>> GOOD AFTERNOON AND WELCOME TO
TODAY'S CLINICAL CENTER GRAND
ROUNDS THE CODE IS 57908.
TIME THIS TO THE JOHNS HOPKINS
PHONE NUMBER SHOWN ON THE SLIDE.
WE CURRENTLY INVITE YOU TO
PROVIDE FEEDBACK BY SCANNING THE
QR CODE ON THE SLIDE.
FOR THOSE APPLYING FOR CME
YOU'LL RECEIVE A SURVEY AND IT
ALLOWS SUGGESTIONS FOR FUTURE
GRAND ROUNDS TOPICS.
FOLLOWING THE PRESENTATION
QUESTIONS WILL BE TAKEN FROM THE
AISLES.
ADDITI
ADDITIONALLY, VIDEOCAST VIEWERS
CAN SUBMIT DURING THE SEND LIVE
FEEDBACK WITH AT THE END OF THE
PRESENTATION.
WE'LL HONORED WITH OUR SPEAKER,
DR. SHEPPARD FROM THE EUNICE
KENNEDY SHRIVER CENTER FOR CHILD
HEALTH AND HUMAN DEVELOPMENT.
SHE'S EARNED HER DEGREE FROM THE
MASSACHUSETTS INSTITUTE OF
TECHNOLOGY AND MEDICAL DEGREE
AND DOCTORATE IN GENETICS AND
BIO INFORMATICS AT THE
UNIVERSITY OF MASSACHUSETTS
MEDICAL SCHOOL.
DR. SHEPPARD THEN COMPLETED
CLINICAL GENETICS AT THE
CHILDREN'S HOSPITAL PHILADELPHIA
AND JOINED AS A CLINICAL
GENETICISTS AND WHILE AT CHOC
SHE COMPLETED AT THE UNIVERSITY
OF PENNSYLVANIA PULLMAN'S SCHOOL
OF MEDICINE AND POSTDOCTORAL
FELLOWSHIP AT CHOC FOCUSSING ON
IMPROVED DIAGNOSTICS AND SHE
JOINED THE NIH AT NICHD AND THE
FOCUS OF HER TRANSLATIONAL
RESEARCH GROUP IS TO DEVELOP
MORE EFFICACIOUS THERAPIES FOR
PATIENTS WITH MALFORMATIONS OF
THE LYMPHATIC SYSTEM.
SHE'S A PROLIFIC INVESTIGATOR
AND BOARD CERTIFIED BY BOTH THE
AMERICAN BOARD OF AMERICAN
GENETICS AND GENOMICS AND THE
AMERICAN BOARD OF PEDIATRICS AND
CO-AUTHORED PIER REVIEWED
ARTICLES AND RECEIVED MANY
AWARDS AS THE AUTHOR OF THE MOST
SIGNIFICANT CONTRIBUTION TO THE
AMERICAN JOURNAL OF GENETICS BY
A JUNIOR INVESTIGATOR.
HER TITLE IS GENOMICS INFORMED
PRECISION MEDICINE FOR
INDIVIDUALS WITH LYMPHATIC
ANOMALIES.
>> THANK YOU SO MUCH FOR THE
VERY KIND INTRODUCTION.
THESE ARE MY DISCLOSURES AND
THIS PATIENT WAS BORN AFTER A
PREGNANCY WITH MULTIPLE
CONGENITAL ANOMALIES AND THIS IS
A PHOTOGRAPH OF HIM AFTER BIRTH.
DURING PREGNANCY HE HAD AN
IRREGULAR HEARTBEAT AND THOUGH
THIS WAS TRYING TO BE CONTROLLED
HE DEVELOPED SWELLING IN
MULTIPLE BODY COMPARTMENTS KNOWN
AS NON-IMMUNE FETAL HIDROX AND
WAS BORN PREMATURELY AND YOU CAN
SEE HE REQUIRES VENTILATION
SUPPORT AND SEE THE MALFORMATION
S INCLUDING THE SKIN COLORED
PLAQUES AND A PATTERN ON HIS
BODY.
THE EYELID COLOBOMA AND
PAPILLOMA EYELID AND POST SET
EARS AND AFTER ARRHYTHMIA HE
CONTINUED TO HAVE ISSUES WITH
FLUID IN THE ABDOMEN AND FLUID
AROUND THE LUNGS AND IT WAS
SUSPECTED HE HAD A PROBLEM WITH
HIS LYMPHATIC VASCULATURE.
THE LYMPHATICS HAVE THREE
FUNCTIONS.
