GOING ON IS ACTUALLY
SITTING IN BETWEEN INTERFACE OF
LIPID DROPLETS TO FACILITATE
FATTY ACID TRAFFICKING AND SOME
OF THE FATTY ACID GET TRAFFIC TO
GO OUT AND FURTHER DEGRADATION
AND IF YOU HAVE HYPO GENIC
MUTANT WE HAVE THE BUILDUP OF
LIPIDS PROTEINS LIPID DROPLETS
AND LIKELY MAY CAUSE NEURO
STRESS. EMPHASIZE ABOUT
THINKING THEY INVOLVING THE
ORGANELLE BIOLOGY AND INVOLVING
LIPIDS AND FATTY ACID
HOMEOSTASIS HERE JUST A LITTLE
FEW PROTEINS HAVE A LASTING SEEN
THE LIPIDS FATTY ACID HERE ARE
ISSUE TO AND ALSO FASTING AND
PURSUANT TO FATTY ACID
TRAFFICKING TO THE CHROME SOEMS
TO ELIMINATING THE BUILDUP AND
ALSO FACILITATE SO WE HAVE
EVIDENCE TO SUGGEST THAT THE MAY
LIKELY INVOLVE THIS MORE FOE
GENESIS TO SUPPORT FATTY ACID
TRAFFICKING ALSO LIMITED TO
SUPPORT THE IDEA THAT THE DOMAIN
CAN ACTUALLY FORM A COMPILATION
OF THE CULTURE TO EXPOSE THE PXI
REGION FOR -- SORRY -- FOR THE
LIPID DROPLET PROCESS AND
COMPACT. AND IN OTHER FRONTS
ACTUALLY WE ARE DEVELOPING FROM
TOOLS AND ACTUALLY COMPOUND AND
WE WANT TO USE THE HELP US UNDER
STON HOW IT IS RELEVANT TO
PHYSIOLOGY AND HOW THEY'RE
IMPAIRED.
I WANT TO THANK MY PH.D. --
SORRY ADVISOR. SO THIS WORK WAS
DONE IN HER LAB WITH A GROUP OF
MANY PEOPLE. I WANT TO SAY
THANK YOU TO FOR THE MANY
DISCUSSIONS AND I HOPE TO
CONTINUE THE DISCUSSIONS AND TRY
TO MOVE FORWARD TO THE
THERAPEUTICS IN THIS FIELD. AND
ALSO IN RESEARCH PAPERS IN MY
LAB AT SAINT JUDE AND MY TWO
SENIOR PERSONNEL AND ALSO THE
FOUNDING AND THANK YOU I'M
LOOKING FORWARD TO THE Q AND A
SESSION.
>> THANK YOU DR. CHANG. SO OUR
NEXT SPEAKER IS ERIC, DR.
SAMARUT.
>> ERIC SAMARUT: YES, THANK
YOU. I'M SHARING MY SCREEN NOW.
CAN YOU SEE IT HERE?
>> YES.
>> ERIC SAMARUT: GRAY. WELL.
THANK YOU VERY MUCH. SO THANK
YOU FIRST TO INVITING ME. I'M A
SPECIALIST AND I LEARNED A LOT
TODAY AND YESTERDAY AND TODAY
I'M GOING TO SHOW YOU WHAT WE'VE
BEEN DOING IN A COMPANY I
COFOUNDED KOLD MODELIS WHERE
WE'RE PLAYING WITH IN VIVO
BIOLOGY AND DATA SCIENCE AND
TRYING TO IDENTIFY MECHANIC
INSIGHTS AND SPEED UP DRUG
DISCOVERY FOR RARE DISEASES.
AS A FIRST DISCUSSION SLIDE I'M
WEARING MULTIPLE HATS. I'M A
RESEARCHER OUT OF UNIVERSITY OF
MONTREAL. FOCUSSING ON GENOMICS
OF RARE DISORDERS BUT I'M ALSO A
COFOUNDER OF MULTIPLE BIO TEXT
AND I'M GOING TO SHOW YOU THE
WORK THAT WE HAVE BEEN -- WE ARE
DOING AT MODELIS THIS BIOTECH
COMPANY IS REALLY WILLING TO
ACCELERATE DRUG DISCOVERY FOR
FOCUSING ON RARE GENETIC
DISORDERS.
AND SO I'M SURE YOU WON'T LEARN
MUCH FROM THESE SLIDES, BUT YOU
ALL KNOW THAT RARE IS NOT RARE
AND SO THIS IS REALLY THE
PROBLEM THAT WE ARE TRYING TO
TACKLE AT MODELIS IS HOW CAN WE
JUST BRING ANSWERS OR TRY TO --
TO START PROJECTS FOR ALL THESE
ORPHAN RARE DISEASES, SO YOU
KNOW THAT AMONG THE 700 MILLION
PEOPLE WORLD WIDE CONNECTED BY
RARE DISEASES HALF OF THEM ARE
CHILDREN, AND MANY OF THESE
DISEASES ARE REALLY LIFE
THREATENING. AND ONLY FIVE
PERCENT OF THEM HAVE SO-CALLED
TREATMENTS LEAVING 95 PERCENT OF
THESE DISEASES BEHIND AS ORPHAN
RARE DISEASES.
AT MODELIS WHAT WE THINKS IS
IMPAIRING DRUG DEVELOPMENT THE
DISEASES ARE SO RARE SOME ARE
EVEN MORE RARE THAN OTHERS, THAT
WE -- THE FACT THAT WE DON'T
KNOW MUCH ABOUT THE MECHANISM
AND WE DON'T KNOW EXACTLY WHAT
ARE THE UNDERLYING MECHANISM
IMPAIRING DEVELOPMENT TWO WAYS,
FIRST ONE REALLY LEADS TO
FAILURE IN CLINICAL TRIALS
BECAUSE MOST DRUGS THAT DO NOT
MAKE IT THEY FAIL FOR
PHARMACOLOGICAL REASON, THEY DO
NOT FAIL FOR PHARMACOLOGICAL
REASONS BUT EFFICACY REASONS,
THAT CREATES LIMITS IN THE
FIELD. THERE ARE SO MANY
DISEASES WE CAN'T JUST INITIATE
LIKE TARGET-BASED DRUG DISCOVERY
PROGRAM ON THEM.
AT MODELIS WE BELIEVE THAT TO
THE ABILITY TO IDENTIFY DISEASE
RELEVANT MAKE THEM A FACTION
INSTRUMENTAL AND HELP IDENTIFY
BETTER DRUGS FASTER AND IT CAN
ENABLE US TO WORK AND DEVELOP
DRUGS -- DRUG AGREEMENT PROGRAM
FOR DISEASES THAT HAVE BEEN
UNTOUCHED SO FAR.
HOW DO WE DO THIS? YOU SEE WE
WORK EXCLUSIVELY IN VIVO BUT
USING SIMPLE ANIMAL MODELS
BECAUSE WE WANT TO GO FAST AND
I'LL EXPLAIN LATER WHY THEY ARE
INTERESTING.
SO WE WORK WITH MICROSCOPIC
WORMS AND ZEBRA FISH. GENETIC
MODELS OF DISEASES I'LL EXPLAIN
LATER BUT FROM THESE IN VIVO
MODEL WE ACQUIRE DATA AND THEN
WE FEED IMAGINARY ALGORITHM WE
DEVELOPED AT THE COMPANY. THESE
IMAGINARY ALGORITHM MAKE SENSE
ABOUT THESE BIOLOGICAL IN VIVO
DATA. AND THE END HERE IS TO
START TO FIND THE PATH FOR THESE
RARE DISEASES FOR WHICH WE HAVE
NO IDEA WHAT'S GOING WRONG. SO
THE IDEA IS CAN WE IDENTIFY NOT
ONLY MECHANISMS FOR CONFIRM SOME
PREDICTED MECHANISMS AND -- AND
VALIDATE THE FACT THAT THEY ARE
PLAYING AN IMPORTANT ROLE IN THE
ET KNOW GENICIERAL NI -- LET ME PRESENT TH ESE
YOU'VE HEARD ABOUT THEM
MICROSCOPIC WORMS VERY NICE
BECAUSE THEY ARE TINY, SMALL
CHEAP TO HANDLE AND TO RAISE,
AND THEY SHARE QUITE A LOT OF
OUR GENES I'LL GET INTO THAT
LATER WE ALSO WORK WITH ZEBRA
FISH MAYBE MORE POPULAR. SMALL
TROPICAL FISH WE DON'T WORK WITH
ADULTS BUT WORK WITH AGE AND
LARVA AND THEY ARE A CONVENIENT
MODEL BECAUSE THEY ARE
RELATIVELY CHEAP AND YOU CAN DO
A LOT OF THINGS ON THOSE GUYS.
SO AS I SAID THEY ARE EASY TO
HANDLE, MICROSCOPIC HERE ARE A
LOT OF ADULT WORMS IN THERE THAT
YOU CAN'T EVEN SEE WITH YOUR
BARE EYES AND ZEBRA FISH AS I
SAID NOT WORKING WITH ADULT BUT
EMBRYO AND LARVAE BECAUSE THREE
DAY OLD LARVAE IS FUNCTIONAL
MINI ADULT BRAIN MUSCLE
EVERYTHING IS ALREADY
FUNCTIONAL.
AND WHEN YOU LOOK AT THE GENETIC
CONTENT OF THESE GUYS, THAT'S
SURPRISING THAT WE SHARE ABOUT
65 PERCENT OF OTHER GENES WITH
WORMS, 84 WITH FISH AND 90 ISH
WITH RODENTS, BUT WHAT'S
INTERESTING IS THE AMOUNT OF
EGGS THAT THESE GUYS PRODUCE,
YOU CAN HAVE 150 EGGS PER DAY,
200 EGGS PER WEEK FOR FEMALE
FISH WHILE ONLY TEN ISH PUPS FOR
A MOUSE MODEL. SPEED IS HIGH IN
THAT STAGE ALTHOUGH THE
COMPLEXITY IS QUITE LOW COMPARED
TO WORKING WITH MAMMALIAN MODEL.
THAT BRINGS ME TO PRESENT THAT
MODEL ON THAT GRAPH I LIKE THIS
ONE BECAUSE IT'S LIKE PLOTTING
THE HIGH FREQUENCY OF THE
DIFFERENT MODELS WE'RE WORKING
WITH COMPARED TO THEIR
PHYSIOLOGICAL COMPLEXITY SO ON
ONE HAND YOU HAVE THESE IN VITRO
MODELS EXTRAORDINARY MATTER IN
FOR HIGH FRU TOWS STUDIES
PROBLEM WITH BIOLOGICAL
RELEVANCE DEPEND DEPENDING ON
THE DISEASE YOU WANT TO STUDY ON
THE OTHER SIDE YOU HAVE HUMAN
NON HUMAN PRIMATES RODENTS THEY
ARE VALUABLE PHYSIOLOGICALLY
COMPLEX BUT THE MODELS CAN BE
CHALLENGIN
CHALLENGING, YOU SEE ME COMING,
ADDING HERE, PHYSIOLOGICALLY
COMPLEX ENOUGH AND THEY ARE
INTERESTINGLY POSITIONED ON THAT
CRAFT TO BE MODEL TO WORK WITH.
SO THEY ARE ALSO VERY EASY TO
WORK WITH IN TERMS OF GENETIC --
I MEAN THEY ARE VERY ACCESSIBLE
FOR GENETIC STUDIES AND
PHARMACOLOGICAL STUDIES APPLY
ALL THE LATEST TECHNIQUES, SO
WHAT WE ARE DOING WHEN WE
STARTLEA
PROJECT GENERIC MODELS, THESE
MODELS WILL BE CARRYING PATIENT
SPECIFIC MUTATION. THEN WE CAN
CHARACTERIZE THE PHENOTYPE OF
THESE MODELS AND SEE IF ITWORTH
DOING DRUG SCREENING ON THEM.
THAT'S INTERESTING WHEN YOU
CONSIDER 80% OF THE GENES IN
HUMAN THAT ARE AS I SAID
DISEASES THESE 80% OF THESE
GENES ARE IN FISH AND WORM. SO
YOU CAN REALLY MODEL THE BROAD
SPECTRUM OF THE DISORDER GOING
FROM LIKE DEVELOPMENTAL DISEASES
NEUROLOGICAL METABOLISM
DISORDERS CANCER AND AGING. AT
MODELIS OUR MAIN EXPERTISE IS IN
NEUROSCIENCES, SO WE ARE
FOCUSING ON NEUROLOGICAL
DISORDERS AND NEURO METABOLIC
DISORDERS BUT NO LIMIT IN TERMS
OF WHAT KIND OF DISEASES WE
COULD MIMIC THE ONLY LIMITATION
IS THE GENE CONCERNED IN THESE
GUYS HERE.
SO WHAT ARE WE DOING ONCE WE
HAVE LIKE WORM AND FISH MODELS?
WE, AS I SAID, THEY ARE SMALL,
THEY ARE EASY TO WORK WITH. AND
SO WHAT WE CAN DO IS SCREEN THE
EFFECT OF THOUSANDS OF SMALL
MOLECULES ON THEM. SO WHAT WE
DO IS WE JUST TAKE LIKE
COMMERCIALLY AVAILABLE LIBRARIES
OR -- AND/OR SPECIFIC LIBRARIES
FROM PARTNERS THAT WE ESTABLISH,
SO WE -- WE GET ACCESS TO
PRIVATE MOLECULES FROM
PHARMACEUTICAL COMPANIES FOR
EXAMPLE, THEN YOU TEST THE
EFFICACY OF THESE MOLECULES ON A
SPECIFIC PHENOTYPE. YOU START
WITH WORMS BECAUSE THAT'S THE
EASIER TO START WITH. AND THEN
SELECT THE ONE HAVING A POSITIVE
EFFECT ON THESE WORMS AND
CONFIRM EFFECT IN A FISH MODEL
AND THEN GO INTO IPC OR RODENT
MODELS AND WHAT YOU ARE LEFT
WITH AT THE END ARE
INTERESTINGLY LEAD CANDIDATE
LEAD MOLECULES WORKING IN
EVOLUTIONARY DISTANT SPECIES, IF
IT WORKS THERE'S A GREAT CHANCE
IT'S CARVER A MECHANISM
EVOLUTION.
SO THESE LEADS ARE INTERESTING
ON THEIR OWN BECAUSE IF THESE
DRUGS ARE REPRODUCIBLE WE CAN
THINK ABOUT DOING DRUG
REPURPOSING AND MOVING FORWARD
INTO THE CLINIC WITH THESE
DRUGS.
BUT WE BELIEVE THAT THE MAIN
VALUE OF THIS SCREENING APPROACH
IS TO STUDY THIS IN VIVO DATA.
SO WHAT WE HAVE BEEN DEVELOPING
IS AN AI MACHINE LEARNING
APPROACH TO TRY TO MAKE SENSE
OUT OF THESE IN VIVO DATA. WE
HAVE SO MUCH DATA ABOUT THE
EFFECT OF INDIVIDUAL SMALL
MOLECULE THAT WE BELIEVE THERE
IS SOMETHING WE CAN DO HERE. SO
IF WE SEE THAT FROM A DIFFERENT
ANGLE AS I SAID THE FIRST STEP
IS GENERIC MODEL TO GENERIC DATA
COMPILE THEM SO FOR THAT WE ARE
INTEGRATING OUR DATA ACQUIRED IN
OUR MODEL BUT WE ALSO GETTING
ANY PUBLICLY AVAILABLE DATABASES
IF AVAILABLE FOR THESE DISEASE.
AND THEN THE NEXT BIG STEP IS
INTEGRATE THAT INTO A COMPUTER
AND MACHINERY ALGORITHM. SO
WHAT THE COMPUTER IS BASICALLY
DOING IS LOOK AT ALL THE
MOLECULE AND THE EFFECT ON A
SPECIFIC PHENOTYPE AND BY
PREDICTING THE MOLECULAR TARGETS
OF EACH OF THOSE MOLECULE CAN
BUILD A MAP RESEMBLE A 3D BAR
CODE I'LL SHOW YOU ONE LATER
CREATES A 3D BAR CODE THAT SHOWS
ALL THE TARGETS ARE PARTICULARLY
ENRICHED FROM A PARTICULAR
DISEASE. THESE TARGET
ENRICHMENT CLUSTERS YOU CAN
PREDICT SPECIFIC PATHWAYS AND
THESE PATHWAYS CAN BE SEEN AS
DISEASE INSIDES MEANS THESE
PATHWAYS ARE IMPORTANT FOR THE
DISEASE BECAUSE IF YOU MODULATE
THEM WITH DIFFERENT MOLECULES
IT'S HAVING AN EFFECT ON THE
PHENOTYPE.
SO ONCE WE HAVE THESE DISEASE
INSIGHTS IDENTIFIED WE CAN JUST
VALIDATE THEM PHARMACOLOGICALLY
AND GENETICALLY IN OUR MODEL AND
ONCE YOU CONFIRM THERE IS AN
INTERESTING NEW MECHANISM THAT
IS IMPORTANT FOR THE DISEASE YOU
CAN INITIATE THE DEVELOPMENT,
STRATEGIES SO AS I SAID IT COULD
BE DRUG REPURPOSING IF YOU HAVE
AN INTERESTING DRUG THAT EFFECTS
THESE PATHWAYS BUT YOU CAN THINK
ABOUT LIKE PERSON THERAPIES THAT
CAN BE SMALL MOLECULE FOR ASO OR
ANYTHING.
BUT THE BEAUTY OF THIS MODEL
LIKE A WILL SELF FED PLATFORM.
THESE DATA THAT FEED THE MODEL
FEED THE SOFTWARE, AND THAT THE
ALGORITHM IS GETTING EVEN MORE
ROBUST AT PREDICTING MECHANISM.
SO YOU REALLY HAVE LIKE A SNOW
BALL THAT IS GETTING FOREIGN AND
THAT YOUR MODEL IS GETTING
STRONGER AND STRONGER WITH THE
MODEL THAT YOU GENERATE.
SO WITH THOSE WE HAVE SORRY
DIFFERENT DRUG DISCOVERY
PROGRAMS, DIFFERENT STAGE, THE
ONE I'M GOING TO FOCUS ON
OBVIOUSLY TODAY ARE SPG4 PROGRAM
AS YOU SEE IT'S QUITE EARLY SO I
DON'T HAVE MUCH TO SHOW YOU BUT
I WILL SHOW YOU WHAT WE HAVE SO
FAR.
JUST TO SHOW YOU AN EXAMPLE OF
THE 3D BAR CODE THESE ARE THE
MAP THAT OUR MACHINE LEARNING
APPROACH IS GIVING. SO HERE YOU
HAVE ALL THE PREDICTIVE TARGETS
OF MOLECULE THAT IS HAVING A
POSITIVE OR NEGATIVE EFFECT ON
THE WORM PHENOTYPE AND THE
SOFTWARE IS TRYING TO PLOT THESE
TARGETS AGAINST THEMSELVES AND
SO YOU SEE THESE ENRICHMENT,
THESE SMALL LIKE HIGHLIGHTED
SQUARES THAT GETS FORMED AMONG
ALL THOSE TARGETS AND WHEN YOU
LOOK INTO A SPECIFIC SOME OF
THESE CLUSTERS YOU CAN SEE
PATHWAY ENRICHMENT. AND FOR
EXAMPLE IN THE CONTEXT OF
HUNTING TON WE IDENTIFY ONE
PATHWAY IN THE CONTEXT OF
HUNTINGTON I CAN DISCLOSE IT
HERE BUT YOU CAN TEST THE
EFFICACY OF THESE MOLECULES ON
MULTIPLE COMPLIMENTARY
PHENOTYPES. AS YOU SEE THE
NEURO PATHWAY OF THESE DISEASE
IS PERFORMING EVEN WELL AND
BETTER THAN SOME WELL KNOWN DRUG
THAT ARE CURRENTLY UNDER
CLINICAL TRIAL FOR HUNTINGTON.