TO ABSORB PROTEIN RICH FLUID
FROM THE TISSUES AND TRANSFER IT
BACK TO THE BLOOD VASCULAR
SYSTEM AND ABSORB FAT AND
TRANSPORT IMMUNE CELLS AND IF WE
SUSPECT SOMEONE HAS A PROBLEM
PATIENTS CAN HAVE CONTRAST
INJECTED BY LYMPH NODES AND
INTERNODAL IMAGES THROUGH THE
MESS EN TERRY OR LIVER
LYMPHATICS AND THE PATIENTS ARE
IMAGED BY MRI TO EVALUATE THE
CENTRAL FLOW PATTERN.
IN A TYPICAL PATIENT THIS IS
WHAT YOU MIGHT SEE.
THIS IS THE THORACIC DUCT HERE
WITH THE LIVER INJECTION THEY'RE
NICE THIN VESSELS.
IN CONTRAST IN OUR PATIENT, THE
CENTRAL LYMPHATIC IMAGING SHOWED
CENTRAL LYMPHATIC CONDUCTING
ANOMALY MALFORM S WHERE WE KNOW
THE CENTRAL LYMPHATIC FLOW IS
COMPLETELY ABNORMAL.
IN CONTRAST TO A TYPICAL HUMAN,
WE CAN SEE IN OUR PATIENT
THERE'S A TON OF CONTRAST
SPILLING OUT HERE INTO THE RETRO
PER I TIN YUM AND IN THE LIVER
INJECTION YOU CAN SEE THE
SPILLING OF ABDOMINAL
MALFORMATION AND PROFUSION INTO
THE LUNGS.
THE TREATMENT FOR THE PATIENTS
ARE MOSTLY SYMPTOMATIC AND WE
HAVE WHERE LYMPHATICS CAN BE
CONNECTED TO VEINS TO ALLEVIATE
SOME PRESSURE AND ASSIST WITH
DRAINING AND MEDICAL GRADE SUPER
GLUE CAN BE INJECTED INTO LEAKY
VESSELS AND MEDICINES I'LL TELL
YOU A LITTLE BIT MORE ABOUT
TODAY WHICH ARE MORE COMMONLY IN
USE TODAY THAN AT THE TIME THIS
PATIENT WAS BORN.
UNFORTUNATELY HE PASSED AWAY AS
YOU CAN SEE HIS MALL FORMATIONS
WERE VERY DIFFUSE AND WASN'T
REALLY ELIGIBLE FOR THESE
TREATMENTS AND IT DROVE HOME TO
ME HOW DO DELIVER PERSONALIZED
TREATMENT AND MALFORMATIONS CAN
CAUSE SIGNIFICANT DISABILITY.
EVEN SIMPLE LYMPHATIC
MALFORMALITIES CAN CAUSE LARGE
PROBLEMS AND PEDIATRIC
LYMPHEDEMA WHERE PATIENTS HAVE
SWOLEN LIMBS OR COMPLEX
LYMPHATIC ANOMALIES WHICH IS
BUCKET TERM FOR FOUR DISORDERS
WHERE THERE'S MALFORMATIONS
THROUGHOUT THE BODY INCLUDING
CENTRAL CONDUCTING ANOMALY WHERE
THERE'S ABNORMAL FLOW IN THE
CENTRAL LYMPHATICS AND GENETIC
ANOMALY WHERE WE SEE
MALFORMATIONS IN THE BONE AND
SPLEEN AND WHERE WE SEE
MALFORMATIONS IN THE BONE, MEDIA
STINUM AND THEY OCCUR IN 1 IN
4,000 LIVE BIRTHS.
WHEN WE THINK OF THE CURRENT
LIMITATIONS FOR DIAGNOSIS AND
TREATMENT FOR THESE PATIENTS
IT'S SIMILAR TO THAT OF OTHER
RARE DISORDERS.
MANY ARE RARE AND HETEROGENEOUS
ESPECIALLY THESE COMPLEX
LYMPHATIC ANOMALIES AND CAN
RESULT IN THIS DIAGNOSIS.
WE HAVE A LIMITED UNDERSTAND OF
THESE DISORDERS BUT I'LL TELL
YOU ABOUT THE GROUP MY WORK HAS
DONE TO IMPROVE THIS.
FINALLY, WE HAVE FEW MEDICAL
TREATMENTS THAT TARGET THE
UNDERLYING CAUSE WITH ONLY ONE
MEDICINE THAT'S FDA
CONDITIONALLY APPROVED AT THIS
TIME.
ALIGNING WITH THE STRATEGIC PLAN
TO IDENTIFY GENOMIC CHANGE TO
EXPLAIN OR PREDICT FETAL
CONDITIONS AND TO FURTHER THE
UNDERSTANDING OF THE CELLULAR
AND STRUCTURAL BASIS THROUGH
WHAT WE KNOW ABOUT THIS DISEASE
MODELS AND TO ADVANCE GENOMICS
TO ADVANCE EFFECTIVE AND SAFE
THERAPEUTICS FOR CHILDREN.
WHEN WE BREAK IT DOWN TO TREAT A
PATIENT BASED ON THEIR PHENOTYPE
WE NEED TO MAKE SURE WE CAN HAVE
A TRUE DIAGNOSIS.
WE ALSO NEED AN UNDERSTANDING OF
THE MOLECULAR PATHOGENESIS AND
FINALLY WE NEED TO ACTUALLY
UNDERSTAND HOW THAT TREATMENT
AFFECTS PATIENT OUTCOMES.
TODAY I'LL TALK ABOUT THE STEPS
MY LAB HAS TAKEN AND THE GENETIC
TESTING FOR THIS PATIENT POMP
AND ESTABLISHMENT OF THE NATURAL
HISTORY STUDY AT THE NIH
CLINICAL CENTER IN COLLABORATION
PROBABLY WITH MANY IN THE
AUDIENCE AND MANY WATCHING
ONLINE.
I'LL TALK BRIEFLY ABOUT OUR WORK
WITH K RAS RELATED ANOMALIES IN
THE LAB AND HOW THIS HAS LED TO
THE TRANSITION OF PATIENTS TO
OFF LABEL AND WHY BASED ON WHAT
WE KNOW WE STILL NEED TO WORK
FURTHER TO UNDER THE WHAT OUR
NOVEL THERAPIES WE CAN USE TO
TREAT THESE PATIENTS.
WHEN WE THINK OF IMPROVING THE
DIAGNOSIS WE'RE THINKING OF TWO
THINGS, PHENOTYPES OR THE
CLINICAL SYSTEMS PATIENTS HAVE
AS WELL AS GENOTYPES OR THE
GENETIC CAUSES.
WE'RE REALLY ASKING THREE MAJOR
QUESTIONS.
SO WHAT ARE THESE PHENOTYPES AND
GENOTYPES THAT DEFINE DISEASE.
HOW DO THESE DISORDERS EVOLVE OR
CHANGE OVER TIME, AND THEN WHAT
BIOMARKERS OR OTHER CLINICAL
RESPONSE MEASURES CAN BE USED TO
MONITOR DISEASE PROGRESSION AND
RESPONSE?
AND SO FIRST WHEN WE STARTED
THIS WORK THERE WERE VERY LITTLE
KNOWN CAUSES FOR THESE RARE
GENETIC DISORDERS CALLED CENTRAL
CONDUCTING LYMPHATIC ANOMALY.
I'LL SHOW THE FIGURE THROUGHOUT
THE TALK AND SO I WANT TO ORIENT
YOU.
WE KNOW BOTH THE KINASE AND RAS
SIGNALLING PATHWAY ARE IMPORTANT
FOR VASCULAR DEVELOPMENT.
WE SEE A GROWTH FACTOR BINDING
TO THE KINASE LEADING TO THE AKT
MFOR OR RAS SIGNALLING.
AND WHEN I FIRST STARTED THE
WORK IN MY POSTDOCTORAL
FELLOWSHIP WE ONLY KNEW TWO
CAUSES.
ONE WAS A RECEPTOR KINASE AND
ONE OTHER.
THE FIRST STEP WE DID WAS LOOK
IN A COHORT OF PATIENTS IN A
SINGLE CENTER STUDY TO
UNDERSTAND WHAT WERE THE GENETIC
CAUSES.
SO THIS IS THE LARGEST COHORT TO
DAY AND WERE ABILITY TO IDENTIFY
11 NEW GENETIC CAUSES.
THE MAJORITY LED TO
DYSREGULATION OF RAS PATHWAY
SIGNALLING.
AS A GENETICISTS WE'RE ALWAYS
LOOKING TO CLUES TO PINPOINT
DIAGNOSIS.
WE THINK OF THESE AS UNIQUE OR
OFFICIAL FEATURES AND WONDERED
IF WE COULD DO THIS WITH THE
CENTRAL LYMPHATICS AS WELL.
INDEED THAT'S WHAT WE FOUND.