A VALIDATION FOR THIS APPROACH
MAKES SENSE AND REUNRAVEL LIKE
NOVEL DISEASE INSIGHTS FOR
DISORDERS FOR WHICH THE
MECHANICS THE PATHOGENIC
MECHANICS NOT COMPLETELY
UNDERSTOOD UNBUYSED AND BIASED
APPROACH TO A.
LET ME JUMP INTO SPG4 COMPLEX AT
MODELIS THIS YOUNG LADY LIVING
IN FRANCE BEEN IN A WHEELCHAIR
SINCE HER YOUNG AGE. HER
PARENTS STARTED AN ASSOCIATION A
FOUNDATION CALLED ENORVV
CLINICALLY DIAGNOSED WITH
CEREBRAL PALSY, ALL THE TESTS
CAME BACK NEGATIVE, NO ANSWERS,
WE MET WITH THIS FAMILY AND WE
THOUGHT THAT WE SHOULD START A
PROJECT TRYING TO IDENTIFY NEW
VARIANT, NEW GENE BECAUSE
APPARENTLY SHE DIDN'T HAVE LIKE
A KNOWN GENE THAT WAS CAUSING
HSP. SO WE SENT THEM SWABS AND
THAT WAS PRE COVID SO SHE DIDN'T
KNOW THAT SHE WOULD QUICKLY KNOW
WHAT A SWAB IS, SO SHE SWABBED
AND WE DID SEQUENCING ON THE
TRIO AND WE DIDN'T HAVE TO DIG
MUCH FURTHER BECAUSE ACTUALLY WE
IDENTIFIED A WELL KNOWN PATH JOE
ANYONE NICK MUTATION IN R499H,
DOMINANT KNOWN TO BE CAUSING
SPG4. SO AS SPG4 SHE COULD PUT
A WORD ON THE DISEASE.
SO WE WORKED WITH THE PARENTS
AND THE FOUNDATION AND FAMILY TO
REALLY LIKE START A PROJECT
ON -- ON TRYING TO INITIATE A
PROJECT ON DRUG DISCOVERY AT
MODELIS ON SPG4 WE WORKED WITH
PROFESSIONALS TO DO A NICE STORY
TELLING, BECAUSE THIS NEW
DIAGNOSIS WAS A SPRING BOARD FOR
THE FAMILY. AND SO WE TRY TO
CLEARLY EXPLAIN WHAT WE WERE
WILLING TO DO USING FISHES AND
DRUG REPURPOSING AND IDENTIFY
THE DRUGS AND MAKING WORM AND
FISH SWIM BETTER. AND WE RAISED
A SIGNIFICANT AMOUNT OF MONEY
THAT ALLOWED US TO START THE
PROJECT. AND I'M ALWAYS AMAZED
ABOUT HOW DYNAMIC THESE FAMILIES
ARE AND TO SEE ALL THE EFFORTS
THEY ARE PUTTING IN, THEY'RE
REALLY, LIKE, SCIENTISTS. SO
WHAT WE STARTED WITH IS THE
GENERIC WORM MODELS AND WE
DECIDED TO DO TWO DIFFERENT WORM
MODELS, ONE WOULD BE A FULL GENE
DILUTION, AND THE OTHER ONE
WOULD MIMIC THE MUTATION THAT IS
AT POSITION 396 IN WORM BUT AS
YOU MIGHT NOT BE ABLE TO SEE ON
THIS ALIGNMENT THIS AMINO ACID
IS WELL CONSERVED IN FISH AND
WORM. SO WE DECIDED TO MIMIC
EXACTLY THE MUTATION IN A WORM
STRING. WHAT'S GREAT USING
MIMICS IS YOU HAVE A LIBRARY OF
CODES. THIS CHRISTMAS TREE HERE
YOU HAVE MIMICODES THAT CAN BE
VERY NICE FOR DOING LIKE THE
FUNCTIONAL STUDIES.
SO WE DID THESE MODELS AND THE
FIRST THING WE CHECKED SO AT
MODELIS WE HAVE ACCESS TO
SOFTWARE, DEVICES, ANYTHING THAT
CAN REALLY SCAN THE MORPHOLOGY
THE SHAPE EVERYTHING OF WORMS
YOU SEE LIKE GENETICALLY
TRACKED, IT'S BASICALLY WHEN YOU
CROSS THE SECURITY IN THE
AIRPORT AND YOU SCAN AND WE SEE
YOU NAKED THAT'S THE SAME THING
WE SEE EVERYTHING ON THESE GUYS.
THE FIRST THING WE REALIZE WHEN
LOOKING AT THEIR SIZE A DAY ONE
OF ADULT HOOD YOU DON'T SEE MUCH
OF A DIFFERENCE BUT THEN THEY
DON'T GROW AS GOOD AS THE DAY
ONE AND TWO, YOU SEE THE BODY IS
SIGNIFICANTLY SMALLER THAN THE
SIBLINGS, AND THESE DIFFERENCE
INCREASES WITH AGE. SO THAT'S
INTERESTING BECAUSE WE OBSERVE
THESE KIND OF BODY SIZE
REDUCTION IN AUTO SPASTIC
SYNDROMES WHERE IT'S AFFECTING
THE MUSCLE AND THE SPASTICITY IN
THE MUSCLE CAN MAKE THE MUSCLE
SHRINK AND THE WHOLE BODY NOT
GROWING AS IT SHOULD AND IT'S
SHRINKING, THAT'S THE FIRST
INDICATION THAT WE POTENTIALLY
HAD SOME INTERESTING HERE.
THE SECOND THING YOU WANTS TO
CHECK WHEN YOU WORK WITH MIM I
CANODES IS THE LIFE SPAN, ABOUT
30 DAYS AS YOU CAN SEE HERE IN
BLACK THESE GUYS THEY START TO
DIE AND THEY HAVE LIKE YOU HAVE
ONLY 50 PERCENT SURVIVAL ABOUT
20, 22 DAYS OF LIFE. BUT WHEN
WE LOOK AT THE LIFE SPAN OF THE
MUTATION OR POINT MUTATION HERE
YOU SEE THE MUTANT WORMS THEY
START TO DIE EARLIER, AND YOU
HAVE ABOUT 50% OF SURVIVAL AT
DAY 14.
SO THAT WAS ALSO AN INDICATION
THAT SOMETHING IS GOING WRONG IN
THOSE -- IN THOSE ANIMALS.
THE NEXT THING WE WANTED TO
CHECK IS HOW WERE THEY AGING?
WE KNOW HSP ARE AGE AGAIN DENT
AND PROGRESSIVE DISORDERS SO WE
WANTED TO SEE HOW THEY WERE
AGEING AND WHAT YOU NEED TO KNOW
IS THAT WORMS WHEN THEY AGE THEY
GET AS -- AS HUMAN THEY GET MORE
AND MORE -- LESS NIMBLE AND THEY
GET ULTIMATELY PARALYZED.
SO WHAT WE DO IS WE POKE A
LITTLE MIMIC TODAY AND SEE IF
IT'S REACTING AND MOVING AWAY
FROM THIS IF YOU DO THIS ON AN
OLD WORM THESE GUYS CANNOT MOVE
AWAY. THEY ARE NOT DEAD BECAUSE
IF YOU ZOOM IN YOU CAN SEE THE
IT'S STILL PUMPING, TOO OLD TO
MOVE AWAY SO KIND OF PARALYZED.
SO IF YOU QUANTIFY THE AMOUNT OF
PERCENTAGE OF WORM THAT GETS
PARALYZED OVER TIME YOU SEE THAT
FOR WILD TYPE HERE IN BLACK AT
12 DAYS OF ADULT HOODS
APPROXIMATELY HALF OF THEIR LIFE
YOU HAVE ABOUT 30% OF WORMS THAT
GET PARALYZED. BUT THIS AMOUNT
IS GOING UP TO 50 OR 60% FOR THE
MUTANT WORM SO THAT WAS AGAIN
ONE MORE SIGN THAT THESE WORM
ARE NOT IN GOOD SHAPE.
SO SORRY I GET BACK TO THE
PREVIOUS SLIDE THAT'S A
PHENOTYPE THAT'S INTERESTING BUT
HERE WE'RE LOOKING 12 DAYS AFTER
GETTING ADULT WORM AND THAT'S
TOO LONG TO DO DRUG SCREENING,
TOO LONG FOR US. WHAT WE WOULD
LIKE IS GET A VERY ACUTE AND
FAST PHENOTYPE. AND ACTUALLY
WHAT HAS DEVELOPED IN WORMS
THESE GUYS NORMALLY CRAWL ON
SOLID SURFACES BUT IF YOU PUT
THEM IN LIQUID CULTURE THEY TRY
TO SWIM AS YOU CAN SEE HERE.
THAT'S NOT THEIR NATURAL
BEHAVIOR THEY ARE SWIMMERS BUT
THEY DON'T LIKE TO DO THAT FOR
HOURSMENT BUT WE REALIZED IF YOU
PUT WORMS IN A LIQUID CULTURE
WELL LIKE THIS IF THESE WORMS
SHOW A PROBLEM OF MOTILITY
DEFECTS THIS DEFECT WILL BE SEEN
VERY QUICKLY BECAUSE THIS KIND
OF BEHAVIOR IS VERY ENERGY
CONSUMING. SO A PROGRESSIVE
PHENOTYPE THAT MIGHT TAKE DAYS
TO ALTER ON A PLATE ON WHICH
THEY ARE USUALLY CRAWLING AND
WITHIN MINUTES OR HOURS ON
LIQUID CULTURE. THIS IS WHAT WE
SAW. YOU CAN SEE GRAPHIC IN
DAYS BUT IN MINUTES. IF YOU
FOLLOW HOW THEY WERE SWIMMING OR
TRYING TO SWIM OVER 10 HOURS WE
SEE THAT THE WILD TYPE WORMS GET
A LITTLE BIT EXHAUSTED BUT THEY
SURVIVE. BUT YOU SEE THE
DECREASE AND THE SIGNIFICANT
REDUCTION IN THE MOTILITY OF
THESE WORMS WHEN THEY ARE ON
LIQUID CULTURE AND YOU SEE THE
DECREASE THAT WE SEE THAT THESE
GUYS ARE GETTING EXHAUSTED
FASTER THAN THE OTHERS AND SWIM
MUCH SLOWER THAN THEIR WILD TYPE
CONTROLS.
SO THIS IS A VERY INTERESTING
PHENOTYPE BECAUSE THIS IS FAST
AND THIS CAN BE PERFORMED ON 96
WELL PLATES SO MEANS THAT YOU
CAN JUST TEST THE EFFECT OF
DIFFERENT TREATMENT VERY QUICKLY
TO SEE IF IT'S HELPING THE WORMS
TO SWIM BETTER, BASICALLY.
AND TO BE SURE THAT THE
PHENOTYPE WAS SPECIFIC TO A
SPASTIC-RELATED SYNDROME WE
DECIDED TO TREAT -- SORRY -- WE
LOOKED AT THEIR MUSCLE HEALTH.
SO WE HAVE SOME TRANSGENIC WORM
STRAIN THAT EXPRESSED INTO MYO
GENERAL FIBERS AND YOU CAN
QUANTIFY QUALIFY MUSCLE AS LOW
DEFECTS, GOOD LOOKING YOU SEE
YOU HAVE A SMOOTH ORGANIZATION
OF THE DIFFERENT MUSCLE FIBERS
OR YOU CAN START TO SEE SOME
DEFECTS WITH LIKE THESE KIND OF
HOLES OR CLUSTERS OF FIBERS
TOGETHER AND WHEN WE LOOKED AT
HOW THE MUSCLE LOOKING IN OUR
WORM POPULATION WAS NOT A
DRASTIC PHENOTYPE BUT SAW
SIGNIFICANCE ON THE FIRST DAY OF
ADULT HOOD WHERE YOU HAD LESS
GOOD LOOKING MUSCLE FIBERS IN
THE POINT MUTATION, NOT
SIGNIFICANT IN THE KNOCK OUT
THAT COULD BE INTERESTING BUT A
TREND LIKE HAVING NOT HEALTHY
MUSCLE AND THAT'S AGAIN RELEVANT
IN A CONTEXT OF A SPASTIC
DISORDER.
TO BE SURE THIS PHENOTYPE WAS
RELATED TO SPASTICITY WE DECIDE
OD TO TREAT SWIMMING WORMS WITH
BACLOFEN, THE REDUCTION OF
MOTILITY THAT WE ARE SEEING IN
OUR FEN KNOW TYPE I JUST SHOWED
YOU, THIS LOOKS SPECIFIC TO A
SPASTIC PROBLEM IF YOU GIVE THEM
A MUSCLE RELAXANT THEY SWIM
BETTER.
THIS IS WHERE WE ARE AND I'M
SORRY I CANNOT SHOW YOU MORE
BECAUSE WE DON'T HAVE MORE AS I
SAID WE STARTED A LONG TIME AGO
SO WE ARE AT THAT STAGE AND WE
CAN'T WAIT TO GET THE FINAL --
FINAL DRAWING. SO SOON ENOUGH
WE'LL HAVE ALL THE DATA.
SO WE HAD ALL THE SCREENING WITH
45,000 MOLECULES I TALKED TO YOU
ABOUT WE HAVE DONE ABOUT 1/3 OF
THIS ONCE WE HAVE ALL THE DATA
WE FEED THE MACHINE WITH THIS
AND HOPEFULLY GET A NICE 3D BIO
CODE POTENTIALLY NEW MECHANISMS
THAT WE MIGHT IDENTIFY.
SO THAT'S IT FOR ME. I WILL
THANKS OBVIOUSLY EVERYBODY AT
MODELIS ESPECIALLY SARAH LEADING
THE HPP PROGRAM, AND WE'VE BEEN
WORKING VERY INTERESTING
COLLABORATIVE PROJECT WE'VE BEEN
DOING WITH THE FAMILY THEMSELVES
AND PRESIDENT PEOPLE AT THE
UNIVERSITY HELPED IDENTIFYING
THE MUTE TAGS IN THE GENOME AND
THANK YOU VERY MUCH I'M WAITING
FOR THE ROUND TABLE FOR ASKING
QUESTIONS I GUESS FOR ANSWERING
QUESTIONS.
>> THANK YOU VERY MUCH. BACK TO
YOU.
>> THANK YOU VERY MUCH FOR A
WONDERFUL SESSION. SO WE'RE
GOING TO MOVE INTO THE LAST
SYMPOSIUM ON THERAPEUTICS AND
THREE EXCELLENT SPEAKERS AND
THEN Q AND A AND DISCUSSION FOR
THE WHOLE PANEL.
SO THE FIRST SPEAKER WILL BE DR.
KATHARINE ALTER WHO YOU MET
YESTERDAY FOR THOSE WHO WERE ON.
THOSE ARE NEW TODAY BOARD
CERTIFIED IN PEDIATRICS AND
NEURO MUSCULAR MEDICINE MEDICAL
DIRECTOR OF THE NIH REHAB
MEDICINE SHE HAS PARTICULAR
EXPERTISE IN CEREBRAL PALSY PASS
STICK OUTCOME MEASURES FOR A LOT
OF THE CLINICAL TRIALS CLINICAL
THERAPEUTIC TRIALS FOR RARE
DISEASE AT NIH AND SHE HAS SEEN
MANY OF THESE PATIENTS.
NEXT SPEAKER WILL BE MIGUEL
ESTEVESING AND HE IS IT A SOC
PROFESSORS HE RECEIVED HIS PH.D.
FROM THE UNIVERSITY OF PORT TOW
IN PORTUGAL WHERE HE STARTED HIS
WORK IN GENE THERAPY.
MASSACHUSETTS MEDICAL SCHOOL
FOCUSES ON DEVELOPMENT OF
LIPOSOME MAL STORAGE DISEASES,
HUNTINGTON'S DISEASE. ALS,
BRAIN TUMORS, NOVEL AV CAP LETS
ON TARGET TISSUES IN THESE
DISEASES WITH A PARTICULAR FOCUS
ON THE CNS. HE LEADS THE GENE
THERAPY CONSORTIUM WITH A
FOCUSED TO DEVELOP GENE THERAPY.
HE'S ALSO PART OF THE CLINICAL
TRIAL THAT DR. TIP SPOKE ABOUT
YESTERDAY FOR GN1 AND ALSO DOING
WORK ON SPG4 AND FINAL SPEAKER
IS DR. JAHANNAZ DASTGIR DID HER
PEDIATRIC TRAINING AT BOSTON'S
CHILDREN'S HOSPITAL. AT
MASSACHUSETTS GENERAL HOSPITAL
AT HARVARD CAME TO NIH TO DO AN
ADDITIONAL FELLOWSHIP IN RARE
NEURO MUSCULAR DISEASES IN
CHILDHOOD SECTION. SHE THEN
WENT TO COLUMBIA, WHERE SHE WAS
PROFESSOR FOR A FEW YEARS AND
NOW AT CHILDREN'S HOSPITAL IN
NEW JERSEY WHERE SHE DIRECTS THE
MUSCULAR DYSTROPHY CLINIC AND
PEDIATRIC NEURO MUSCULAR PROGRAM
AND EXPERTISE IN GENE THERAPY
FOR MANY SMA PATIENTS SHE TREATS
AND RECENTLY HAS MOVED TO
APPLIED THERAPEUTICS WHERE
MEDICAL DIRECTOR OF THE
DEFICIENCY SO GREAT PERSPECTIVE
ON RARE DISEASES FROM A
CLINICIAN PERSPECTIVE ALSO FROM
A PHARMACEUTICAL PERSPECTIVE.
WE THANK EVERYBODY N ON THE
PANEL AND WILL START WITH DR.
ALTER. DR. ALTER I THINK YOU'RE
MUTED.
>> KATHARINE ALTER: SORRY ARYAN
I HAD TO RESHARE. CAN YOU HEAR
ME NOW?
>> YES AND IF YOU DON'T MIND
PUTTING YOUR SLIDES IN? THANKS.
>> KATHARINE ALTER: THERE WE IT
GO. SORRY ABOUT THAT I'M ZOOMED
CHALLENGED LIKE SOME OTHER
CLINICIANS. I'M GOING TO BE
COVERING SWITCHING GEARS HERE A
LITTLE BIT FROM THE PHYSIOLOGY
AND GENETICS REALM INTO THE
CLINICAL REALM AND I'M PRIMARILY
A CLINICIAN WHO BACKED INTO
RESEARCH AND AM FULL TIME DOING
RESEARCH AT NIH NOW AND TALKING
ABOUT REHABILITATION CARE FOR
CHILDREN WITH HSP BUT REALLY
WANT TO TALK MORE
PHILOSOPHICALLY THAN ABOUT
INDIVIDUALIZED TREATMENT WHICH
YOU'LL UNDERSTAND MORE WHEN I GO
THROUGH MY TALK. I HAVE NO
DISCLOSURES, AND MY TALK WILL
PROBABLY -- I'M GOING TO TALK
ABOUT DIMENSIONS OF DISABILITY
AND THE IMPORTANCE OF
STANDARDIZED IN OUR ASSESSMENTS
AND COMMUNICATION TO TALK ABOUT
THE CURRENT EVIDENCE FOR
REHABILITATION THERAPY AND HOW
WE OPTIMIZE THE TREATMENT BOTH
FOR CLINICAL CARE AND GOING
FORWARD WITH RESEARCH.
ONE OF THE FOCUSES I GUESS I
SHOULD SAY IS FROM A
REHABILITATION PERSPECTIVE THAT
WE ALWAYS FOCUS ON A CHILD'S
ABILITY NOT DISABILITY. AND TRY
TO GIVE A CHILD INTER PENS IN
WHATEVER WAY WE CAN REGARDLESS
OF IMPAIRMENT.