HERE ARE CENTRAL LYMPHATIC
IMAGING.
CENTRAL LYMPHATIC IMAGES OF
PATIENTS WITH THREE DIFFERENT
GENETIC DISORDERS.
PTPN11 LEADS TO DYSREGULATION OF
THE RAS PATHWAY AND WHAT WE SEE
IS THIS POSTERIOR THORACIC FLOW
AND INDIVIDUALS WITH TRISOMY 21
HAVE THESE DILATED VESSELS IN
THE PAIN AND NECK AND WHEN YOU
LOOK AT THE PREGNANCY SCREENING
FOR DOWN SYNDROME AND OTHER
CHROMOSOMAL ABNORMALITY SEEING
THIS MAKES SENSE AND PIEZ01 WE
SEE THE CONNECTION TO THE
LYMPHATICS.
AND THOUGH IN THE INITIAL STUDY
OUR NUMBERS FOR THE SYNDROMES
WAS NOT HUGE THESE ARE PATTERNS
WE'VE SEEN RECAPITULATED AND
ADDITIONAL PATIENTS IMAGED SINCE
THIS STUDY.
AND OVER ALL 65% HAVE AN
IDENTIFIABLE GENETIC CAUSE BUT
MANY HASN'T HAD TESTING THAT CAN
ADDRESS SOMATIC MOSAICISM.
THAT'S WHEN WE THINK OF HAVING A
DIFFERENT GENETIC PROFILE IN
DIFFERENT AREAS OF OUR BODY.
WHICH IS REPRESENTED BY BLUE
HERE.
AND SO WHAT WE KNOW FOR VASCULAR
MALFORMING AS IN GENERAL IS MANY
FUNCTION LIKE TUMORS OR CANCER
IN THE SENSE THEY HAVE A
DIFFERENT GENETIC PROFILE THAN
THE REPLAINED -- REMAINDER OF
THE BODY REPRESENTED BY BLUE
CELLS HERE.
TYPICALLY IF YOU WANT TO
IDENTIFY A GENETIC CAUSE YOU
HAVE TO SAMPLE THE BLUE CELLS
NOT JUST THE WHOLE BODY OR AREA
OF UNAFFECTED TISSUE.
SO TYPICALLY BLOOD SAMPLING OR
SALIVA SAMPLING ONE MIGHT DO
WON'T WORK.
WHEN PATIENT HAVE MALFORMATIONS
ON DIFFERENT AREAS OF THE BODY
TYPICALLY WE CAN TAKE A
BYPRODUCT BUT CENTRAL LYMPHATICS
IT CAN BE HARD TO ACCESS AND IT
CAN EXACERBATE DISEASE IN THIS
POPULATION.
WE TURNED TO NUCLEIC ACIDS.
TYPICALLY WHEN WE DO GENETIC
TESTING WE'RE SAMPLING THE DNA
INSIDE CELLS REPRESENTED HERE IN
BLUE.
WE KNOW THERE'S FLUID FOR
EXAMPLE CELL FREE DNA.
SO WHAT WE DID IS USED DISCARDED
FLUID BEING DRAINED AS PART OF
ANY CLINICAL PROCEDURE FOR
GENETIC TESTING.
ESSENTIALLY WE CENTRIFUGED THIS
AND ISOLATED CELL-FREE DNA AND
THEN SEQUENCED THE MALFORMATION
PANELS.
WE WERE ABLE TO EVALUATE THE
GENETIC CAUSES IN COHORTS WITH
VASCULAR ANOMALIES.
WE WERE ABLE TO IDENTIFY AND
THERE WERE GENETIC CHANGES GERM
LINED MEANING THE WHOLE BODY OR
MOS
MOSAIC.
AND SO WHEN WE LOOKED
SPECIFICALLY AT THE PATIENT I
TALKED TO YOU ABOUT BEFORE IN
THE FIRST STUDY WHAT WE SAW
COMPARISON IN THE PROSPECTIVE
STUDY WE WERE ABLE TO IDENTIFY A
GENETIC CAUSE IN 41% OF THOSE
PATIENTS.
I THINK ONE OF THE INTERESTING
THINGS ABOUT THE STUDY IS WE
WERE ABLE TO EXPAND THE GENETIC
CAUSES IN THE THREE DIFFERENT
TYPES OF LYMPHATIC ANOMALIES.
ONE THING WE KNEW OR THOUGHT WE
KNEW IS WE THOUGHT THERE WERE
DISTINCT GENOTYPE AND PHENOTYPE
CORRELATIONS SO THAT FOR EXAMPLE
YOU HAD GENERALIZED MODALITY AND
IN M RAV YOU HAD KAPOSIFORM
CONDITIONS.
WE SAW K RAS IN ALL OF THESE.
SO TO LOOK AT DEFINING DISEASE
FURTHER AT THE NIH CLINICAL
CENTER I ESTABLISHED A
LONGITUDINAL NATURAL HISTORY
STUDY FOR PATIENTS OF LYMPHATIC
ANOMALIES AND ENROLLED 35
PARTICIPANTS TO DATE AND THIS IS
THE WORK OF A HUGE TEAM AND
THAT'S ALLOWING US TO LOOK AT
THE PHENOTYPES GENOTYPES AND
INTERACTIONS OF FLOW IN THE
PATIENT POPULATION.
1:THIS COULD NOT BE DONE WITHOUT
OUR COLLABORATORS AS WELL.
TO LOOK AT GENOTYPES OF DISEASE
AT THIS PATIENT POPULATION WE'RE
LOOKING AT MOSAIC CAUSES WHICH
ALLOW US THROUGH A CELL FREE
VASCULAR MALFORMATION PANEL AND
SEQUENCING LOOKING AT GERM LINE
CAUSES IN COLLABORATION WITH THE
FOLKS AT NIAD AND LOOKING AT
METRICS FOR FUTURE CLINICAL
TRIALS.
WE'RE LOOKING AT THIS IN
COLLABORATION AND LOOKING TO
EXPAND OUR PATIENT POPULATION TO
SPANISH AND WE MEASURE THE
IMPACT OF LYMPHATIC DISEASE IN
BOTH THE PHYSICAL AND EMOTIONAL
WELL BEING OF PATIENTS.
WE'RE ALSO LOOKING AT BIOMARKERS
IN LYMPHATIC FLUID, BLOOD AND
URINE AND IT'S LED BY A
POSTDOCTORAL FELLOW IN MY LAB.
TO SUMMARIZE WE APPLIED
APPROACHES INCLUDING CELL FREE
DNA FOR THE GENETIC TESTING AND
ALLOWED US TO DISCOVER 22 CAUSES
FOR PATIENTS WITH LYMPHATIC
ANORMA
ANOMALIES AND WE FURTHER
DELINEATED THE DISEASES AND TAKE
WHAT WE LEARNED IN THE NATURAL
HISTORY STUDY AND HELP US
UNDERSTAND THE MOLECULAR
PATHOGENESIS OF DISEASE USING
PRECLINICAL MODELS AND USE THE
MODELS TO DEVELOP THERAPEUTICS.
SO K RAS IS TYPICALLY SIGNALS
THROUGH THE RAS KINASE PATHWAY
AND HAS CROSS TALK WITH THE
SIGNALLING PATHWAY.
WE REALLY PURSUED THIS AS A GENE
IN MY LAB TO STUDY BECAUSE WE
KNOW IT'S ONE OF THE MOST COMMON
CAUSES FOR COMPLEX LYMPHATIC
ANOMALIES.
SEE THE NUMBER OF PARTICIPANTS
IN OUR STUDY.
ON THE Y AXIS BY GENE.
ON THE X AXIS WE SEE K RAS IS
REALLY THE SECOND MOST COMMON
CAUSE SHORTLY BEHIND K3CA.
WE ALSO KNOW FROM OUR CLINICAL
EXPERIENCE K RAS IS AN
AGGRESSIVE PATIENTS -- THESE
PATIENTS TEND TO HAVE MORE
AGGRESSIVE DISEASE.
AND SO WHAT WE DID WAS EVALUATE
THE PHENOTYPE IN PATIENTS WITH
CENTRAL CONDUCTING ANOMALY AND
EMPHA DEMA AND THERE WAS A
PHOTOGRAPH OF FOUR PATIENTS WITH
DIFFERENT MOSAIC VARIANTS.
YOU CAN SEE THE VARIANT ALLELE
FRACTION BETWEEN 3% IN THE
AFFECTED TISSUE UP TO 38% AND
THESE WERE DIFFERENT VARIOUS
SAMPLES INCLUDING LYMPHATIC
MALFORMATION, SKIN AND BONE.
THEY ALL HAVE DIFFERENT AREAS OF
CENTRAL LYMPHATIC PROFUSION AND
BACK FLOW IN THE SPLEEN HERE AND
HERE BACKFLOW IN THE PENIS AND
SCROTUM.