MOST OF THE TALKS THAT HAVE GONE
BEFORE ME TALKING ABOUT
PATHOPHYSIOLOGY GENETICS AND
EMPATHY MODELMENT GOING TO SHIFT
GEARS TALKING ABOUT IMPAIRMENTS
PROBLEMS OF BODY STRUCTURE AND
FUNCTION CAUSED BY A CHANGE IN
PATHOPHYSIOLOGY AND MY PRIMARY
INTEREST IS TREATING IMPAIRMENTS
TO IMPROVE A CHILD'S ANNE
ABILITY TO FUNCTION AND THEIR
ACTIVITY LEVEL AND THEIR ABILITY
TO PARTICIPATE IN THEIR
COMMUNITY. BUT THERE'S ALSO A
NUMBER OF ENVIRONMENTAL FACTORS
AND PERSONAL FACTORS AND WE HAVE
TO DECIDE WHICH OF THESE TO
DEVELOP REHABILITATION WHICH OF
THESE ARE YOU TREATING. BECAUSE
WE'RE NOT JUST TREATING BODY
STRUCTURE AND FUNCTION ON ITS
OWN BUT FOR A PURPOSE TO IMPROVE
PATIENT FUNCTION.
WHEN WE TALK SPECIFICALLY ABOUT
UPPER MOTOR NEURON SYNDROMES IN
CHILDHOOD WE STILL HAVE A
VARIETY IMPAIRMENTS INCLUDING
POSITIVE AND NEGATIVE YOU CAN
LOOK AT THIS AS A GAIN OR LOSS
OF FUNCTION IN THIS REALM AS
WELL AS FAR AS IMPAIRMENT AND
THE THINGS WE SEE AND PATIENTS
SEE AND THERAPISTS OFTEN SEE
MOST -- MOST EASILY ARE THE
POSITIVE OR GAIN IN FUNCTION
ABNORMAL REFLEXES, BUT ALSO JUST
AS EQUALLY IMPORTANT ARE
NEGATIVE SIGNS AND SYMPTOMS OR
THE LOSS OF FUNCTION, INCLUDING
LOSS OF SELECTIVE MOTOR CONTROL,
WEAKNESS OR HYPO TONE YAW AND
SENSORY DEFICITS, REALLY THE
COMBINATION OF ALL THESE
IMPAIRMENTS THAT LEAD TO NOT
ONLY THE PATIENT'S FUNCTIONAL
LIMITATION BUT ALSO FOR CHILDREN
WHO ARE STILL GROWING AND
DEVELOPING INTO SECONDARY
IMPAIRMENT SUCH AS MUSCULAR
SKELETAL DISEASE AND
CONTRACTURES AND JOINT
DISLOCATION.
WHEN DEVELOPING A TREATMENT PLAN
WE ALWAYS HAVE TO START WITH
WHAT'S MOST IMPORTANT. AND
REALLY WHAT'S MOST IMPORTANT IS
THAT WE RECOGNIZE THE -- THAT
THESE PATIENTS HAVE MULTIPLE
IMPAIRMENTS NOT JUST SPASTICITY
AND SIGNIFICANT FUNGICIDE
VARIABILITY IN WHAT YOU SEE WITH
THESE IMPAIRMENTS AND THE
IMPAIRMENTS ARE AFFECT ALL
DOMAINS OF A PATIENT'S FUNCTION
SO IF YOU CHOOSE A TREATMENT FOR
AN IMPAIRMENT THAT REALLY ISN'T
CAUSE AGO PROBLEM FOR THAT
PATIENT OR A FUNCTIONAL GOAL
THAT REALLY ISN'T ACHIEVABLE FOR
THE PATIENT YOUR THERAPY IS
GOING TO FAIL.
SO YOU REALLY NEED TO CORRECTLY
IDENTIFY THE IMPAIRMENT, MEASURE
THE IMPAIRMENTS AND WHAT ARE THE
FUNCTIONAL GOALS FOR
REHABILITATION PROGRAM AND SET
REALISTIC GOALS FOR A PATIENT
FOR THERAPY TO REALLY SUCCEED.
SO TO BEGIN WITH AND I KNOW THIS
IS MENTIONED IN PREVIOUS TALKS
YESTERDAY, THAT TO START OFF WE
ALL NEED TO TALK AND COMMUNICATE
WITH ONE ANOTHER, AND WE NEED TO
USE THE SAME LANGUAGE.
AND PART OF THIS IS CORRECTLY
IDENTIFYING MEASURING AT THE
IMPAIRMENT LEVEL AND THEN
IDENTIFYING WHAT THE PATIENT'S
FUNCTIONAL LIMITATIONS ARE, ONE
OF THE THINGS I'M WORKING ON,
INCLUDING IN TRIALS WITH DR.
TIFTON AND OTHER CLINICS
RESEARCHERS THAT NIH ARE
ESTABLISHING QUANTITATIVE
BIOMARKERS WE CAN USE FOR
CLINICAL RESEARCH. INCLUDING
QUANTITATIVE MARKERS IN THE
REHABILITATION REALM.
THIS IS GOING TO HELP US IN THE
FUTURE DETERMINE WHICH
TREATMENTS ARE MOST EFFECTIVE
AND WHICH CAN BE -- WHICH
TREATMENTS CAN BE USED AND THEN
MARKETED I GUESS IN A PATIENT
SENSE FOR RESEARCH.
WE CAN MEASURE RESPONSE TO
TREATMENT MORE EASILY IF WE'RE
QUANTITATING THE EFFECTS OF THE
TREATMENT. AND I'M GOING TO
START BRIEFLY GOING BACK TO THE
IMPAIRMENT LEVEL BECAUSE I WANT
TO MAKE SURE WE'RE ALL USING THE
SAME LANGUAGE IF PASS CITIES
CITY YOU FEEL IT A BIT BUT MORE
RAPIDLY YOU MOVE THE LIMB IT'S
IMPORTANT YOU EXAMINE THE
PATIENT CORRECTLY IN THE CORRECT
POSITION IN TERMS FOR THE
QUADRICEPSES A POSITION PATIENT
PRONE ALWAYS USED FOR CLINICAL
TRIALS OR THERAPY BECAUSE IT'S
MANDATED BY THE FDA IS MODIFIED
OR STANDARD ASHWORTH SKILL.
DOESN'T USUALLY MEASURE PASS
CITIES CITY ONLY PERFORMED AT
ONE SPEED THE SPEED OF THE LIMB
FALLING THROUGH GRAVITY WHICH IS
NOT FAST. AND SO IT MEASURES
NOT ONLY POTENTIAL SPAS CITIES
FESS ELEMENTS OF THE MUSCLE. A
MORE SPECIFIC MEASURE IS
MODIFIED SCALE. EXAM HERE SEE
THIS SPASTIC CATCH WHEN I
RAPIDLY FLEX THE KNEE AT ABOUT
20 DEGREES THIS PATIENT HAS AN
R1 AT ABOUT 20 DEGREES. BECAUSE
OF SPASTICITY. SO THE TARDU
SCALE WHEN COMMUNICATING ONE
ANOTHER ABOUT SPASTICITY A MORE
SPECIFIC MEASURE OF SPASTICITY
THAN THE ASHER SCALE AND IF
WE'RE LOOKING FOR OTHER
IMPAIRMENTS MOTOR IMPAIRMENTS IN
MOVEMENT DISORDERS HYPER 20
ASSESSMENT TOOL IS A GREAT
DISCRIM NAH ACTIVE SCALE THAT
CAN HELP US IDENTIFY OTHER
MOVEMENT DISORDERS THAT MAY BE
PRESENT IN PATIENTS WITH HSP BUT
YOU WON'T SEE UNLESS YOU LOOK
FOR THEM. GIVING A SHOUT OUT TO
THE TOOLS WHEN WE TALK ABOUT
SPASTICITY EVERYONE'S CONCERNED
ABOUT THE NEGATIVE IMPACT SPAS
CITIES STEE. AQUINAS FEET BUT
SPASTICITY HAS POSITIVE BENEFITS
HELPS MAINTAIN MUSCLE TONE
CIRCULATORY FUNCTION TO PREVENT
DVT. S AND ASSIST FUNCTION.
PATIENT WITH CEREBRAL PALSY MAY
NOT LOOK LIKE IT HYPER FLEX YAW
AND SPASTICITY BUT PRIMARY
IMPAIRMENT HYPERTONIA. THE
TREATMENT IS VERY DIFFERENT. IF
YOU IDENTIFY THE IMPROVEMENT
IMPACT OF IMPAIRMENT ANDISM IN
CHILDREN YOU MAY DEVELOP THE
WRONG TREATMENT FOR THAT
PATIENT.
WHEN WE LOOK AT REHABILITATION
WE SEE OUR THERAPIES ARE
ADDRESSING PRIMARILY THE
IMPAIRMENT LEVEL WE'RE LOOKING
AT ACTIVITY BASED THERAPY
STRENGTHENING, MEDICAL SIDE
SPASTICITY MANAGEMENT ON THE
POSITIVE SIDE. REMEMBER OUR
FUNCTIONAL GOALS FOR TREATING
IMPAIRMENTS ARE IN THESE OTHER
REALMS, SO I'M TRYING TO
SEPARATE OUT OR SHOW THAT YOU
KNOW ALTHOUGH WE'RE LOOKING AT
IMPAIRMENT THAT THE GOAL REALLY
IS FUNCTIONAL INDEPENDENT AND
ADDRESSING THESE THROUGH
THERAPEUTIC WHATEVER MODALITIES
THAT WE CAN ACHIEVE IT'S FOR AN
INDIVIDUAL PATIENT.
AND IN -- WE'VE GOT MANY REALMS
THAT REHABILITATION OCCURS IN
NOT JUST IN A CENTER BUT IN THE
CENTER THE BAG OF CONTRIBUTION
INCLUDE STRENGTHENING FOREST
ACCEPT ACTIVE TREATMENT TO WORK
ON STRENGTH AND BALANCE MOBILITY
TRAINING AND FEEDING THERAPIES,
MOTOR TORE, WE ALSO HAVE
REHABILITATION TO SUPPORT
PATIENT FUNCTION IN RESEARCH
CLINICAL REALM COMMUNICATION
DIFFICULTIES. USING MEDICATION
TO IMPROVE ABILITY TO
COMMUNICATE NEEDS AND THOUGHTS
WITH OTHERS. USE REHABILITATION
ROBOTICS IN CHILDREN AN NIH LED
STUDY FOR AN EX SKOE SKELETON
DEVICE FOR PATIENTS TO ASSIST
PATIENTS IN WALKING AND A
FUNCTIONAL LEFT VENTRICLE
STIMULATION CAST AND/OR THOUGHT
TICKS AND A WHOLE REALM OF
MOBILITY ASSISTED DEVICES FROM
WALKERS CANES AND CRUTCHES TO
EARLY TREATMENT MOBILITY
LIMITATIONS IN CHILDREN
PROVIDING POWER MOBILITY TO VERY
YOUNG CHILDREN FOR WHEELCHAIR
POWER MOBILITY FOR OLDER
CHILDREN.
WE BILL TAGS IN THE COMMUNITY IS
IMPORTANT WE WANT KIDS TO BE
FUNCTIONAL IN COMMUNITY NOT JUST
THERAPY GYM. I DON'T WANT MY
KIDS WHO ARE IN REHAB TO BE JUST
IN A THERAPY GYM I WANT THEM OUT
IN THE COMMUNITY DOING GOLF
SWIMMING, DOING CLIMBING,
SKIING, BALLET PROGRAM AND
ADAPTIVE BALLET PROGRAM IN THE
WASHINGTON AREA AND AN ICE
SKATING PROGRAM AS WELL SO WHEN
A KID IS ASKED BY THEIR PEERS ON
MONDAY WHAT DID YOU DO THIS
WEEKEND I WENT SKIING AND I WENT
TO BALLET, YOU KNOW, I TOOK
SWIMMING CLASSES NOT THAT I WENT
TO PHYSICAL THERAPY OR
OCCUPATIONAL THERAPY.
ANOTHER CONSIDERATION BESIDES
TYPE OF THERAPY WE DO IS
INTENSITY AND DURATION. THE
QUESTION RAISED INTENSIVE
THERAPY ARE MORE EFFECTIVE OR
EQUALLY EFFECTIVE TO ROUTINE
THERAPIES THAT PERFORM ON A
REGULAR BASIS. ONGOING TRIALS
BUT CURRENTLY LIMITED
METAANALYSIS SHOWED A SMALL TO
MODE DES EFFECT SIZE OF BUNCHING
THERAPY TOGETHER TO DO INTENSIVE
TWO TO THREE TIMES A YEAR FOR A
COUPLE OF WEEKS RATHER THAN
DOING ONCE A WEEK THERAPY
FOREVER.
AND THERE ARE SOME FAMILIES THAT
TYPE OF THERAPY WORKS BETTER OR
IN ADDITION TO THEIR ROUTINE
THERAPY.
SO NOW THE QUESTION IS WHAT'S
THE EVIDENCE FOR REHABILITATION
THERAPIES? AND THE PROBLEM IS
THAT THERE ISN'T GREAT EVIDENCE.
PART OF THIS IS WHAT WORKS BEST
AND WHAT WORKS BEST FOR WHO.
THAT QUESTION IS REALLY NEEDS TO
BE ANSWERED. AGAIN ALL OF THESE
THINGS WE CAN DO BUT WHICH
INTERVENTIONS ARE GOING TO BE
EFFECTIVE. SOME THINGS ARE
COLORED RED AND SOME THINGS
GREEN WHEN I GO TO MY NEXT SLIDE
WHEN WE SELECT INTERVENTIONS WE
NEED TO DETERMINE WHETHER A
SPECIFIC TREATMENT CAN BE
EFFECTIVE. DOES THE INTENSITY
AND TREATMENT EFFECT EFFICACY
AND IF THAT THERAPY ISN'T
EFFECTIVE ARE THERE OTHER TYPES
OF THERAPIES THAT SHOULD BE
CONSIDERED FOR A PATIENT AND HOW
DO YOU ACHIEVE THIS? THIS IS A
SLIDE FROM A REVIEW PAPER BY
NOVAK PUBLISHED IN 2013 IN
DEVELOPMENTAL MEDICINE ALL THE
THERAPIES THROUGHOUT THERE IS
WITH CEREBRAL PALSY AND ANOTHER
UPPER MOTOR NEURON SYNDROME
WE'VE BEEN TALKING ABOUT THROUGH
THIS LAST TWO DAYS AND SHE
DEVISED THIS SCHEME WHICH I
THINK IS GREAT, WHICH IS A GREEN
LIGHT WHICH IS THERAPIES THAT
YOU SHOULD DEFINITELY CONSIDER
TO IMPROVE AND BE EFFECTIVE.
ORANGE WHICH IS THEY MIGHT BE
EFFECTIVE AND RED IS YOU
SHOULDN'T DO THEM BECAUSE THESE
THINGS DON'T WORK. AND THEY'VE
BE
BEEN PROVEN TO NOT WORK.
IS IT WORTH IT LINE. SOME
THINGS YOU SEE FOR THERAPY AND
MOTOR THERAPIES ARE DEFINITELY
WORTH IT AND HAVE BEEN PROVEN TO
BE EFFECTIVE. LIKE MOTOR
THERAPY OR HABIT THERAPIMENT
HOME PROGRAMS PROVEN TO BE
EFFECTIVE NAMED THERAPY NEURO
DON'T TALL TREATMENT NDT PROVEN
TO BE NECK EFFECTIVE BUT OFTEN
CONTINUALLY USED IN THE
COMMUNITY. SO I LIKE TO SET THE
FRAMEWORK OF HOW WE START
LOOKING AT WHAT THERAPIES TO
PROVIDE BASED ON THIS MEDIC
REVIEW. QUESTION BEYOND
EFFICACY INTERVENTION IS WHAT
CAN FAMILIES FEASIBLY DO?
BECAUSE THEY HAVE OTHER
CHILDREN, THEY HAVE WORK WE'VE
HEARD FROM SEVERAL FAMILY
MEMBERS THE AMOUNT OF BURDEN
THAT IT IS ON FAMILIES TO TRY TO
NEGOTIATE ALL THE THINGS THAT
THEY NEED TO DO IN THEIR LIFE
AND THEN TAKE THEIR KIDS TO AS
MANY THERAPIES AS WE PRESCRIBE
FOR THEM. AND TO GET INSURANCE
COVERAGE OR TO FIGHT WITH THE
INSURANCE COMPANY BECAUSE THE
INSURANCE COMPANY DENIES PIECES
OF EQUIPMENT OR THERAPY.
AND THE LAST PIECE OF THIS IS
REALLY THE CHILD CENTER PIECE OF
IT, WHICH IS KIDS NEED TO BE
KIDS. AND KIDS WITH HSP ALSO
NEED TO BE KIDS AND THEY NEED
TIME FOR UNSTRUCTURED PLAY AND
JUST TO BE A KID. AND YOU CAN'T
KEEP KIDS IN THERAPY 24/7 OR
THEY CAN'T BE A KID. SO
NARROWING THE EVIDENCE FOR
THERAPY DR. NOVAK DID ANOTHER
REVIEW IN 2019 AND A LOT MORE
THERAPIES THAT WE'VE HAD MORE
TRIALS ON, BUT WHEN WE NARROW
THE LIST OF INTERVENTIONS IT'S
REALLY BASED ON COMPARATIVE
TREATMENT TRIAL. SO WHEN WE
LOOK AT INTERVENTION A,
OFTENTIMES INTERVENTION A
BEGINNING IS SHOWN TO HAVE
POSITIVE RESULTS, BUT AND IT
LEAKS WHEN A NULLER OF LONG LIST
OF THERAPIES WE TRY AS YOU SEE
ON THE SLIDE ON THE RIGHT BUT
WHEN YOU DO COMPARATIVE TRIALS
OF INTERVENTION A AND B, THESE
ARE RANDOMIZED CLINICAL TRIALS
TO LOOK AT WHAT'S MORE EFFECTIVE
MANY TREATMENTS WE FOR YEARS
THOUGHT WERE EFFECTIVE NBT SHOWN
TO BE NEF TEKT ACTIVE E
INFECTIVE. RATHER THAN BASED ON
HISTORY AND WHAT WAS DONE IN THE
PAST.
SO WHO IS MOST LIKELY TO BEN
FISHT FROM WHAT THERAPY IS
DEPENDENT REALLY IN PART BASED
ON WHAT THEIR IMPAIRMENT IS,
THERE'S SO MUCH PHENOTYPIC
VARIABILITY HOW DO YOU SORT OUT
REGRESSION VARIABILITY BETWEEN
PATIENTS AND GROWTH AND
DEVELOPMENT, AND DETERMINE WHAT
THE EFFECTS ARE AND THESE
PATIENTS BOTH HAVE THE SAME
CONDITION BUT OBVIOUSLY THEIR
IMPAIRMENT LEVEL IS VERY
DIFFERENT. AND YOU NEED TO
DETERMINE WHETHER BENEFIT THE
SAME LEVEL OF BENEFIT CAN BE
MEASURED FOR BOTH OF THESE
PATIENTS IN THE CLINICAL TRIAL
WHEN THEY'RE SO DIFFERENT.
CAN YOU REALLY MEASURE AN EQUAL
AMOUNT OF BENEFIT OR IS THERE AN
ABSOLUTE AMOUNT OF CHANGE THAT
CAN BE APPLIED TO ALL KIDS? AND
THE ANSWER IS PROBABLY NO.
IT'S PROBABLY BETTER TO
DETERMINE A MORE PERSONAL
MEANINGFUL GOAL FOR AN
INDIVIDUAL PATIENT RATHER THAN
FOR A GROUP ITSELF.