REALLY INTERESTINGLY WE ALSO
FOUND THAT PART OF THE LYMPHATIC
PHENOTYPE IN THE K RAS RELATED
ANOMALIES INCLUDED THIS
MALFORMATION STAINED AND YOU AND
YOU CAN SEE THE DILATED VASCULAR
SPACES AND IT'S HIGHLIGHTED BY A
LYMPHATIC ENDOTHELIAL CELL
MARKER.
WE WANTED TO UNDERSTAND WHAT IS
GOING TO BE THE BEST TARGETED
THERAPY FOR THESE PATIENTS.
SO DR. DENISE ADAMS HAS REALLY
ESTABLISHED THE FIELD BIS THE
PIVOTAL STUDY WHERE SHE LOOKED
AT THE EFFICACY AND SAFETY OF
RAPAMYCIN AND OVER ALL MANY
PATIENTS HAD AN IMPROVED
RESPONSE THAT WHEN WE THINK
ABOUT PATIENTS WITH CENTRAL
CONDUCTING ANOMALY THERE WERE
THREE PATIENTS AND THEY ALL HAD
PROGRESS DISEASE EVEN ON THERAPY
THEIR DISEASE WORSENED.
SO WE HYPOTHESIZED IN THE K RAS
PATIENTS BASED ON WHAT WE KNEW
BASED ON OTHER STUDIES THAT WERE
GOING ON AT CHOC THAT MEK
INHIBITORS MAY BE MORE
EFFICACIOUS AND WE USED THE
ZEBRAFISH AND THE GENETICS ARE
WELL CONSERVED WITH HUMANS AND
WE HAVE THESE UNIQUE
CAPABILITIES FOR US TO IMAGE AND
ALSO EVALUATE THE VASCULATURE.
SO WE HAVE THESE TRANS GENETIC
ZEBRAFISH WHERE THEY SCAN
EXPRESS THE PROTEINS IN THE
LYMPHATIC AND BONE VASCULATURE
AND BECAUSE THEY DEVELOP RAPIDLY
AND EXTERNALLY FROM THE MOTHER
WE CAN SEE HOW THE VASCULATURE
DEVELOPS OR MAYBE DEVELOPS
ABNORMALLY WHEN WE INTRODUCE
DIFFERENT GENETIC CHANGES WHICH
ARE PRETTY EASY FOR US TO DO IN
THE ZEBRAFISH AND ONE ADULT
FEMALE MAY HAVE 200 TO 300 EGGS
AND CAN FACILITATE DRUG
SCREENING.
WE CREATED A ZEBRAFISH MODEL
USING AN MRC1A PROMOTER TO DRIVE
EXPRESSION OF WILD TYPE K RAS AS
A CONTROL OR ONE OF THE PATIENT
ALLELES IN THE ZEBRAFISH
ENDOTHELIUM.
HERE'S IMAGES OF THE ZEBRAFISH
IN THE CONTROL.
THEY'RE HEALTHY AND THE VESSELS
LOOK NICE AND THIN AND ARE NOT
DILATED AND IN THE PATIENT
ZEBRAFISH THERE'S EDEMA AND
INTESTINAL EDEMA AND SEE THE
VESSELS LOOK QUITE DIALATE AND
WHEN YOU CREATE THE MOLT IT'S
IMPORTANT TO VALIDATE WHAT YOU
SEE HAPPENING MEC MOLECULARLY
AND WE TOOK THE ZEBRAFISH MODELS
AND SUBJECT THEM AT FIVE DAYS TO
RNA SEQUENCING.
THIS IS A RADAR PLOT AND OUTSIDE
YOU SEE THE TERMS AND IN ORANGE
HOW UP REGULATED THAT IS IN THE
MODEL COMPARED TO THE CONTROL.
AS WE COULD EXPECT WE SEE THIS
UP REGULATION OF GENES AND
TRANSCRIPTS ASSOCIATED WITH
TRANSDUCTION IN SMALL GTPAs AND
ASSOCIATIONS WITH ANGIOGENESIS
AND ENDOTHELIAL CELL MIGRATION
SO IN THE ZEBRAFISH WE WANTED TO
UNDERSTAND WHAT DRUGS WERE
EFFICACIOUS.
TO DO THIS WE USE OUR MODEL AND
THEN TREAT THEM WITH DRUGS FROM
TWO DAYS TO FIVE DAYS OLD AND
THEN WE CAN IMAGE THE ZEBRAFISH
AND ESSENTIALLY CAN SCREEN FOR
THIS EDEMA AS A METRIC OF HOW
WELL THE DRUG IS WORKING.
SO FIRST WE LOOKED AT MTOR
INHIBITORS AND ONE USED OFFLABOR
AND OSI 27 AN MTOR INHIBITOR AND
WE SAW KEV DEF
NEXT WE LOOKED AT DIFFERENT MEK
INHIBITORS AND VASCULAR
MALFORMATIONS ARE SUCH A SMALL
PROPORTION OF PATIENTS COMPARED
TO CANCER.
YOU CAN IMAGINE IF A COMPANY CAN
MAKE A LOT OF MONEY FROM A
CANCER DRUG THEY PROBABLY DON'T
WANT YOU TO GIVE THEIR DRUG NOT
APPROVED FOR ONE INDICATION TO A
SMALLER INDICATION AND DISCOVER
A SIDE EFFECT.
ONE THERAPEUTIC MAY HAVE A
DIFFERENT AFFECT IN DIFFERENT
CELL TYPES SO IT'S IMPORTANT FOR
US WHEN WE'RE LOOKING AT
LYMPHATIC ENDOTHELIUM TO
UNDERSTAND WHAT MAY WORK BEST.
SO REALLY ALL THE MEK INHIBITORS
WE LOOKED AT TRENDED TOWARDS
REDUCTION IN THE PERCENT OF
LARVAE WITH EDEMA AND WE FOUND
THERE WERE A FEW THAT LED TO A
SIGNIFICANT REDUCTION.
AND WHEN WE LOOKED AT THIS
MOLECULARLY THE MEK INHIBITORS
TO A REDUCTION IN THE
UPREGULATION OF TRANSCRIPTS NOW
YOU CAN SEE IN GREEN ARE THE RNA
SEQUENCING TREATMENT AFTER ONE
OF THE MEK INHIBITORS THAT LED
TO SIGNIFICANT REDUCTION.
AND WHEN WE LOOKED SPECIFICALLY
AT TERMS AND TRANSCRIPTS THAT
ARE ASSOCIATED WITH
LYMPHANGIOGENESIS HIGHLIGHTED
HERE WE SAW AFTER THE
COBIMETINIB AND THESE ARE TESTED
IN HUMANS IN THEIR INITIAL
TRIALS.
SO HERE WE USE A LYMPHATIC
ORGANOID SPROUTING ASSAY AND CAN
USE HUMAN ENDOTHELIUM CELLS AND
USE THEM IN WELLS WITH THE GEL
AND THIS ALLOWS THE CELLS TO
STICK TO THEMSELVES SINCE THEY
CAN'T STICK TO THE BOTTOM OF THE
PLATE AND THEN CAN IMPLANT THEM
AND LOOK AT THE SPROUTING
BEHAVIOR OF THESE STEROIDS.
AND THIS IS AN EXAMPLE OF WHAT
MINE LOOKS LIKE.
HERE ARE IMAGES FROM OUR
CONTROLS TREATED WITH CONTROL
DMSO OR TWO MEK INHIBITORS.
WHAT IS HARD TO COMPLETELY
APPRECIATE BUT IN THE CONTROL
YOU CAN SEE THIS IS THE TYPICAL
SPROUTING BEHAVIOR BUT IN THE
TWO-PATIENT VARIANT IT LOOKS
LIKE THERE MAY BE MORE AND
LONGER SPROUTS.
AND IT LOOKS LIKE IN GENERAL THE
SPROUTING BEHAVIOR IS DECREASED
WITH THE TREATMENT.
SO WHEN WE QUANTIFY THIS WE CAN
LOOK AT IT IN DIFFERENT WAYS ONE
IS LOOKING AT THE CUMULATIVE
LENGTH FOR SPROUD SPROUT AND
SEE THE TWO PATIENT VARIANTS IN
THE GRAY AND DARKER GRAY.
WHAT WE SEE IS THERE'S A
SIGNIFICANT REDUCTION IN THAT
LENGTH AFTER TREATMENT WITH
EITHER THE TWO TREATMENTS.
AND SIMILARLY WHEN WE LOOK AT
THE NUMBER OF SPROUTS PER SPHERE
WE SEE A SIGNIFICANT REDUCTION
FOR BOTH THE PATIENT VARIANTS
WITH BOTH THE MEK INHIBITORS
CHOSEN.
FINALLY WHEN WE LOOK AT THE
SPROUT LINE PER SPEAR WE SEE A
SIGNIFICANT REDUCTION FOR THE
G12D VARIANT.