AND THIS LEADS ME TO THE
DISCUSSION OF SKIP THAT IS TO
TALK ABOUT THIS ISSUE OF
VARIABILITY BETWEEN INDIVIDUALS
AND PERSONALIZED REHABILITATION
PROGRAMS.
BECAUSE THE TREATMENT REALLY
NEEDS FOR COMPLEX NEUROLOGICAL
DISORDERS MAY BE MORE EFFECTIVE
IF YOU ADJUST THE TREATMENT
BASED ON INDIVIDUAL PATIENT K
CONSCIOUSES AND WE KNOW THAT
SPANS FROM DREAMS FROM THE
PATIENT FUNCTIONAL GOALS WHAT
THAT THERAPY MIGHT BE.
PERSONALIZED MEDICINE IS -- GOES
BACK TO THE 1960S, WHEN IT WAS
FIRST IDENTIFIED THAT NOT ALL
MEDICATIONS WERE -- ARE 100
PERCENT EFFECTIVE FOR INDIVIDUAL
PEOPLE, AND THAT THERE'S GENETIC
VARIATIONS IN PEOPLE AND HOW
THEY METABOLIZE THE MEDICATIONS,
SO WE HAVE APPLIED THAT
PRINCIPLE TO REHABILITATION
SAYING ONE SIZE FITS ALL DOESN'T
WORK FOR OUR PATIENTS. AND IT
MAY BE MORE COST AND TIME
EFFICIENT TO FILE A TREATMENT
PLAN AND IT ALSO MAY REVIVE
THERAPIES THAT WERE FELT TO BE
INEFFECTIVE BECAUSE THEY WERE
ONLY EFFECTIVE FOR A SMALL
SUBGROUP OF PATIENTS.
BUT THAT TREATMENT IS VERY
EFFECTIVE FOR THAT SMALL SUBSET
AND IF YOU INDIVIDUAL THE
THERAPY AND REANALYZE THE DATA
YOU CAN SEE IT MAY WORK
PERSONALIZED DATA FOR RESEARCH
AND VARIABILITY AND HOW WE
MEASURE OUTCOMES HOW WE DO THIS
HOW WE SET UP PERSONALIZED
REHAB. LOOK AT DATA MINING,
LOOK AT ASSOCIATIONS FOR
INDIVIDUAL DATA AND DO
COMPARATIVE EFFECTIVENESS TRIALS
AND EVEN SINGLE SUBJECT DESIGN
AND WEIGHTLESS CONTROL TRIALS
CAN HELP US GET TO THIS
EFFICACY.
AN EXAMPLE OF THIS IS WHAT WAS
DONE IN THE ADULT STROKE WORLD,
WHERE THEY LOOKED AT -- AT THE
EFFICACY OF INTERVENTIONS AND
EFFICACY REALLY BASED ON THE
SEVERITY OF THE PATIENT
PREDICTED OUTCOME BETTER THAN
THE OUT ACTUAL TREATMENT THAT
WAS PERFORMED SO PATIENTS THAT
ARE MORE IMPAIRED HAD A
DIFFERENT FUNCTIONAL OUTCOME
THAN THOSE THAT ARE LESS
IMPAIRED AND ADJUSTMENTS OF
REHABILITATION PROGRAMS
IMPLEMENTED BASED ON THE RESULTS
OF THIS RESEARCH SO YOU CAN
ADJUST THE FUNCTIONAL GOALS FOR
A PATIENT WITH A MORE SEVERE
DISABILITY AND ONE WITH A
PATIENT WITH LESS SEVERE
DISABILITY.
AND P MY CONCLUSIONS REALLY ARE
REHABILITATIONS OR HABILITATION
IN YOUNG CHILDREN CRITICAL FOR
TREATMENT AND THE TREATMENT
SHOULDN'T BE CONSTRAINED BY THE
LACK OF EVIDENCE AS THEY ARE
NOW. I KNOW AS A CLINICIAN I
HEAR FROM INSURANCE COMPANIES
THAT THEY WON'T APPROVE CERTAIN
TREATMENTS BECAUSE THERE ARE NO
RESEARCH TO SUPPORT FOR INSTANCE
THE MOST RECENT ONE I HEARD WAS
FROM A MEDICAL INSURANCE COMPANY
WHO REFUSED TO PROVIDE A
WHEELCHAIR FOR A PATIENT BECAUSE
THE PATIENT WAS SIX YEARS OLD
AND THAT SOMEONE COULD JUST
CARRY THE CHILD TO AND FROM
WHATEVER IT WAS BECAUSE THERE
WAS ALWAYS AN ADULT WITH A
SIX-YEAR-OLD CHILD AND IT TOOK
ME ABOUT THREE HOURS WITH THE
DISCUSSION OF THE MEDICAL
DIRECTOR OF THE INSURANCE
PROGRAM FOR THEM TO UNDERSTAND
WHERE WHY THE CHILD NEEDED A
WHEELCHAIR. THAT GOES ON DAILY
FOR CLINICIANS TO GET APPROVAL
FOR THERAPY AND IT GOES ON DAILY
FOR FAMILIES AS WELL.
SO GOING FORWARD WE ALSO NEED TO
KNOW WHAT THERAPY AND HOW MUCH.
WHAT WORKS? THE CURRENT LEVEL
EVIDENCE IS INSUFFICIENT SO WE
NEED MORE HIGH QUALITY TRIALS TO
DO THAT WE REALLY NEED TO BETTER
MEASURE IMPRAICHAIRMENIMPAIRMENT, MEASURE
FUNCTION AND OUTCOMES AND
INDIVIDUALIZED TREATMENT TRIALS.
AND THANKS VERY MUCH TO ALL OF
OUR FAMILIES AND TO ALL THE
OTHER SPEAKERS AND TO DIANE WHO
IS MY LAB CHIEF WHO WAS INVOLVED
IN SOME OF THESE SLIDES.
THANK YOU.
>> THANK YOU SO MUCH FOR A
BEAUTIFUL PRESENTATION, SO
IMPORTANT FOR THE PATIENT'S
QUALITY OF LIFE TO CONSIDER
THESE REHAB INTERVENTIONSMENT
NEXT WE'LL MOVE ONTO MIGUEL
ESTEVES ABOUT GENE THERAPY.
>> MIGUEL ESTEVES: HELLO
EVERYONE. THANK YOU FOR THE
ORGANIZERS FOR INVITING ME.
I'LL TRY TO BE RELATIVELY BRIEF
ON THIS WE'RE RUNNING LATE I
WON'T JUST SAY WE'RE DOING AAV
GENE THERAPY. BUT I'LL BE MORE
BRIEF THAN WAS ANTICIPATED.
BRIEF INTRODUCTION TO ASSOCIATED
VIRUSES, STARTED AS A
CONTAMINANT DIDN'T DESERVE ITS
OWN NAME. WAS FOUND AS A
CONTAMINANT IN 1965 AND
MAINTAINED AS A CURIOSITY FOR
MOST OF ITS LIFE UNTIL DISCOVERY
THAT IT ACTUALLY CAN HANDLE
GENES QUITE EFFICIENTLY IN VIVO.
THE WILD TYPE VIRUS IS SIMPLE.
IT'S A SINGLE STRANDED DNA VIRUS
COMPOSED OF TWO GENES AND P
MAKES LINE PROTEINS AT LEAST AS
FAR AS WE KNOW IT'S SPENT MOST
OF ITS LIFE THINKING IT MADE
SEVEN WE DISCOVERED MORE
RECENTLY NINE PROTEINS, REALLY 0
TO 25 NAN MOMETERS AND THAT POSES
LIMITATIONS ON WHAT YOU CAN
ENCODE INTO THE VIRUS, THE SIZE
OF THE GENOME IS 4.7KB AND ONE
OF THE SAFETY FEATURES OF THE
ADD DEAN KNOW ASSOCIATED VIRUSES
THEY DON'T REPLICATE THEY DON'T
HAVE NECESSARY FUNCTIONS TO DO
SO THEREFORE CLASSIFIED BECAUSE
THEIR REPLICATION BEGINS ON THE
VIRUS HERPES SIMPLEX VIRUS.
IN TERMS OF HOW COMMON VECTORS
ARE MADE THE ONLY ELEMENTS OF
GENOME THAT WILD TYPE GENOME
THAT REMAIN THE RECOMBINANT
VIRUS TERMINAL PEAKS THAT TRANS
YET SET OF INTEREST THAT CARRIES
ALL THE ELEMENTS THAT YOU NEED
TO EXPRESS A GENE YOU KNOW CELL,
THE REASON THAT OF COURSE THEY
BECOME THE DOMINANT FORCE OR
DOMINANT PLATFORM FOR IN VIVO
GENE CLI
GENE DELIVERY. HIGHLY
EFFICIENT. ONE COULD ACTUALLY
CALCULATE THAT TO MOIS THE
ENTIRE BODY HUNDRED FOLD
DEFICIENCIES ARE RELATIVE THE
BEST WE HAVE CURRENTLY. ONE OF
THE ADVANTAGES IT HAZARDOUS NOT
INTEGRATE INTO THE GENOME AND
FOR THE MOST PART MAYBE A SMALL
PERCENTAGE OF THAT HAPPENS, IT'S
LOW GENEO TOXIC POTENTIAL, IT
CAN BE THE RIGHT TISSUE CAN BE
LONG-TERM GENE EXPRESSION. BUT
BECAUSE IT DOES NOT INTEGRATE
THE GENOME WRONG PLATFORM TO USE
FOR THE CELLS SUCH AS BONE
MARROW. SO OTHER PLATFORMS ARE
MORE ADEQUATE FOR THAT.
IN TERMS OF RESPONSES FOR THE
MOST PART CONTROLLED BY
EXPRESSION BUT WE ALSO HAVE THAT
FROM LATEST CLINICAL TRIALS
EXTREME DOSES THAT CAN BE
PROBLEMATIC AND HAVE RESULTED IN
SUCH CASES IN PATIENTS THAT MORE
RECENTLY.
IN THAMERMS OF -- ONE OF THE
INTERESTING PROPERTIES YOU CAN
USE THE SAME SET TO PUT IT
INSIDE PACKAGE INSIDE DIFFERENT
CAPSULES, IN TERMS OF THE
CENTRAL NERVOUS SYSTEM THE WORLD
CHANGED QUITE DRAMATICALLY IN
2009 WITH DISCOVERY THAT 89
CROSSES THE BLOOD BRAIN BARRIER
IN GENE THERAPY AB9 HAS THE
LEADING CAP SET TO DEVELOP
PROGRAMS TO TREAT NEUROLOGICAL
DISEASES ALTHOUGH IT'S FAR FROM
PERFECT IN TERMS OF THE
EFFICIENCY TRANSFER BUT THE BEST
WE HAVE IS FAR AND OF COURSE
QUITE A BIT OF CLINICAL
EXPERIENCE USING AAV9 GENE
TRANSFER.
IN ADDITION TO THE CHOICE OF CAP
SAID, THERE'S ALSO WILD TYPE
THAT CAN BE MODIFIED BY LEADING
SMALL SEQUENCE WHEREBY THE
GENOME IS PACKETED -- PACKAGED
IN THE DOUBLE STRAND SELF
COMPLEMENTARY GENOME,
DESCRIPTION OUT THERE DOUBLE
STRANDED CONTRARY TO THE SINGLE
STRAND GENOMES THAT HAVE TO BE
COMPORTED AND REALLY RENDERS
THEM CONSIDERABLY LESS
EFFICIENT. SEVERAL
CONSIDERATIONS WHEN DESIGNING
THE AAV VECTORS FROM THE CAP
SAID ALL THE WAY TO THE TYPE OF
GENOME THAT YOU'RE USING AND OF
COURSE LUNCH DOES NOT COME FREE
COMPLEMENTARY VECTORS ARE MORE
EFFICIENT BUT ALSO 2.4KB SO YOU
RENDER THAT TYPE OF DESIGN MAY
OR MAY NOT BE USEFUL OR USED
USABLE FOR EVERY GENE THAT ONE
WOULD WANT TO TRY AND DELIVER
FOR THERAPEUTIC PURPOSES.
OF COURSE THE BRAIN HAS THE
PERFECT DELIVERY VEHICLE, WHICH
IS THE BRAIN VAS SKVASCULAR SURE,
10 MICRONS AWAY FROM BLOOD
VESSEL WONDERFUL IT EXISTS
UNFORTUNATELY OR FORTUNATELY I
SUPPOSE WE HAVE A BLOOD BRAIN
BARRIER EFFICIENT TO DIFFUSING
INTO THE BRAIN. WE OFTEN IN A
GROUP THAT WORKING AND WITH
DISEASE WE ALWAYS SAY IF A WAS
ONLY CAUSED BY LIVER DISEASE WE
WOULD BE MUCH FURTHER AWAY THAN
WE ARE TODAY.
DELIVER VECTORS PRETTY MUCH FOR
EVERY OTHER MOLECULE IS
CHALLENGING THE BLOOD BRAIN
BARRIER PREVENTS US FROM DOING
SIMPLE IV ADMINISTRATIONS FOR
THE MOST PART, AND OFTEN IN
TERMS OF SMALL DRUGS THAT
MEDICINAL CHEMISTRY PROGRESSED
ENORMOUSLY WE KNOW WHAT CHEMICAL
MOIETIES AND FEATURES ALLOW
SMALL MOLECULES TO CROSS THE
BLOOD BRAIN BARRIER
UNDERSTANDING OF COURSE TALKING
ABOUT A VERY SMALL DOSE THAT
ENDS NUPT BRAIN OF COURSE ENDS
UP IN THE LIVER AND AAV NO
DIFFERENT THAT MOST OF IT ENDS
UP IN THE LIVER.
IN TERMS OF PHYSICAL METHODS TO
BYPASS, THE FIRST ITERATION FOR
NEUROLOGICAL DISEASES IT HAVE
THE APPROACH THAT WAS USED WAS
CERTAINLY THE INTERCRANIAL
DELIVERY CONTINUES TO BE USED,
PARKINS
PARKINSON'S DISEASE, UNDERSTAND
DIFFUSION, FROM LOCALIZED
DIFFUSION ALTERNATIVE APPROACH
CSF DELIVERY MULTIPLE ROUTES ONE
CAN USE MITRAL VENTRICLE,
POPULAR ONE RIGHT NOW FOR
DELIVERY OF AAV VECTORS FOR
NEUROLOGICAL DISEASE NOT JUST
FOR ME BUT WE USUALLY DELIVERING
THROUGH CSF WHICH CAUSE ISSUES
IN TERMS OF THE DISTRIBUTION AND
THE DOSES THAT NECESSARY.
NOW, I JUST WANTED TO MAKE SOME
CONSIDERATIONS THAT YOU'LL SEE
THAT I'LL TOUCH ON A FEW POINTS
RAISED BEFORE FOR DESIGNING AN
AV VECTOR TAKE A SIMPLE APPROACH
SLAP A CDMA TO THE VECTOR THAT
EVERYBODY USES TRY YOUR BEST
THAT'S PERFECTLY FINE TO DO, BUT
I THINK SPAST IS ONE PEOPLE
SHOULD TRY CAREFULLY MICRO JEWEL
PROTEIN I THINK STRONG POTENTIAL
FOR TOXICITY WITH OVER
EXPRESSION WE ENCOUNTERED THIS A
FEW YEARS AGO THAT ACTUALLY YOU
DO PAY A PRICE IF YOU ASK
NEURONS TO MAKE TOO MUCH OF A
PROTEIN MOST PEOPLE THINK IT'S
FAIRLY OFFENSIVE.
OTHER ASPECT OF COURSE WE HEARD
BEFORE TWO VARIANTS PRODUCED BY
THE SAME MRNA, IN THE FIELD
DEBATED FOR A LONG TIME MICRO
NICHL OF ACTION FOR MUTATION A
LOSS OF FUNCTION OR FUNCTION
TYPE OF MUTATION THAT HAS
DIFFERENT IMPLICATIONS FOR THE
TYPE OF DESIGN THAT YOU USE IN
THE AV.
ONE THE QUESTIONS I ASKED MYSELF
DO WE REALLY UNDERSTAND WHAT THE
CELL TYPES OUR TARGET CELL TYPES
ARE? AND YOU KNOW THIS MORNING,
JUST FOR FUN POINTS I WENT
THROUGH QUITE A FEW DATABASES TO
TRY TO ANSWER THAT QUESTION.
AND AS PETER MENTIONED EARLIER
DURING THESE STUDIES EXPRESSION
WAS DISTRIBUTED QUITE WIDELY
THROUGHOUT THE BODY, BUT THERE
NO MEANS OF THE OHM PLACE IN THE
BODY EXPRESSED AT THOSE HIGH
LEVELS SEE HERE IN HEART MUSCLE
SKELETAL MUSCLE THE PROTEIN IS
EXPRESSED AT VERY HIGH LEVELS
EVEN HIGHER THAN ELSEWHERE IN
THE CEREBRAL CORTEX. KEEP IN
MIND THAT ASPECT IF YOU LOOK AT
THE TISSUE LEVEL THE RNA LEVELS
ACTUALLY BECOMES EVEN MORE
INTERESTING BECAUSE IN FACT IT
SEEMS LIKE THE HIGHEST
EXPRESSION LEVEL OF RNA OR
HIGHEST LEVELS OF R. NA ARE
WHITE MATTER OF COURSE NOT TOO
FAR IN THE AREAS CERTAINLY IN
THE BRAIN, AND AS YOU SEE HERE
THE EXPRESSION ARE THE PRIFL
TISSUES AS WELL.
SO INTERESTING TO THINK ABOUT
WHAT OTHER ASPECTS OF THE
DISEASE MAY WE BE MISSING, STILL
CLINICALLY, THAT MAY BE ALTERED
DUE TO THE THAT THESE PATIENTS
CARRY. EXPRESS SEEMINGLY M1
EXPRESSED IN THE SPINAL CORD
QUITE A BIT. AT THE SINGLE CELL
LEVEL AGAIN IT'S REALLY QUITE
INTERESTING TO SEE THAT IN THE
CENTRUM THE RESISTS THE HIGHEST
EXPRESSION IS ACTUALLY OBSERVED
IN THE DANGER SITES AND IT'S
IMPORTANT TO CONSIDER THAT EVEN
WHAT WE HEARD TOGETHERS ABOUT
AXONAL, WHITE MATTER DISEASES
THAT HAVE PROFOUND NEUROLOGICAL
IMPACTS AND WONDER IF DELIVERY
OF GENES OR ASOS TO NEURONS
ALONE WILL SUFFICE TO ACTUALLY
CORRECT A DISEASE PHENOTYPE. SO
ACTUALLY QUITE IMPORTANT TO
THINK ABOUT WHAT TYPES OF CELLS
DO WE NEED TO TARGET TO ACTUALLY
ACHIEVE A THERAPEUTIC TREND.
OF COURSE WE'RE NOT AT THE STAGE
WHERE WE ACTUALLY CAN DELIVER AT
WILL WITH EVERY SINGLE CELL PACK
THAT WE WANT. SO TO CERTAIN
EXTENT THE EXPERIMENTS WE'RE
DOING ARE EM POOERL PEESHG CAL
IN NATURE DESIGN FOR TESTING AND
ANIMAL MODEL. SO YOU CAN SEE
HERE SORT OF AGAIN AT THE TISSUE
LEVEL THAT THERE'S A LOT OF RNA
INFORMATION FOR MULTIPLE
TISSUES, AND ONCE AGAIN AT THE
RNA LEVEL THE CELL LEVEL HIGHEST
EXPRESSION LEVELS ARE IN THE
SITE LINEAGE.
SO AN INTERESTING ASPECT TO
CONSIDERMENT IF YOU LOOK AT
ANOTHER DATABASE TO DROP IS FROM
AT MIT YOU CAN LOOK IN HERE
LAYER FIVE NEURONS REALLY
EXPRESS THE HIGHEST LEVELS IN
THE FRONTAL CORTEX BUT FOLLOWED
IMMEDIATELY BY THE SITES AS WELL
AND IF YOU LOOK FOR INSTANCE IN
THE CEREBELLUM WHERE WE SAW
BEFORE THE HIGHEST LEVEL OF
EXPRESSION YOU CAN SEE AGAIN ALL
THE SITES AND NEURONS THEY ARE
ACTUALLY EXPRESSED AT VERY HIGH
LEVELS.
IF YOU LOOK YET AT ANOTHER
DATABASE AND EACH ONE OF THEM
HAS ADVENTURES ON ITS OWN FOR
INSTANCE SPINAL CORD WE DIDN'T
SEE ANYTHING FOR THE SPINAL CORD
BEFORE BUT HERE ON GTEX PORTAL
AT MIT YOU CAN SEE HERE THEY ARE
AGAIN IN THE SPINAL CORD NOT
TERRIBLY SURPRISING EVEN THE
PHENOTYPE OF THE DISEASE AND
THIS IS WHAT PROMPTED A QUESTION
FOR ME YESTERDAY, IN TERMS OF
THE DIFFERENT ISOFORMS AND IT
LOOKS LIKE THERE ARE TWO TYPES
OF MRNAS THAT ARE USED DIFFERENT
ISOFORMS THE PROTEIN THE ONES
MOSTLY USED IS ONE THAT SOME
EVIDENCE TO SUGGEST THAT MRNA
WITHOUT AXONAL FOUR AND SEE HERE
EXPRESSED IN THE BRAIN QUITE A
BIT. BECOMES MORE COMPLICATED
TO DEVELOP A GENE THERAPY WHERE
YOU CAN ALTERNATIVELY SPLICE A
PARTICULAR AXON NOT QUITE
IMPOSSIBLE BUT IS IT TRUE OR
NOT? I DON'T THINK THERE'S
ENOUGH INFORMATION ON THAT
FRONT.
SO JUST TO SUMMARIZE THE ASPECT
OF THE DESIGN AS I MENTIONED TO
YOU BEFORE THE SIZE OF THE GENE
MATTERS OR THE SIZE AT LEAST OF
THE CODING SEQUENCE DOES MATTER
1.85KB FOR SPASTIN AND
UNFORTUNATELY A SING GREL STRAND
10 HUNDRED FOLD AT LEAST FACT OF
THE MATTER IS IF WE USE A VECTOR
SOFT COMPLIMENTARY YOU HAVE TO
HAVE IVR AND SO YOU ARE LEFT
WITHOUT 250 PAIRS TO PUT IN
THERE PROMOTING, WHILE THAT'S
NOT A LOT OF SPACE FOR A
PROMOTER ONE COULD TAKE SOME
COMPROMISES DOING THAT BUT A
SINGLE STRAND AAV VECTOR
DESIGNED SO MORE SPACE TO
INCLUDE REGULATORY ELEMENTS.
THEN COMING BACK TO THAT IDEA OF
TOXICITY, THE QUESTION IS DO WE
USE THE SUPER STRONG YOU KNOW
MANY PROGRAMS BASED ON USING
PROMOTER, IN FACT THE XS AND
NOVARTIS DRUG FOR SMA IS
ACTUALLY BASED ON USING
PROMOTERS ACTUALLY ALWAYS A
SURPRISE TO ME NOT INCREDIBLY
TOXIC BUT IT DOES WORK PRETTY
WELL OTHERS ONE CAN CONSIDER.
NEURONAL DRIVEN. THE OTHER
APPROACH ONE THAT I ACTUALLY
FAVOR I THINK THERE'S A LOT OF
PEOPLE USING IT I THINK MAKES
SENSE USING WEAK PROMOTERS AND
WEAK PROMOTERS I PERSONALLY
THINK IN GENERAL CELLS CAN ADAPT
TO HAVING LOWER AMOUNTS OF A
PROTEIN PERHAPS BETTER THAN
HAVING A CONSTANT LEVEL
EXTREMELY HIGH WHERE YOU CAN
ENGAGE UNFOLDED RESPONSES, SO
THE NOTION OF ACTUALLY USING
WHEAT PROMOTERS QUITE A BIT OF
MERIT THE QUESTION ABOUT THESE
WEAK PROMOTERS DO THEY EXPRESS
EVERYTHING WE NEED. THE ANSWER
IS ABSOLUTELY NOT. WELL
ACTUALLY THAT'S NOT QUITE TRUE
IN FACT IF YOU CHANGE THE
PROMOTER FROM ONE OF THESE
UBIQUITOUS, BASIC PROTEIN
PROMOTER IN FACT LO AND BEHOLD
IT TRANS DO YOU SAYS, YOU CAN'T
HAVE GENE EXPRESS ON ALL VENDOR
SITES. THE GENE TRANSFER
PROPERTIES OF A VECTOR WITH AAV
ARE OBVIOUSLY DETERMINED BY THE
CAP SAID WE ALL UNDERSTAND THAT
INTRINSIC A PROPERTY TO BE ABLE
TO ENTER CELLS BUT OUR
PERCEPTION OF TROEPISM IS
DRIVEN BY WHAT WE USE THE TRUE
TROPISM ON AAV VECTORS, OTHER
POSSIBILITY ONE MORE POSSIBLE
BECAUSE SINGLE CELL APAC THE
EXPRESS SORE TRYING TO FINALED
PROMOTE TORE ELEMENT NECESSARY
TO DRIVE NORMAL ELEMENT
EXPRESSION AS YOU HEARD BEFORE
CHANGING CAPACITY IS PRETTY
SMALL SO YOU REALLY HAVE TO TRY
TO MINIMIZE A NUMBER OF ELEMENTS
THAT YOU USE TO DRIVE GENE
EXPRESSION.
IDEALLY WE WOULD DIVIDE
CASSETTES THAT USE THE MINIMUM
PROMOTERS THAT ARE NECESSARY TO
EXPRESS THE GENE IN ITS PROPER
LEVELS AND CERTAIN CELL TYPES.
NOW WHETHER THE AAV HAS THE
RIGHT SIZE OR THE TRANSIENT
CAPACITY TO INCLUDE ALL THE
ELEMENTS THAT REMAINS TO BE
SEEN.
IN TERMS OF REGULATORY ELEMENTS
POLYASE YOU CAN USE DIFFERENT
POLYASE AND DO YOU USE
UNTRANSLATED REGIONS, AS 3
PRIME? OFTEN THEY INCLUDE
MICRORNA TARGETS SO THAT'S
ANOTHER FACTOR TO TAKE INTO
ACCOUNT WHETHER THAT'S SOMETHING
THAT WE WOULD LIKE TO INCLUDE OR
NOT. AND OF COURSE ALL OF THIS
BOILS DOWN TO WHAT I SAID
EVERYTHING HAS TO FIT WITHIN
4.75KB A BIT OF AN EXERCISE IN
TRIAL AND ERROR AND INCLUDE MORE
ELEMENT THAT WE FIND A PROBLEM
IF THERE IS NO PROBLEM THAT WE
HOPE THINGS MOVE ON AND WORK
WELL.
THEN THE FINAL QUESTION IS, YOU
KNOW, WHAT IS THE GENE TRANSFER
CODE? THAT DEPENDS ON THE
MECHANISM IF IT'S A LOSS OF
FUNCTION TYPE OF DISEASE THAT
CAN MUTATIONS CAUSE LOSS OF
FUNCTION IN PROTEIN WE FIND
OURSELVES IN PURE
SUPPLEMENTATION TYPE OF
APPROACH, ON THE OTHER HAND, IF
YOU HAVE DISEASE THAT MUTATION
GAIN FUNCTION MUTATIONS, WELL
ACTUALLY JUST PUTTING IN THE
NORMAL COPY OF A GENE IS LIKELY
NOT GOING TO SOLVE THE PROBLEM
SO IDEALLY WHAT YOU WANT TO DO
IS COMBINE A SILENCING AND
REPLACEMENT APPROACH SO DUAL
FUNCTION TYPE OF DESIGN AND AS
YOU UNDERSTAND BECAUSE I DO WORK
WITH PETER USING HIS MOUSE MODEL
OBVIOUSLY WE SUBSCRIBE TO THAT
NOTION THAT IN FACT YOU NEED TO
DO BOTH TO ACHIEVE A THERAPEUTIC
EFFECT.
NOW ONE MAY POSIT THAT NOT EVERY
MUTATION IS NECESSARILY A
FUNCTION MUTATION THAT'S ONLY
SOME OF THEM MIGHT BE, AND THAT
IS POSSIBLE, BUT THERE AGAIN,
THE ISSUE IS IF YOU DESIGN
VECTORS THAT ARE ONLY USEFUL FOR
ONE SUBSET OF MUTATIONS, WELL
FOR DISEASE THAT IS ALREADY
ULTRA RARE AND NOW YOU CAN ONLY
TREAT A SLICE OF THAT
POPULATION, WELL EVENTUALLY YOU
CAN'T FIND PATIENTS OR YOU HAVE
A LOT OF DIFFICULTY FINDING
PATIENTS AND THEN STRUGGLE WITH
EVEN MORE COMPLICATED QUESTION
OF DO I KNOW EXACTLY WHAT EACH
MUTATION IS? FUNCTION OR LOSS
OF FUNCTION. SO PRAGMATIC
APPROACH THAT WE'RE TAKING IS
WELL LOOK, REGARDLESS OF THE
MECHANISM, IF WE SILENCING,
SILENCE THE ENDOGENOUS AND
REPLACE THEM WITH NORMAL
PROTEIN, WELL THAT WOULD BE
OKAY. AND THE RISK THERE IS
RELATIVELY SMALL BECAUSE IN
EVERY CELL WE CAN SILENCE THE
GENE WE'RE ALSO EXPRESSING THE
GENE. SO ON THE OTHER HAND, IF
THE TWO THINGS WILL YOU THINK
LINK FROM EACH OTHER THAT COULD
BECOME A PROBLEM BECAUSE AFTER
ALL EVOLUTION DID A FABULOUS JOB
OF HAVING THESE GENES AND
EXPRESSING THEM SO THE NOTION
THAT WE INCLUDE REALLY SILENCED
GENES LEFT AND RIGHT OF COURSE
PERSONALLY I THINK THAT'S
LAUGHING IN THE FACE OF
EVOLUTION BUT YOU KNOW WE'LL SEE
WHAT THAT BRINGS IN CLINICAL
TRIALS.
WHERE WE STAND TODAY IN THE
COLLABORATION WITH PETER AND
OSCAR CHANG'S LAB THAT GENERATE
THE DESIGN FIRST GENERATION OF
PASS SPASTIC VECTORS ONGOING AND
WE DESIGN NOW A SECOND
GENERATION OF VECTORS TO
INTRODUCE THEM TO TAKING SOME OF
THESE CONSIDERATIONS THAT I'VE
MADE ARE ON.
I THINK THAT'S IT. I TOOK A
LITTLE LONGER THAN I ANTICIPATED
I APOLOGIZE.
>> THAT'S WONDERFUL THANK YOU
VERY MUCH SO IMPORTANT FOR SHARE
YOURS EXPERTISE. SO WE HAVE ONE
LAST SPEAKER RUNNING A BIT OVER
TIME BUT I WANT TO MAKE SURE WE
HAVE GOOD TIME FOR Q AND A AND
DISCUSSIONS SO WE CAN REMAIN ON
THE ZOOM CALL A LITTLE PAST 2:00
FENDI
DEPENDING ON POOEMS
AVAILABILITY. WE WON'T GET CAN
YOU TELL OFF. FINAL SPEAKER IS
JAHANNAZ DASTGIR. THANK YOU SO
MU
MUCH.
>> JAHANNAZ DASTGIR: HI
EVERYBODY THANK YOU AIR REAN FOR
HAVING ME HERE TODAY AND THANK
YOU ALL FOR YOUR ATTENTION.
SO AS I HOPE YOU ALL CAN HEAR ME
OKAY. AS AIR REAN HAD MENTIONED
EARLIER MY BACKGROUND WAS PRETTY
MUCH SPENDING 10 YEARS IN
FELLOWSHIP AND THEN GOING ON TO
BE IN ACADEMIA, I CONTINUED TO
WORK AS A CLINICIAN PART TIME
AND JUST STARTED TO TAKE A
POSITION I TOOK A POSITION OVER
THE PAST YEAR IN A SMALL BIOTECH
COMPANY THAT'S BEEN DEVELOPING A
DRUG FOR SORE BIT TALL DEE HIGH
DRAUJ GENERAL NAYS DEFICIENCY
NEURO MUSCULAR SPECIALIST
PEDIATRIC BY TRAINING AND ALSO
HAVE A VERY STRONG INTEREST IN
NEURO GENETIC DISORDERS AS WELL
PROBABLY PLACED IN ME DURING MY
TIME AT NIH WHICH I'M GRATEFUL
FOR.
SO ARYAN HAD ASKED WHAT DO SMALL
STARTUP COMPANIES LOOK FOR SNO
SN SO WHAT I'VE LEARNED I'M
GOING TO SHARE WITH YOU TODAY.
SO FIRST OF ALL, IS THERE A
DRUG? SO I WAS SO GRATEFUL TO
SEE ALL OF THE EXCITING
INFORMATION HERE ON SPG4
PATIENTS I ACTUALLY HAVE TWO IN
MY OWN PRACTICE SO IT'S VERY
EXCITING FOR THEM.
SO YOU KNOW AS I THINK WAS
MENTIONED IN THE MODELIS TALK AS
WELL. SOME COMPANIES DO HAVE AN
INDICATOR -- THEY TRY TO
REPURPOSE DRUGS THAT HAVE BEEN
PURPOSELY USED FOR OTHER
INDICATIONS, THE EASIEST EXAMPLE
I'M FAMILIAR WITH A COMPANY
CALLED PHARM X FOR EXAMPLE THEY
DEVELOPED AICALLY OWE DRUG A
COMBINATION OF THREE DRUGS
TYPICALLY USED IN PRACTICE AND
SAFELY EVEN IN THE PEDIATRIC FOR
EXAMPLE. THROUGH SCREENINGS OF
CHEMICAL LIBRARIES THEY NOTICED
THIS WORKED FOR CM T1A, SHARK
MARINE TOOTH 1A. THEN YOU HAVE
ACADEMIC OR LAB DEVELOPED DRUGS
GENE THERAPY OR SMALL MOLECULES
PARTICULAR CULTURE OR PATHWAY.
AND THEN HOW DO YOU PEAK THEIR
INTEREST? SO IF A COMPANY IS
ALREADY DEVELOPING A DRUG WITH A
SPECIFIC THERAPEUTIC TARGET FOR
ONE DISORDER AND ANOTHER
DISORDER WITH THE SAME
THERAPEUTIC TARGET IS DISCOVERED
IN PUBLICATIONS THEY WILL GO
THROUGH IT. THAT'S HAPPENED
WITH THE CURRENTLY WORK FOR
APPLIED THERAPEUTICS. SO
BASICALLY THEY HAD A DRUG THAT'S
AN REDUCTASE INHIBITOR DEVELOPED
FOR DIABETIC CARDIOMYOPATHY
PRIMARILY. AND THEN THIS PAPER
WAB WAS PUBLISHED IN NATURE
GENETICS IN MAY OF 2020, THEY
SAID MUTATIONS COMMONLY
TREATABLE WITH IMPLICATIONS FOR
DIABETES OH, MY GOSH OUR DRUG
ACTUALLY INHIBITS PRU PRODUCTION
OF SORBITOL LET'S DO IT. THIS
BIOTECH COMPANY OPERATES AT A
FASTER PACE THAN BIG PHARMA
EXCITED TO GET THIS DRUG ON THE
PIPELINE AND HIRED ME TO DEVELOP
THE PROGRAM THERE.
SO IT'S IMPORTANT, YOUR
PUBLICATIONS ACTUALLY REALLY
MATTER, WHICH IS GREAT.
ANOTHER WAY TO PIQUE THEIR
INTEREST OKAY FINE YOU DON'T
HAVE ALL YOUR DATA YET TOGETHER
OR LONGITUDINAL DATA YET
TOGETHER PUT OUT A PAPER PRESENT
ABSTRACTS AND MEETINGS THESE
GUYS ARE ALL AT MEETINGS ALL THE
TIME EXCITED TO SEE ANY OTHER
IMPLICATIONS OF THE DRUGS THEY
MIGHT HAVE.
REACH OUT TO THE COMPANY
DIRECTLY. I'VE LEARNED IF
THERE'S AN E-MAIL ON THE WEBSITE
FOR A PROGRAM THAT E-MAIL
DOESN'T GO TO NOWHERE YOU MIGHT
THINK MOST PLACES YOU REACH OUT
NOT GET TO THE RIGHT PEOPLE.
USUALLY A PATIENT ADVOCACY
PERSON WHO IS PART OF THAT WHO
WILL FUNNEL IT TO A MEDICAL
DIRECTOR, AND THEN IF IT'S A
SMALLER COMPANY, FOR EXAMPLE IF
I GET IT, I GIVE IT DIRECTLY TO
THE CM O, OR THE CEO, IT'S A
VERY CLOSE KNIT RELATIONSHIP SO
NEVER UNDER ESTIMATE REACHING
OUT TO PEOPLE DIRECTLY, IN
SMALLER COMPANIES I IMAGINE BIG
PHARMA IT'S VERY DIFFERENT.
AND THEN THE NEXT THING IS ARE
THERE PATIENTS? SO THIS IS VERY
IMPORTANT. SO FOR EXAMPLE IF
YOU WANT TO MAKE SURE THAT THE
COMPANIES ARE INTERESTED YOU
NEED PATIENT NUMBERS RIGHT? SO
THE WAY FOR EXAMPLE I CAN USE
THE SEXAMPLES OF WHAT WE'VE BEEN
WORKING ON, WHEN THE GENE WAS
IDENTIFIED WHO WERE THE FIRST
PEOPLE WE WENT TO TRY TO TO FIND
PATIENTS ARE THE PEOPLE ON THE
PAPER. HOW MANY PATIENTS DO YOU
HAVE EXACTLY IS THAT ENOUGH FOR
US TO DO A TRIAL? THEN YOU DO
SOMETHING WHERE YOU REACH OUT TO
REGISTRIES I HIGHLIGHTED THIS
AFTER LISTENING TO SOME OF THE
TALKS HERE. SO DURING THE
SYMPOSIUM THAT YOU KNOW WHEN YOU
WERE TALKING ABOUT I THINK IT
WAS THAT ONE PHYSICIAN AT BOSTON
CHILDREN'S I THINK DR. TRAINER
WAS TALKING ABOUT THAT PHYSICIAN
I'M FOR GETTING HIS NAME NOW
APOLOGIZE, SAYING IT WAS 2
MILLION DOLLARS TO DO WHAT HE
WAS DOING AND IT WAS A LOT.
YOUR PERSPECTIVE ON MONEY
COMPLETELY CHANGES WHEN YOU
START WORKING FOR PHARMACEUTICAL
COMPANIES IN ALL HONESTY. AND 2
MILLION DOLLARS IS A LOT BUT NOT
A LOT. IF THAT MAKES ANY SENSE.
SO THESE COMPANIES HAVE MONEY.
SO IF YOU HAVE A SMALL
FOUNDATION, WHO HAS A REGISTRY
OF PATIENTS, FOR EXAMPLE IF A
STUDY IS TRYING TO FIND
PATIENTS, THERE'S OFTEN
RELATIONSHIPS BETWEEN THE
BIOTECH PHARMA -- PHARMA COMPANY
AND THE REGISTRY WHERE THEY WILL
GIVE YOU INFORMATION ON THE
PATIENT DATA. THEY MIGHT REACH
OUT TO THE PATIENT ON YOUR
BEHALF BUT YOU WILL GET NO
IDENTIFYING INFORMATION. WE
HAVE 20 PATIENTS WITH THIS, BLAH
BLAH BLAH BLAH, OKAY YOU HAVE TO
GIVE US A CERTAIN AMOUNT OF
MONEY TO GET ACCESS TO THIS
INFORMATION, FOR EXAMPLE. I WAS
SHOCKED TO LEARN THAT BUT IN THE
SAME TIME I WAS LIKE WOW THIS IS
GREAT BECAUSE ACTUALLY THE
BIOTECH OR PHARMA COMPANY IS
ACTUALLY GIVING MONEY TO THE
REGISTRIES WHICH IS GREAT
BECAUSE IN THE END WHAT IS THE
REGISTRY DOING WITH THAT MONEY.
THE REGISTRY IS USUALLY TRIED
TIED TO A FOUNDATION SUPPORTING
RESEARCH.
SO IT'S KIND OF A SELF FEEDING
MECHANISM IS IN SOME WAYS WHICH
I WAS EXCITED TO SEE. THAT IS
ONE WAY THERE IS ACTUALLY GREAT
UTILITY TO IDENTIFY PATIENTS AND
HAVE A GREAT REGISTRY WHICH I
BELIEVE SPG4 HAS, WHICH IS
GREAT.
SPONSORED GENETIC TESTING IS
ANOTHER WAY TO FIND PATIENTS. I
KNOW WE HAVE THE CP PANEL, FOR
EXAMPLE, THAT PICKS UP THE
MUTATION THROUGH IN VITAE I SENT
IT OUT MYSELF THIS IS EXCELLENT
AND ALSO JUST YOU KNOW LISTING
AT THE BOTTOM SO AND SO IS
WORKING ON THIS DISEASE, AND YOU
KNOW YOU CAN CONTACT THEM IF
YOU'RE INTERESTED ON ADDITIONAL
RESEARCH OR WHAT NOT.
THAT'S IMPORTANT. AND ALSO
PROMOTING AWARENESS AMONG CP
CLINICS, PHYSIATRISTS AND
NEUROLOGISTS SO JUST BASED ON MY
OWN CLINICAL BACKGROUND FOR
EXAMPLE I REMEMBER WORKING IN
SOME SPASTICITY CLINICS OUTSIDE
OF NIH AND THE WHOLE POINT OF
THESE PASPASTICITY WHAT IS THE
CAUSE OF THE SPASTICITY SOME HAD
KNOWN STROKES BUT A LOOT DIDN'T
HAS ANYBODY DONE GENETICS ON
THESE PATIENTS? YOU WOULD BE
SURPRISED I THINK THERE ARE A
LOT OF REALLY BIG NUMBERS MUCH
PATIENTS OUT THERE THAT HAVE
UNIDENTIFIED SPG, LET ALONE
SPG4, THE NEXT THING COMPANIES
OFTEN LOOK FOR IS IF THERE IS A
PROPER ANIMAL MODEL SO RAT,
MOUSE, FLY, COW, WORM, DOES THE
ANIMAL MODEL MATCH THE HUMAN
PHENOTYPE? AGAIN ANOTHER SOURCE
OF MONEY FOR RESEARCH IF YOU DO
DEVELOP SOMETHING TO PROMOTE
DEVELOPING THESE MODELS IS THAT
THESE MODELS CAN BE PURCHASED IN
ORDER TO -- LIKE YOU COULD BE
FINANCIALLY SUPPORTED TO HELP
TEST THE DRUG EFFICACY. A
SYMBIOTIC RELATIONSHIP BETWEEN
PHARMA AND ACADEMIA AND PHARMA
AND SCIENTISTS, FOR EXAMPLE,
USUALLY STARTS OUT WHERE YOU
HAVE IN VITRO TESTING CELL DATA
ANIMAL MODELS, HEALTHY
VOLUNTEERS PILOT STUDY IN PHASE
THREE.
ONCE YOU GET THE ANIMAL MODEL IN
PLACE AND YOU CAN TEST THE DRUG
ON THE ANIMAL MOWED MODEL YOU'RE
PRETTY MUCH DONE WITH THE MOST
IMPORTANT PART OF THE DRUG
DEVELOPMENT PHASE ASIDE FROM THE
CLINICAL OUTCOMES WHICH I'LL
TALK TO YOU LATER.
SO THIS IS ONE PART THAT I THINK
IS VERY IMPORTANT TO THINK ABOUT
AND I THINK IS OFTEN A RATE
LIMITING STEP AND VERY, VERY
IMPORTANT TO DRUG DEVELOPMENT.
SO IT IS THE HARDEST THING IS TO
HAVE A -- TO GET A DRUG THE
HARDEST ITEM THAT YOU NEED TO
FIND, IN ORDER TO GET A DRUG
APPROVED, IS A FUNCTIONAL
CLINICAL OUTCOME MEASURE.
SO THIS IS SOMETHING THAT NEEDS
TO BE RESPONSIVE TO CHANGE OVER
TIME. AND IT MEASURES PRIMARILY
WHAT IS SOUGHT AFTER BY THE FDA
TO PROVE THAT THE DRUG WORKS.
NOW WE DEFINITELY INVEST A LOT
IN BIOMARKERS SUCH AS
PHARMACODYNAMIC EFFECTS USING
THE EXAMPLE OF WHAT WE'RE
WORKING ON RIGHT NOW. SORBITOL
IS A BLOOD ASSAY WE CAN CHECK
THE SKY HIGH IN PATIENTS
RESPONDS TO DRUG USE BUT IS THAT
ENOUGH? IT'S USUALLY NOT ENOUGH
EVEN IF YOU HAVE A BLOOD
BIOMARKER YOU REALLY NEED A
FUNCTIONAL CLINICAL OUTCOME
MEASURE TO SUPPORT THE FACT THAT
EVEN IF -- LIKE SO WHAT DOES IT
EVEN MATTER IF THE SORBITOL
LEVELS DROP IS WHAT THE FDA IS
GOING TO SAY. DOES IT MATTER?
HOW DO YOU KNOW IT MATTERS IT'S
THE FUNCTIONAL CLINICAL OUTCOMES
THAT MATTER. THE WAY TO
IDENTIFY WHETHER OR NOT THE
FUNCTIONAL CLINICAL OUTCOME IS
GOING TO MATTER IS HAVING A
NATURAL HISTORY STUDY.
FOR EXAMPLE IN OUR DRUG GROUP,
FOR EXAMPLE IN OUR FOR OUR
DISEASE WE'RE WORKING ON THERE
WAS NO NATURAL HISTORY ON SORB,
ON CM T BUT NOT SPECIFIC TO SORB
AND CREATES A LOT OF STRESS IN
TERMS OF TRYING TO IDENTIFY
WHAT'S THE PRIMARY OUTCOME
MEASURE SECONDARY WHAT'S GOING
TO WORK FOR THE FDA WHAT WILL
THEY ACCEPT. IT LEADS TO A LOT
OF STRESS.
HAVING THAT INFORMATION ALREADY
AHEAD OF TIME IS INVALUABLE. SO
HAVING, LIKE, AT LEAST A
TWO-YEAR PERIOD OF A PROSPECTIVE
TRIAL ON A NATURAL HISTORY STUDY
THAT YOU CAN PUT TOGETHER AS A
GROUP AND I KNOW THERE ARE
TRIALS ALREADY IN SPASTIC
PARAPLEG
PARAPLEGIA, I DON'T KNOW IF IT'S
SPECIFICALLY TO SPG4, BUT HAVING
INVALUABLE AND MAKE THAT NEXT
STEP OF GOING FROM ANIMAL TO
HUMAN TRIALS VERY EASY.
THE OTHER THING I THINK IS VERY
IMPORTANT AND SO BEAUTIFUL TO
SEE ALL OF YOU HERE TOGETHERS,
IN THIS SYMPOSIA IS YOU NEED TO
HAVE A COHESIVE PHYSICIAN
SCIENTIST COLLABORATION ON HOW
TO MEASURE OUTCOMES IN THIS
PATIENT POPULATION.
SO MAKING SURE YOU ARE ALL ON
THE SAME PAGE MAKING SURE THERE
IS NO BACK AND FORTH ON WHICH IS
THE BEST OUTCOME MEASURE, HAVE
THAT DISCUSSION BEFORE YOU
PRESENT IT TO THE COMPANY, FOR
EXAMPLE, MAKE SURE THAT YOU
PRESENT AS A UNIFIED FRONT. I
THINK THIS IS HUGE. AND GIVES
YOU A LOT OF STRENGTH AND POWER
AS A COMMUNITY.
AND AGAIN, ONCE YOU HAVE THIS
NATURAL HISTORY DATA, THE WAY
THE MONEY CAN BE CYCLED BACK
TOWARDS RESEARCH AND SUPPORTING
RESEARCH IS THAT SOMETIMES THIS
NATURAL HISTORY DATA CAN
ACTUALLY BE PURCHASED AS WELL.
SO AGAIN, NO PATIENT IDENTIFYING
INFORMATION BUT YOU DO GET YOU
KNOW WHEN THE PHARMA COMPANY
WANTS TO KNOW WHAT DOES THE
NATURAL HISTORY STUDY SHOW YOU
CAN SAY I WILL GIVE YOU THIS
INFORMATION BUT IT COMES AT A
PRICE. IT'S FINE TO DO THAT
BECAUSE IT'S A WAY TO YOU KNOW
MAKE SURE ACADEMIA IS SUPPORTED
AND MONEY GOES TO GRANTS IN
TERMS OF RESEARCH AND SUPPORTS
THE CONSORTIUM AND MEETINGS THAT
YOU'RE HAVING AND WHAT NOT.
SO AFTER THAT, YOU -- SO IF YOU
DO ACTUALLY HAVE LIKE A DRUG, AN
ANIMAL MODEL AND NATURAL
HISTORY, YOU HAVE TO ASK
YOURSELF, IS THIS COMPOUND
DRUGABLE? SO CAN THE
PHARMACODYNAMIC EFFECTS OF THE
DRUG BE MONITORED? YOU KNOW YOU
NEED TO BE ABLE TO MONITOR THE
DRUG ACTION AND EFFICACY, YOU
NEED TO KNOW IF THERE'S A
BIOMARKER RELEVANT TO THE
DISEASE PROCESS THAT NEEDS TO BE
DEVELOPED AND THE OTHER THING
THAT GETS CHECKED WHEN DOING
DRUG DEVELOPMENT AND
PHARMACODYNAMICS I MEAN PHARMACO
PHARMACOKINETICS IMPORTANT TO
DETERMINE FOR ABSORPTION
DISTRIBUTION METABOLISM AND
EXECUTION.
IS THERE A POTENTIAL RISK OF
DRUG TOXICITY AND OTHER
COMPONENTS IN DRUG FORMULATION
AND MANUFACTURING ARE CHEMICAL
STABILIZERS AND THERE'S A
DRAMATIC EFFECT ON BIO
AVAILABILITY AND DRUG EFFICACY
SO ONCE YOU GET PAST THE PHASE
OF THIS DRUG IS SAFE WE CAN DO
PHARMACODYNAMIC AND
PHARMACOKINETIC STUDIES AFTER
THAT YOU HAVE TO START THINKING
HOW CAN THIS DRUG BE FORM
SCOMPLATD THE MANUFACTURING
COSTS, LIKE FOR EXAMPLE I KNOW
THERE HAVE BEEN STUDIES ON
CERTAIN CONDITIONS THAT THE
MANUFACTURING OF THE DRUGS
ESPECIALLY WHEN IT COMES TO GENE
THERAPY OR VECTOR DEVELOPMENT IS
INCREDIBLY EXPENSIVE YOU HAVE TO
THINK ABOUT HOW SUSTAINABLE IS
THAT HOW CAN YOU MAKE SURE THAT
DRUG GETS DISTRIBUTED
APPROPRIATELY EVEN AFTER YOU
DEVELOP IT.
AND THEN WHO TO APPROACH IF THEY
TONIGHT REACH OUT TO YOU FIRST?
ALWAYS KNOW FROM MY EXPERIENCE
ON A BIOTECH SIDE PHARMA SIDE
ALL LOOKING TO SIGH IF THERE'S
ANY NEW DATA COMING ABOUT ALL
INTERESTED IN FINDING OUT OTHER
APPLICATIONS OF THE DRUGS WE
MIGHT BE DEVELOPING. AGAIN
WORKING WITH BIOTECH ORTECH OR
SMALL PHARMA IS EASIER, YOU HAVE
EASIER ACCESS TO DECISION MAKERS
AND THESE DECISION MAKERS TEND
TO ACT VERY QUICKLY BECAUSE
AGAIN USING THE EXAMPLE OF
COMPANY THAT I WORK FOR THE CEO
FOR EXAMPLE PURCHASED THE PATENT
TO THE DRUG, AND SHE'S IN DRUG
DEVELOPMENT RIGHT NOW. AND
SHE'S BEEN DEVELOPING FOR QUITE
SOME TIME. AND THEY'RE ALWAYS
LOOKING FOR YOU KNOW ANY OTHER
APPLICATION OF THIS SPECIFIC
DRUG TO AGAIN GET THE ATTENTION
OF INVESTORS AND THEN SUPPORT
THE FURTHER DEVELOPMENT OF THE
DRUG AND KEEP THE COMPANY ALIVE.
SO ANY -- DON'T EVER THINK THAT
ANY QUESTION IS TOO SMALL REACH
OUT TO THEM AND REACH OUT ON THE
WEBSITES AS WELL.
AND THEN FINALLY, YOU CAN STILL
STAY INVOLVED ONCE BIOTECH OR
PHARMA IS INVOLVED, SO
OFTENTIMES YOU KNOW ONCE THE
COMPANY REACHES OUT TO FOR
EXAMPLE THE PERSON ON THE PAPER
HOW MANY PATIENTS DO YOU HAVE
THEY IDENTIFY YOU AS A KEY
OPINION LEADER OR KOL AND THEY
IDENTIFY THESE BASED ON WHO'S AN
AUTHOR A PAPER WHO HAS PATIENTS
IDENTIFIED AS CONSORTIUM OR PART
OF A CONSORTIUM YOU HAVE TO
REALIZE THEY WORK FAST SO FAST
IT'S UNNERVERING, IF YOU WORK IN
ACADEMIA OR COME TO AN ACADEMIC
BACKGROUND LIKE I DO IT'S
ALARMING OH, MY GOD THESE THINGS
ARE MOVING SO SO QUICKLY BUT IN
A WAY IT'S VERY GOOD BECAUSE IT
JUST FORCES THINGS ALONG.
BUT YOU DON'T HAVE TO GO AS FAST
AS THEY'RE GOING I THINK IT'S A
SYMBIOTIC RELATIONSHIP WHERE YOU
WORK TOGETHER AND GET TO A HAPPY
MEDIUM AND NOT GET STUCK IN THE
STAGNATION OF NEEDING MONEY TO
MAKE PROGRESS WITH YOUR WORK
THAT YOU WANT TO DO, HAVING A
COMPANY THAT'S READY TO SUPPLY
YOU FINANCIAL SUPPORT FOR THE
WORK YOU WANT TO DO, AND THEN
KIND OF WORKING TOGETHER AT THE
SAFE AND CORRECT SPEED TO
DEVELOP THE DRUG THAT YOU NEED
FOR -- FOR YOUR DRUG, FOR YOUR
CONDITIONS, SUCH AS SPG4.
SO I WOULD SAY YOU WANT TO LEARN
TO COMPLIMENT BIOTECH OR PHARMA
ALLOWS IF YOU HAVE A GOOD
WORKING RELATIONSHIP BETWEEN
KOLS AND CONSORTIA THIS LEADS TO
MORE MONITORING THE STUD TEE
THAT GETS DEVELOPED MORE OF THE
KOL INPUT INTO THE DRUG
DEVELOPMENT WHICH OVERALL MAKES
IT IT A BETTER STUDY I'M A BIG
PROPONENT OF HAVING ALL THE
PEOPLE INVOLVED EVERYBODY ON
THIS CALL FOR EXAMPLE IF A DRUG
IS GETTING DEVELOPED FOR SPG4 WE
NEED YOUR INPUT NOT EVEN JUST
SCIENTISTS OR CLINICIANS, EVEN
PATIENTS, PATIENTS REALLY
MATTER, PATIENT FAMILIES,
PATIENT ROUND TABLES, GETTING A
REALLY COMPLIMENTARY
RELATIONSHIP WITH A BIOTECH
PHARMA COMPANY IS IMPORTANT.
I WOULD ALSO RECOMMEND THAT IF
YOU HAVE FELLOWS THAT ARE IN
TRAINING, YOU KNOW WHEN I WAS
TRAINING PHARMA WAS ALWAYS
THOUGHT OF BEING THE DARK SIDE
AND IT WASN'T VERY ENCOURAGED,
BUT WHAT ENDS UP HAPPENING IS
YOU GET A LOT OF PEOPLE THAT
AREN'T NECESSARILY THE RIGHT
PEOPLE WHO ARE TRAINED TO
RECOGNIZE, TREAT AND MONITOR
THIS DISEASE WORKING ON THE
TRIAL.
SO IF YOU HAVE A COMPANY THAT
HIRES THE RIGHT PEOPLE THEN YOU
HAVE SOMEONE ON THE INSIDE
MAKING SURE WHATEVER YOU ON THE
OUT SIDE ARE RECOMMENDING GETS
TRANSLATED CORRECTLY TO THE
HIGHER UPS IN THE COMPANY AND
THAT THE STUDY IS DONE CORRECTLY
FROM THE INSIDE.
I DO SEE THERE IS EVOLUTION IN
PHYSICIANS AND A LOT MORE PEOPLE
HAVING AN INTEREST IN WORKING IN
PHARMA I THINK THERE'S A LOT OF
GOOD THAT A LOT OF PEOPLE WITH
EXTENSIVE TRAINING CAN PROVIDE
FROM WITHIN PHARMACEUTICAL
COMPANIES AND BIOTECH COMPANIES
JUST TO MAKE SURE WITHIN THE
INSIDE THAT THINGS GET DONE
CORRECTLY.
SO I HOPE YOU FIND THAT HELPFUL.
AND THANK YOU AGAIN TO ARIANNE
FOR THIS LOVELY OPPORTUNITY TO
SPEAK TODAY.
>> THANK YOU SO MUCH BEAUTIFUL
FOR A LOT OF US LIKE A BLACK BOX
ON HOW TO GET DRUGS FROM
ACADEMIA INTO TRIAL SO THANK YOU
SO MUCH FOR YOUR INSIGHTS AND
WE'LL NOW OPEN THE SESSION TO
QUESTIONS.
MAYBE PEOPLE COULD UNMUTE
THEMSELVES AND ASK THEIR
QUESTIONS AND WE'LL TRY TO --
MAY AND I WILL TRY TO GOOD
EVENING GALLAUDET THROUGH THE
CHAT BUT MANY QUESTIONS
THROUGHOUT THE DAY IF YOU RECALL
YOUR QUESTION AND ASK IT
DIRECTLY THAT WILL MAKE OUR JOB
EASIER. THANK YOU SO MUCH.
>> CAN I ASK A QUESTION.
>> YES PLEASE GO AHEAD.
>> HELLO. I THANK ALL THE
SPEAKERS THIS HAS BEEN A
WONDERFUL SYMPOSIUM THANK YOU SO
MUCH FOR ORGANIZING THIS AND
THANK YOU SO MUCH FOR YOUR WORK
IN THIS FIELD WE WEREN'T ABLE TO
HAVE ALL THE SPEAKERS WE WANTED
BUT WE HOPE TO HEAR FROM YOU IN
AN UP COMING MEETING THANK YOU
FORJOINING.
>> OF COURSE NO PROBLEM. ONE OF
THE QUESTIONS I HAVE IS GENE --
GENE THERAPY, ABOUT GENE
THERAPY, SO WE KNOW THAT AAV ARE
VERY, YOU KNOW THEY ARE VERY
GOOD BECAUSE NON TOXIC BUT
LIMITATION IS THE GENE SIZE BUT
IF WE'RE DEVELOPING PERSONALIZED
MEDICINE APPROACHES AND IN SOME
CASES THE GENE SIZE WILL BE VERY
LARGE AND WE WON'T BE ABLE TO
E
ACCOMMODATE WITHIN THE AAV, AND
FOR PROBLEMS LIKE THIS I WOULD
LIKE TO ASK MY COLLEAGUES,
WHAT'S THE POTENTIAL SOLUTION IN
THE FUTURE? HOW CAN WE
ACCOMMODATE PATIENTS WHOSE
JOOEGENES
ARE LARGER THAN THE SIZE WE CAN
ACCOMMODATE WITHIN THE AAV,
THANK YOU. SO MAYBE MIGUEL MAY
HAVE SOMETHING TO SAY, MAYBE
PETER MAY HAVE SOMETHING TO SAY,
MAYBE DARIOUSH MAY HAVE
SOMETHING TO SAY, I DON'T KNOW
WHO WOULD HAVE AN IDEA.
>> HI HANDE, NICE TO SEE YOU.
SO YEAH WELL WE DEAL WITH THAT,
WE HAVE A PROGRAM IN NF1, SO YOU
KNOW FOR VERY LARGE 8.8KB, YOU
KNOW THERE IS AAV DOES FUNNY
CONTRIBUTION IN THE NUCLEUS, AND
WHAT PEOPLE HAVE FOUND OUT, AND
WE'VE DEMONSTRATED FOR NF1 AS
WELL YOU CAN DEVELOP A TWO
VECTOR SYSTEM. IT BECOMES THE
GENOMES RECOMBINE IN THE NUCLEUS
AND YOU CAN USE DIFFERENT TRICKS
YOU CAN ACTUALLY EXPRESS THE
FULL LENGTH. THAT WORKS WELL.
SO THE DIFFICULTY THAT WAS
ACTUALLY EMPLOYED FIRST BECAUSE
VERY LOCALIZED AREA RELATIVELY
EASY (DEVELOPED IN THE EYE
FIRST) BRAIN A LITTLE MORE
COMPLICATED BECAUSE OF
DEFICIENCIES NOT TREMENDOUSLY
HIGH. SO I THINK FOR DISEASES
LIKE NF1, AND YOU KNOW OTHERS,
OBVIOUSLY, WHERE THE GENE IS TOO
LARGE WE'RE GOING TO HAVE TO
HAVE A LEAK IN EFFICIENCY TO
ACTUALLY BE ABLE TO DO IT
BECAUSE WE'RE HAVING THESE
CONVERSATIONS OVER THE CHAT WITH
DARIOUSH ABOUT YOU KNOW
TRANSACTION OF THE ESSENTIALLY
THE BRAIN FROM A CSF INFUSION A
SUPER REGION OF THE CNS AND I
MEAN IT'S LIMITED IT'S VERY,
VERY LIMITED FOR SURE. SO YOU
KNOW I THINK THE SUCCESS WITH
SPINAL MUSCULAR KIND OF LULLED
US INTO A SENSE WE'RE PRETTY
MUCH DONE WE CAN CURE ANYTHING.
I SUSPECT FOR DISEASE WHERE YOU
DON'T HAVE BY STANDER EFFECTS OR
YOU KNOW AN ENZYME SECRETED,
WHAT HAPPENED SO SMA PERFECT
VECTOR FOR PERFECT DISEASE
PERFECT TROPISM, HOPEFULLY NOT
TOXIC BUT EFFECT ARE YOU KNOW
SMALL, LET'S PUT IT THAT WAY.
>> DO YOU THINK WE SHALL FOCUS
ON THE ANTI VIRUS IN ADDITION TO
AVV? LANSY OFFERS A LARGER SIZE
AND MAYBE WE CAN HAVE LESS TALK
TAME THEM A B MIGUEL: YOU'RE
RIGHT. THE PROBLEM IS
MANUFACTURING.
MANUFACTURING LINKING IS
DIFFICULT. IT IS DIFFICULT.
ISSUES WITH STABILITY OF THE
PRODUCT. ONE THAT HAS TO BE
KEPT AT MINUS 80 AND THE
DEFICIENCY DISTRIBUTION ITSELF
IS MUCH, MUCH MORE LIMITED. SO
IT'S A VERY USEFUL PLATFORM FOR
SURE IT HAS THAT ADVANTAGE,
OBVIOUSLY CAN INTEGRATE NON
DIVIDES CELLS BUT DISTRIBUTION
WISE IS A BIT MORE CHALLENGING,
I THINK. AND MANUFACTURING AS
WE
WELL.
>> I SEE DR. CHIANG HAS RAISED
HIS HAND.
>> THAT'S GOOD TO SEE MIGUEL
AGAIN I HAVE A QUESTION MIGUEL
WE HAVEN'T TALKED ABOUT IT
DURING OUR CONVERSATION. YOU
KNOW INSTEAD OF HAVING THE WHOLE
GENOME LIKE THE GENINGS IN THERE
YOU KNOW TRY TO OVERCOME LIKE
YOU KNOW THE ENSUFFICIENCY OR
THE LOSS OF THE FUNCTION CAN WE
ACTUALLY RESTRATIFY THE APPROACH
TO TARGETING SOME MICRO RNA
USING ANTI ZEN BECAUSE YOU HAVE
KNOWN FOR OTHER DISEASES A LOT
OF MICRO RNA ARE REGULATED TO
REGULATE GENE EXPRESSION.
AND I BET WE CAN FIND A COUPLE
OF MICRO RNA THAT CAN
SPECIFICALLY REGULATE SPATANS
OVER EXPRESSION LEVEL. IF WE
TARGET MICRO RNA KIND OF PIGGY
BACK ON THE ANTI ZEN TECHNOLOGY
WE CAN INSTEAD OF HAVING GENOME
BUT TARGET MICRO RNA SO PROBABLY
YOU KNOW APPROACH TO THE SAME
KIND OF FILE PROJECT WHAT DO YOU
THINK WHAT'S YOUR TAKE ON THAT.
>> MIGUEL ESTEVES: OH, SO WE
DON'T HAVE -- WELL AT LEAST OUR
KNOWLEDGE OF MICRO ASE WE HAVE A
THOUSAND OF THEM? THEY DON'T
REGULATE A SINGLE GENE, RIGHT?
REGULATING A MICRO RNA IT'S
POSSIBLE YOU CERTAINLY CAN USE
SPONGES ESSENTIALLY WHAT'S
CALLED SPONGES FOR MICRO RNA. S
ON THE OTHER HAND I APOLOGIZE
FOR NOT REMEMBERING THE NAME OF
OUR FIRST SPEAKER, THAT IT
REALLY IS USE CORRECT LOTS OF
GENES DO HAVE THESE ANTI SENSE
NOT NON CODING RNAS INVOLVED IN
GENE EXPRESSION.
QUITE A FEW PROGRAMS USING THIS
TO TARGET THESE NON CODING
TRANSCRIPT THAT USUALLY OVERLAP
THE TRANSCRIPTIONAL START SITE.
YEAH YOU CAN ACTUALLY UP
REGULATE GENES THE QUESTION IS
FALLING BACK ON FUNCTION VERSUS
INSUFFICIENCY FOR INSTANCE WE
HAVE COW MODEL. SHE'S REJOINED
AND SHE IDENTIFIED A COW MODEL
THAT IS ACTUALLY I THINK A HAPPY
INSUFFICIENCY BECAUSE THE
ANIMALS NEED TO BE CURIOUS OF
THE MUTANTS OTHERWISE WE'LL HAVE
AN AGGRESSIVE PHENOTYPE. I
DON'T KNOW IF YOU REMEMBER HOW
LONG THEY LIVE IN A SITUATION
LIKE THAT IF YOU HAVE
INTERWHEELS THAT'S NOT GOING TO
HELP YOU BUT I DON'T THINK
THAT'S THE CASE FOR MOST
PATIENTS RIGHT.
>> RIGHT THE SECOND QUESTION I
HAVE IS TO THE PANEL I THINK
HANDE WHO IS EXPERT IN UPPER
MOTOR NEURON STUDIES AS A
SOCIETY TO STUDY SSP, FOCUS ON
UPPER NEURON OR IS THIS A
DISSEAT THAT AFFECTS OTHER TYPES
OF NEURONS I'M NOT 100 PERCENT
CONVINCED SPECIFICALLY CAUSED
MUTE TAGS ON JUST UPPER MOTOR
NEURON TO BE HONEST I KNOW HANDE
HAS A LOT OF DATA DEMONSTRATED A
PATHWAY BUT I'M WONDERING IF
THERE IS ANY YOU KNOW KIND OF
STUDY THAT CAN BE DONE CHECKING
ON EVEN LIKE INHIBITORY NEURONS,
CASES IN ALS LOSS EVER
INHIBITORY MOTOR NEURONS PROCEED
IN LOSS OF MOTOR NEURONS IN ALS
IF SOMEBODY CAN COMMENT ON THAT
THAT WOULD BE GREAT.
>> IN OUR PATIENTS WITH INFANT
TILE ONSET. THE ONE HAVE NEFB
CON STUKS DUKS STUDIES I HAVEN'T
FOUND NEUROPATHY IN UNLIKE OTHER
FORMS OF HSP WHERE NEUROPATHIES
TONED RUN CONCORD NATELY SUCH AS
PG11 I DON'T KNOW WHAT DARIOUSH
HAS FOUND IN HIS PATIENTS I WAS
TRYING TO LOOK AT THAT BEFORE
THIS CONFERENCE BUT I DO THINK
WE NEED TO BE CAREFUL AND GET
NERVE CON DUSHGS STUDIES ON
PATIENTS TO FORMALLY ANSWER THAT
QUESTION.
>> THIS IS KATHARINE ONE OF THE
OTHER ISSUES (INAUDIBLE)
SOMETIMES THESE PATIENTS HAVE
BONING AND CENTRAL CONDUCTION
TIMES SO WE HAVE TO LOOK MORE
PROXIMALLY THAN WE DO WHEN DOING
STANDARD NERVE CONDUCTION
TESTING OF THEM AND DOING SSEPS
TO LOOK FOR CONDUCTION TIME
CHANGES THAT MIGHT PROVIDE
INFORMATION THAT WE DON'T SEE
SOCIALLY.
>> THAT WOULD BE ANOTHER GREAT
STUDY I WOULD LIKE TO LOOK AT
TOGETHER. I HAVE MONITORING ON
SOME PATIENTS WHO HAVE HAD
SCOLIOSIS SURGERY SO MUCH I NEED
TO LOOK AT AND I AGREE WITH YOU.
OF.
>> IF I CAN JUST QUICKLY ADD TO
THAT FROM MY PERSPECTIVE? I
THINK IT'S A VERY IMPORTANT
QUESTION. I THINK THE
INVOLVEMENT OF YOU KNOW OF
PERIPHERAL NERVOUS SYSTEM IS ONE
QUESTION BUT I THINK WHEN WE
THINK ABOUT WHAT BRAIN REGIONS
TO TARGET WITH ANY THERAPY I DO
WORRY WE WOULD PROBABLY HAVE TO
TARGET WIDESPREAD SUPER TUTORIAL
BRAIN REGIONS TO REALLY -- TO
REALLY TACKLE THE UNDERLYING
DISEASE PROCESS. THE FOCUS HERE
IS ON CORTICAL SPINAL TRACKS
BECAUSE FRANKLY THAT'S WHAT WE
SEE PROGRESSING CLINICALLY.
BUT -- BUT IT'S MORE COMPLICATED
THAN THAT. AND WE'VE HAD A
LITTLE BIT OF DISCUSSION OVER
THE CHAT ABOUT HOW TO ACHIEVE
THAT WITH A CURRENT VECTORS, I
THINK IT'S -- IT'S A BIG
CHALLENGE FOR THE FIELD, AND I
THINK WE NEED VERY GOOD
COMPARATIVE STUDIES IN NON HUMAN
PRIMATES TO REALLY TELL WHAT THE
BEST APPROACH IS AND CERTAINLY
WE NEED A NEXT GENERATION OF CAP
SAID AT SOME POINT. BUT I THINK
THIS QUESTION OF SOW DO WE
DEFINE THE TARGET AND HOW GET
TRANSGENIC EXPRESSION WHERE WE
NEED TO GET IT IS A VERY GOOD
ONE AND ONE THAT IS NOT EASY TO
ANSWER, I'M AFRAID.
AND IT'S RELEVANT FOR ALL AGES,
NOT JUST FOR SPG4.
>> IF I COULD ADD A THOUGHT TO
THAT? ONE THE THINGS THAT
OCCURS TO ME IS WHY ARE CORTICAL
SPINAL TRACKS PARTICULARLY
VULNERABLE TO DEGENERATION IN
THIS DISEASE WHEN ALL OF THE
OTHER CELLS OF THE NERVOUS
SYSTEM ALSO EXPRESS SPASTIN AND
EVEN THOUGH THE LEVELS OF
M1SPASTIN ARE EXTREMELY LOW
BELOW THE LEVEL OF DETECTION
STILL TO HAVE A TOXIC EFFECT OUR
STUDIES ON SQUIDS FOR EXAMPLE
SHOW IT'S VANISHING LOW LEVELS
ARE REQUIRED TO HAVE A TOXIC
EFFECT. SO WHAT I'M WONDERING
IS PERHAPS WE SHOULD BE THINKING
ABOUT THE VULNERABILITIES OF THE
THE COURT YAL SPINAL TRACKS
THEY'RE PARTICULARLY LONG AXONS
COMPARED TO MANY OF THE AXONS OF
THE BODY, AND IT REALLY MAY BE A
FAILURE IN THEIR ABILITY TO
UNDERGO SUFFICIENT OTOPOGY TO
DEGREAT THESE MUTANTS, WHEREAS
OTHER CELLS OF THE NERVOUS
SYSTEM OTHER CELLS OF THE BODY
MAY HAVE SUFFICIENT OTOPOGY
SUFFICIENT EFFICIENCY TO DEGRADE
AND KEEP TOXIC EFFECTS AT BAY.
SO I THINK THAT'S ANOTHER AVENUE
THAT WE SHOULD PAY ATTENTION TO,
BECAUSE THERE CERTAINLY ARE
CASES COMPLICATED CASES, WHERE
PATIENTS WITH HSP DO SUFFER
COGNITIVE DIFFICULTIES, FOR
EXAMPLE, AND IT'S THE SAME GENE
MUTATION.
SO I'M THINKING IT'S A
VULNERABILITY ISSUE THAT
NORMALLY SAY THAT THE CENTERS
FOR THE BRAIN RESPONSIBLE FOR
COGNITION AND MEMORY THEY CAN
HANDLE THE LOAD OF A MUTANT
PROTEIN THEY CAN DEGRADE IT FAST
ENOUGH USUALLY BUT NOT ALWAYS.
FOR SOME REASON CORTICAL SPINAL
TRACKS CAN'T. AND IF YOU THINK
OF ALL THOSE 92 POTENTIALLY MORE
JOOE
JEA
GENES THAT CAN MUTATED ALL OF
WHICH GIVE A VERY COMPLICATED
DISEASE SYSTEM IS IT BECAUSE
THEY ALL TAP INTO THE SAME
PATHWAY OR BECAUSE CORTICAL
SPINAL TRACKS ARE JUST SO
VULNERABLE. SO I THINK THAT'S
ANOTHER WAY TO THINK ABOUT ALL.
>> HANDE: PETER I THINK YOU
NAILED IT THIS SHOWS VERY
IMPORTANT BECAUSE LIMITATION IS
EXPRESSED IN ALL CELLS
EVERYWHERE BUT SELECT NEURAL
POPULATIONS SHOW PRIMARY
VULNERABILITY THAT DOESN'T MEAN
OTHERS ARE NOT ALL AFFECTED THIS
MEANS THESE ARE MORE AFFECTED
AND THEY SHOW EARLY
VULNERABILITY AND PROGRESS OF
DEGENERATION THEY START THE RACE
EARLY. AND WE SEE THEIR -- WE
SEE THE OUTCOME AS CORTICAL
SPINAL TRACK DEGENERATION AND SO
FORTH.
AND COMING BACK TO THE INTER
NEAR RONS AND P OTHER CELLS
BEING EFFECTED I THINK INTERTER
NEURONS ALSO AFFECTED BUT I
THINK AS YOU SAY THEY MAY
COMPENSATION MAYBE NOT AS
VULNERABLE BUT CORTICAL SPIEM
NEURONS VERY VULNERABLE. IF
THERE'S ANY PER TER BANS OF
IMBALANCE THEY PAY THE PRICE NO
LUXURY OR LEG ROOM OR WIGGLE WAY
TO BE OKAY. EVERYTHING NEEDS TO
WORK PERFECTLY TO FUNCTION
PERFECT FOR THEM TO FUNCTION.
AND WE SEE COMING BACK TO
LEANNE'S QUESTION THAT BCD
CORTICAL SPINAL MULTI NEURONS
DISPLAY EARLY -- MUCH EARLIER
THAN ANY NEURONS IN THE BRAIN
AND WE CROSS THE MOUSE THAT
PETER ACTUALLY VERY GENEROUSLY
SHARED WITH US HIS SPATIN MODEL
SO THE FACTS VERIFY THEM DO
PROTOOMICS TOGETHER WITH ALL
MIXED CORTICAL CELLS SOMETHING
UNIQUE ABOUT THESE CELLS
SOMETHING INTRINSIC ABOUT THEM
THAT THIS MUTATION MAKES THEM OR
PU
PUSHES THEM TO MUCH EARLIER TO
VULNERABILITY.
COMING BACK DARIA'S QUESTION.
IF WE MOVE TO CLINICAL TRIALS
THERE'S THE SAYING IN TURKISH
THE MOMENT YOU WANT TO CURE THE
EYE, YOU ACTUALLY DESTROY THE
WHOLE THING, YOU KNOW? BECAUSE
YES WE WANT TO CURE THE UPPER
MOTOR NEURONS BUT IF WE'RE
UNSELECTIVE IN OUR EFFORT AND
START SHOOTING EVERYONE AND THEN
WE MAY ACTUALLY GIVE THE GENES
THAT ARE NOT NEEDED OR OVER
EXPRESSION MAY EVEN BE TOXIC TO
SOME UNRELATED CELLS OR GENES,
SO RATHER THAN HAVING AN IMPACT
OVERALL GOOD IMPACT WE MAY HAVE
SOME TOXICITY SOME SIDE EFFECTS
SOME UNWANTED EFFECTS FOR THE
PATIENTS ESPECIALLY THESE ARE
FOR GENE THERAPY ONE TIME AND
LIFELONG EFFECTS THIS WOULD BE
EXTREMELY DANGEROUS. I WOULD BE
VERY CONSCIOUS TO DELIVERING THE
GENES OF INTEREST ONLY TO THE
NEURONS IN NEED WITHOUT
AFFECTING OTHER CELLS AND
NEURONS.
>> RIGHT AND AS MIGUEL POINTED
OUT WE'RE TALKING ABOUT A MICRO
TUBE YAL PROTEIN THAT IF YOU
OVER EXPRESS AT THE CELLS YOU
OBLITERATE THE MICRO TUBULAR RAY
SO GOING FOR A SOMEWHAT LEVEL
EXPRESSION TO HAVE NO OVER
EXPRESSION IS REALLY IMPORTANT.
I THINK ANOTHER PIECE OF THIS
PUZZLE IS THE FACT THAT IN THE
SAME FAMILY ONE FAMILY MEMBER
MAY NOT SEE SYMPTOMS UNTIL HIS
OR HER 70S, ANOTHER FAMILY
MEMBER MAY SEE THE SYMPTOMS AT
CHILDHOOD. AND WHY IS IT? IS
IT BECAUSE THIS PERSON HAS A
MORE -- MORE ACTIVE OTOPAGY THAN
THIS PERSON OR WHAT? IF WE
COULD SOLVE THAT MYSTERY THEN IT
MIGHT ENABLE US TO BETTER
UNDERSTAND THE ISSUE OF
VULNERABILITY AND THEN TREAT THE
ISSUE OF VULNERABILITY IN ORDER
TO HELP PATIENTS OVERCOME.
I THINK ALSO, BEFORE WE CLOSE
THE -- THE SYMPOSIUM, WE NEED TO
GET BACK TO THE ISSUE OF
PEDIATRIC CASES AND INNOVEMBER
VOE CASES AND IS IT THAT THE
SAME MUTATION IN THESE DE NOVO
CASES IS CHILDHOOD ONSET? WHEN
IN HEREDITARY CASES IT'S ADULT
ONSET? AND I THINK IT MUST BE
TELLING US SOMETHING ABOUT THE
GENETIC BACKGROUND THAT A FAMILY
WHO HAS HAD THIS MUTATION FOR
GENERATION AFTER GENERATION
AFTER GENERATION, THEY'RE
OBVIOUSLY REPRODUCTIVELY CAPABLE
OF HANDLING THAT MUTATION WELL
ENOUGH TO GROW UP AND HAVE
CHILDREN AND PASS IT ON.
OTHER PEOPLE, WHOSE FAMILIES
DON'T HAVE THAT MUTATION IN
THEIR BACKGROUND, IT HITS THEM
MUCH HARDER AND THOSE CHILDREN
MAY NEVER GET TO REPRODUCTIVE
AGE.
SO I THINK IT'S TELLING US HOW
IMPORTANT GENETIC BACKGROUND IS.
AND THAT YOU CAN'T CONSIDER JUST
SPG4 IN ISOLATION OF EVERYTHING
ELSE THAT'S GOING ON.
>> I'M NOT SURE THAT'S A
QUESTION?
>> YES, SORRY, GUYS, I THINK
KIND OF GOING TO PETE BAAS'S
COMMENT BUT ALSO -- SORRY WE ALL
KNOW I HAVE A SICK CHILD -- SO
AS -- AS WE RELOOK AT OUR
PATIENT, WHAT IS A GOOD OUTCOME
MEASURE? BECAUSE AS I WATCHED
THE 10-YEAR VIDEOS, I THINK
IT'S -- IT'S GOING TO BE HARD.
I THINK IT'S GOING TO BE HARD TO
FIND WHAT IS A GOOD OUTCOME
MEASURE AND LIKE DR. ALTER
BROUGHT UP SOME OF THESE
PATIENTS NEED THEIR PASS SYS
CITY AND IT HELPS THEM WALK AND
AMBULATE I THINK THAT'S A
SEPARATE QUESTION WE NEED TO
ANSWER.
>> WELL RELATED TO THAT IS WHEN
WE APPLY THE GENE THERAPY ARE WE
TRYING TO STOP THE PROGRESSION
OF THE SYMPTOMS, STOP THE
SYMPTOMS FROM GETTING WORSE OR
DO WE REALLY HAVE A CHANCE OF
REVERSING THE SYMPTOMS,
REVERSING THE DEGENERATION
THAT'S ALREADY HAPPENED? IN
THIS SENSE I THINK THE PEDIATRIC
ONSET CASES ARE -- HAVE THE BEST
POSSIBILITY FOR SUCCESS. TO
TAKE AN ADULT PATIENT AND STOP
THE EXPRESSION OF THE GLUTEN
PROTEIN AND THEN HOPE THAT
CORTICAL SPINAL TRACKS ARE
SOMEHOW GOING TO REGENERATE
APPROPRIATELY, THAT'S A MUCH
GREATER CHALLENGE THAN A CHILD
WHO IS STILL DEVELOPING HIS OR
HER CORTICAL SPINAL TRACKS. SO
I THINK IT'S A VERY HOPEFUL
MESSAGE IN THE FACT THAT WE'RE
TALKING ABOUT CHILDREN.
>> MAY I MAKE A COMMENT?
>> YES GO AHEAD PLEASE.
>> FOR THE OUTCOME MEASURES, I
THINK THOSE ARE IMPORTANT FOR
CLINICAL TRIALS, AS WELL. AND I
THINK THE BEST OUTCOME MEASURE
WOULD BE PHARMACOKINETIC
BIOMARKERS THAT WOULD TELL US
THE TIMING OF MOTOR NEURAL LOSS
IN THESE PATIENTS SO WE CAN
TRACK INVESTIGATE WHETHER A DRUG
TREATMENT OR AAV MEDIATED GENE
DELIVERY TREATMENT OR ANY
THERAPEUTIC TREATMENT WOULD HAVE
AN IMPACT IN THE TIMING AND
EXTENT OF MOTOR NEURAL LOSS AND
THEIR CONNECTIVITY.
FOR KNOWS BIOMARKERS I THINK
REBECCA MADE A GOOD PRESENTATION
THEY HAD THE FAMILIES AVAILABLE
IN OUR SMALL COHORT WE PERFORM
LIP POE DOME MIX, MET THERE
SEEMS TO BE A SIGNATURE ACTUALLY
BASICALLY IN THE LIPIDS THAT
SHOWS THE UPPER MOTOR NEURAL
LOSS. SO OF COURSE MORE WORK
NEEDS TO BE DONE BUT I THINK
THERE IS -- THERE IS LIFE AT THE
END OF THE TUNNEL THAT WE WILL
HAVE BIOMARKERS WITHIN A COUPLE
YEARS.
>> THERE ARE ALSO CLINICAL
BIOMARKERS THAT ARE NECESSARY AS
WELL BECAUSE WE NEED TO MEASURE
FUNCTION AND FUNCTIONAL OUTCOMES
AS WELL, YOU KNOW, SO THAT WE
CORRECT SOMETHING
PHYSIOLOGICALLY WE WANT TO KNOW
THAT THAT HAS AN IMPACT ON
FUNCTION. SO THERE'S A NUMBER
OF THINGS THAT CAN BE USED AND
ARE BEING DEVELOPED THAT ARE,
YOU KNOW, AVAILABLE TO MULTIPLE
SITES LIKE THE USE OF A WEARABLE
SENSORS, RATHER THAN FOR
INSTANCE USING THE GATE LAB
USING WEARABLE SENSORS OR A GATE
MAP OR AN ULTRASOUND BIOMARKERS
OF MUSCLE WE HAVE A LOT OF
OPPORTUNITIES TO LOOK AT THINGS,
BUT I AGREE WITH YOU THAT WE
NEED BIOMARKERS IN BOTH ASPECTS
BOTH IN THE PHYSIO LOGIC AND
THEN THE FUNCTIONAL REALMS.
>> THIS IS ANOTHER ISSUE WITH
MOUSE MODELS THAT WE FACE MAYBE
ON ANOTHER OCCASION I WOULD LIKE
TO TALK MORE WITH CRAIG ABOUT
IT, BECAUSE WHEN WE PURSUE
THERAPIES ALL OF THE BEHAVIORAL
STUDIES AND THE HISTOLOGICAL AN
TOM TOM CAL STUDIES THEY /* /-
ANATOMICAL STUDIES THEY TAKE
MONTHS WE NEED MONTHS TO
ASCERTAIN WHETHER THESE
THERAPIES WITH WORKING OR NOT.
I'M OPEN TO SUGGESTIONS FROM THE
COMMUNITY ON WHAT WE CAN DO
OTHER THAN MONTHS AND MONTHS AND
MONTHS OF CAT WALK BEHAVIOR.
>> SO I HAVE A QUESTION FOR THE
MDS, YOU GUYS PRESENTED VERY
INTERESTING INFORMATION ON SOME
OF THESE PATIENTS. I WORK ON
DISEASES WHERE THERE'S ACTUALLY
NO QUESTION WHERE IT'S A NEURO
GENETIC PROCESS NO ONE QUESTIONS
THAT, ONE OF THE THINGS THAT WAS
STRIKING ABOUT THESE VIDEOS THAT
WERE SEPARATED BY ALMOST A
DECADE IN SOME CASES IS THAT IT
DIDN'T APPEAR TO GET WORSE. SO
I STRUGGLE A LITTLE BIT WITH THE
CONCEPT OF NEURO GENERATION IN
SPG4 IN A DISEASE THAT HAS AN
ONSET AND THEN SEEMS TO BE
STATIC FOR A LONG TIME.
SO IS THAT -- I JUST LIKE TO
HEAR A LITTLE BIT ABOUT THIS --
THE CONCEPT OF NEURO DEN JEJ
RAGS VERSUS THIS FUNCTION WHICH
OBVIOUSLY IS VERY IMPORTANT TO
THAT QUESTION THAT PETER ASKED
ABOUT ESSENTIALLY REVERSE
ABILITY, RIGHT? SO YEAH, THANK
YOU.
>> I KNOW KATHARINE WANTS TO
ANSWER I WANT TO INTERJECT
BRIEFLY A LOT OF FAMILIES
WATCHING ONLINE HAVE E MAFLED
ABOUT THAT BECAUSE THE VIDEOS
DID SEEM MORE STATIC THAN A LOT
OF WHAT THEY EXPERIENCE FROM
THEIR CHILDREN KATHARINE HAS --
>> I WOULD SAY FROM MY
PERSPECTIVE AS A MOTION
ANALYSIS/MOBILITY EXPERT, IS
THAT I DIDN'T THINK THAT THE
GATE WAS STATIC. THAT THEIR
FUNCTION CHANGED FROM MORE A C
MODEL OR SPASTICITY WAS WORSE TO
WEAKNESS WAS MORE PROMINENT
FEATURE IN KIDS AS THEY GOT
OLDER AND THAT'S ACTUALLY
TYPICAL WITH KIDS WITH CEREBRAL
PALSY AS WELL MOST KIDS OR MANY
KIDS THAT I SAW IN MICHELLE'S
VIDEOS THEY SORT OF WENT FROM AN
AQUINAS GATE TORE CROUCH GATE
THE GATE IS EVOLVING THAT'S WHY
I MEANT WE NEED BIOMARKERS
QUANTITATIVE BIOMARKERS IN WHAT
CHANGES IN GATES, AND YOU CAN
LOOK AT GATE SPEEDS THAT
VARIABILITY, WE CAN BE LOOKING
AT OXYGEN CONSUMPTION, METABOLIC
COST OF WALKING, BECAUSE THE
METABOLIC COST OF WALKING WHEN
YOU ARE WEAK ARE REALLY HIGH.
AND SAME THING WITH SPASTICITY
THESE KIDS ARE USING 10 TIMES
THE AMOUNT OF OXYGEN AND
METABOLIC COST THAN KIDS WALKING
WITHOUT THESE CONDITIONS.
GETTING QUANTITATIVE GATE
MEASURES OF SOME SORT I THINK
WILL HELP US DETERMINE HOW
STATIC ARE THESE CONDITIONS.
IT MAY BE MORE THAT THEY'RE
CHANGING, NOT STATIC BUT
CHANGING.
AND SO IT'S -- IT'S GOING TO
REQUIRE MEASUREMENT.
>> THANK YOU FOR SAYING THAT SO
ELOQUENTLY I DO WORK WITH THE
HEAD OF OUR GATE LAB WHO CAN
EXPLAIN THAT. THAT'S WHY I
WANTED TO SHOW THE VIDEOS,
ACTUALLY BECAUSE THERE ARE TWO
SUBSETS. WE DO SEE PATIENTS
WITH SPG4 WHO YOU KNOW I TALKED
WITH A FAMILY ABOUT A Q TUBE THE
OTHER DAY THAT WOULD BE A NEW
THING TO HER IT'S A CLEAR
INDICATION OF WORSENING HOWEVER
ANOTHER SUBSET REALLY HARD TO
MEASURE ALMOST SEEMS LIKE
DIFFICULTY IN MEASUREMENT IS
MORE OF THE PATIENTS THAT I SEE.
AND THAT'S WHAT I WANTED TO
HIGHLIGHT AND GET ALL OF OUR
SMART BRAINS TOGETHER ABOUT,
BECAUSE THE CURRENTS GENE
THERAPIES ARE LIKE THEY WERE
SAYING FOR PATIENTS WHO THERE'S
THIS VERY CLEAR DETERIORATION
WITHIN A VERY SHORT PERIOD OF
TIME. LIKE IN THESE NEEDS WE
SEE THEM CRASH VERY QUICKLY AND
YOU KNOW THAT'S I DIDN'T BROUGHT
UP THESE OTHER QUESTIONS, WHAT
IS THE BENEFIT RISK BENEFIT SIDE
EFFECTS IN OUR HEART WE WANT IT
MAKE THESE PATIENTS BETTER
SUPPORT THEM AND DO THE RIGHT
THINGS BY THE FAMILIES.
SO I THINK THESE ARE THE REALLY
HARD THOUGHTS WE GO THROUGH AS
WE TRY TO TREAT THEM AND DO
EVERYTHING WE CAN FOR THEM.
>> DARIOUSH GO AHEAD.
>> DARIUS: I HAVE A COUPLE
THOUGHTS I THINK THESE ARE ALL
GUED POINTS I THINK TO MIGUEL'S
POINT THE KEY QUESTION HERE IS
HOW MUCH OF THE SYMPTOMS OR
PHENOTYPE IF YOU WILL IS
EXPLAINED BY AN EFFECT ON NEURO
DEVELOPMENT? HOW MUCH IS
DYSFUNCTION HOW MUCH
DEGENERATIVE? I DON'T THINK
ANYONE HAS A GOOD SENSE OF THAT
YET. IT'S NOT JUST A PROBLEM
FOR -- FOR YOU KNOW EARLY ONSET
SPG4 BUT FOR MANY OTHER
DISORDERS THAT WE SORT OF GROUP
INTO THE HSP CATEGORY.
I THINK COMING BACK FROM THE
VIDEOS I'VE PRESENTED FROM THE
DATA FROM OUR EXPERIENCE IN
MEETING 17 CHILDREN WITH THIS
CONDITION, IT SEEMS THAT THERE
ARE DIFFERENT TRAJECTORIES AND I
THINK THERE ARE SOME THAT
CLEARLY PROGRESS VERY FAST I
THINK YOU'VE SEEN OUR DATA THE
MAJORITY OF THE PARROTS WE MEET
REQUIRE WHEELCHAIR VERY EARLY
ON.
I THINK THERE IS A LITTLE BIT OF
A MIXED POPULATION, I THINK THE
ONLY ANSWER TO -- THE ONLY WAY
TO EVEN THIS QUESTION IS WE NEED
TO BUILD A LARGER NATURAL
HISTORY STUDY.
I THINK WE JUST NEED THE
NUMBERS. THAT'S THE ONLY WAY TO
GET REALLY GET AT THIS QUESTION.
I WANT TO COME BACK TO MIGUEL'S
FIRST QUESTION, WHICH WAS HOW
MUCH IS PUT FORWARD OR PETA'S
QUESTION HOW MUCH IS REVERSIBLE.
I DON'T THINK ANYONE CAN ANSWER
THAT QUESTION WITH ANY CERTAINTY
BECAUSE NONE OF THE PRECLINICAL
MODELS PREDICT THAT. IT'S
FRANKLY NEVER BEEN DONE BEFORE.
SO I THINK IT'S VERY -- IT'S
VERY UNCLEAR TO ME HOW MUCH IS
REVERSIBLE. HOW MUCH IS
PREVENTIBLE. AND THAT GETS US
THE QUESTION OF THERAPEUTIC
WINDOW AND MAKES IT EVEN MORE
COMPLICATED.
BUT I WOULD JUST CAUTION AND SAY
I DON'T THINK WE REALLY KNOW HOW
MUCH IS INDEED ADDRESSABLE EVEN
IF YOU RESTORE PERFECT
EXPRESSION OF A NORMAL ALLELE I
THINK THAT'S JUST WE WON'T KNOW
UNTIL WE DO IT IS THE POINT.
>> AND MAYBE WE CAN TRY TO HAVE
ANOTHER FIVE-MINUTE DISCUSSION
AND CLOSE AROUND 2:30 BECAUSE I
KNOW PEOPLE HAVE OTHER THINGS TO
DO ON THEIR WEEKEND SO PLEASE
FEEL FREE IF YOU HAVE OTHER
ADDITIONAL QUESTIONS IN THE LAST
FIVE MINUTES I SEE DR. KIN KNEE
HAS RAISED HIS HAND.
>> WE WERE TALKING ABOUT WE CAN
SORT OF PIGGY BACK ON WHAT
SPINAL CORD INJURY GROUPS HAVE
DONE THE DEGENERATIVE, LIKE
THAT'S INJURY INDUCED SORT OF
DEGENERATION, I THINK IF WE
REALLY BELIEVE THIS DISEASE HAS
A NEURO DEGENERATIVE ELEMENTINGS
IN THERE THERE'S SOME THERAPIES
SHOWING SOME PROMISING RESULT ON
REGENERATE CNS NEURONS CAN BE
PROBABLY APPLIED TO WHAT WE'RE
STUDYING HERE. JUST A THOUGHT
NOT LIKE IT'S VERY MATURE AT THE
MOMENT BUT I THINK WE CAN THINK
ABOUT IT IN WE REALLY THINK
NEURO DEGENERATIVE COMPONENTS
WANT TO PROMOTE EITHER THE
REGENERATION REGROWTH. INCREASE
AND BRANCH INTO MAKE CONNECTIONS
I THINK THAT COULD BE SOMETHING
AT THE THERAPY YOU KNOW YOU CAN
SORT OF THINK ABOUT.
>> ANY OTHER LAST MINUTE BURNING
QUESTIONS OR COMMENTS?
>> MOST OF THE CHAT QUESTIONS
HAVE BEEN ANSWERED ON MY END.
>> MY ONLY LAST COMMENT OR
ACTUALLY WAS JUST TO THANKS TO
ARIANE TO ORGANIZE THIS AND
EVERYONE ELSE THAT WAS IN THE
BACKGROUND COLLEEN, EVERYBODY
THAT WAS HELPING MAKE THIS RUN
SMOOTHLY. SO ARIANE I WISH YOU
COULD HEAR US ALL APPLAUDING
YOU.
>> THANK YOU IT'S BEEN SUCH AN
HONOR I WAS INSPIRED BY THESE
CHILDREN WE SAW AND CHRIS WHO
WOULD CALL ME ON MY OFFICE LINE
WHAT ARE YOU AND THE NIH DOING
FOR MY CHILD. SO THE LEAST I
COULD DO IS PUT SCIENTIST WHO
KNOW ABOUT THIS TOPIC TOGETHER
SO I FEEL HONORED TO HAVE BEEN
ABLE TO DO THAT. THANK YOU
EVERYBODY FOR SPENDING YOUR
FRIDAY AND PART OF SATURDAY WITH
US. I KNOW IT'S GOING TO SPEAR
ALONG A LOT OF CLASH
COLLABORATIONS BETWEEN
SCIENTISTS PRESENT AND I KNOW
IT'S REASSURING FOR THE FAMILIES
THAT PEOPLE ARE THINKING A LOT
ABOUT THIS TOP SXIK A LOT OF
DISCUSSION GOING TO THIS.
>> THANK YOU FORJOINING.
>> THANK YOU ALL VERY MUCH.
IT'S SO MEANINGFUL TO SEE
EVERYBODY COLLABORATING WE HOPE
WE CAN FACILITATE MORE AND LEAD
KIND OF DISCUSSIONS IN THE
FUTURE AND I'M HERE TO ASSIST
FROM A PATIENT ADVOCACY
PERSPECTIVE AS MUCH AS POSSIBLE
THANK YOU ALL.
>> THANK YOU SO MUCH.
>> I WILL BE IN TOUCH WITH NEXT
STEPS. THANK YOU.