SO JUST TO SUMMARIZE THIS PART
WE HAD THIS PATIENT COHORT OF
PATIENTS WITH LYMPHATIC
ANOMALIES DUE TO K RAS.
WE USED ZEBRAFISH AND CELL
MODELS TO UNDERSTAND WHAT
EFFICACIOUS THERAPY WOULD BE AND
MEK INHIBITORS WERE MORE
EFFICACIOUS THAN THE MTOR
INHIBITORS.
SO WHY WOULD WE USE THIS IN
PATIENTS?
SO BASED ON THE WORK AND OTHER
WORK THAT WAS BEING DONE BY
OTHER GROUPS, WE THOUGHT ABOUT
TRANSITIONING SOME OF OUR
PATIENTS TO MEK INHIBITERS.
THEY HAD TO HAVE A KNOWN OR
SUSPECTED MOLECULAR CAUSE THAT
INCREASED SIGNALLING AND HAD TO
HAVE A FAILURE OF CONVENTIONAL
THERAPIES AND DIMINISHED STATUS
AND POOR QUALITY OF LIFE.
SO THIS IS ONE OF OUR PATIENTS
WHO IS TREATED OFF LABEL.
HE PRESENTED WITH KYLO THORAX
YOU CAN SEE IN THE MRI HE HAS A
SIGNIFICANT AREA OF FLUID.
HIS THIS IS KAPOSI HEME TOSE IS
AND HAD HIS ON HIS IMAGING.
AS WELL AS AN ELEVATED D DIMER.
HE WAS STARTED ON THIS AND HAS
SOME IMPROVEMENT AND WE
IDENTIFIED THIS HOT SPOT
RECURRING AND RAS VARIANT SEEN
BEFORE IN KAPOSI FORM LYM
YOU CAN SEE WE HAVE A REALLY
SIGNIFICANT IMPROVEMENT IN THE
REDUCTION OF THOSE EFFUSIONS.
HIS D DIMER ALSO DECREASED FROM
37 TO 13 AND WAS REALLY
NORMALIZED BY TWO CYCLES OF
THERAPY AND FINALLY HIS
PULMONARY FUNCTION TEST WERE
IMPROVED AS WELL.
SO IN COLLABORATION WITH
DR. SNYDER AND A RESIDENT AT
GEORGETOWN WE LOOKED AT THE
RESPONSES OF OUR PATIENTS WITH
DIFFERENT TYPES OF VASCULAR
MALFORMATION TREATED BY SINGLE
I.N.D. OR OFF LABEL WITH MEK
INHIBITION TYPICALLY WITH
COBIMETINIB AND A QUARTER OF
THESE HAD COMPLETE RESOLUTION OF
THEIR PRESENTING SYMPTOMS.
AND SOME HAS IMPROVEMENT BUT NOT
COMPLETE RESOLUTION AND FIVE HAD
STABLE DISEASE WHICH OVER ALL WE
CONSIDER TO BE A POSITIVE
RESPONSE BECAUSE WE KNOW MANY OF
THESE DISORDERS ARE PROGRESSIVE.
ONE PATIENT HAD PROGRESSIVE
DISEASE BUT SHE WAS QUITE SICK
AND SO I'M NOT SURE THAT
NECESSARILY REALLY IS DUE TO THE
INHIBITOR OR THE INHIBITOR NOT
WORKING.
AND WHEN WE THINK OVERALL AT HOW
GENOMICS CAN ALTER AND CHANGE
TREATMENT.
WHAT WE FOUND IN THE LARGER
STUDY WHEN WE LOOKED AT PATIENTS
ON MEDICAL THERAPY, WHAT WE
FOUND -- WHAT THE GENOMIC
DIAGNOSIS WAS ABLE TO SUPPORT
FOR MANY PATIENTS LED TO A
CHANGE OR INITIATION IN THERAPY
IN ALMOST TWO-THIRDS THAT WERE
CONSIDERING OR ON MEDICAL
THERAPY.
WHEN WE LOOKED AT THE RESPONSE
METRICS WE FOUND TWO-THIRDS ON
MEDICAL THERAPY ACTUALLY HAD
IMPROVEMENT.
AND SO ALL OF THESE THINGS TAKEN
TOGETHER ARE REALLY EXCITING BUT
THEY ALSO SHOW US THAT OUR
THERAPY IS NOT PERFECT AND WE
NEED TO KEEP LOOKING.
AND SO ONE OF THE QUESTIONS WE
ASKED OURSELVES, DOES THERAPY
RESPONSE ACTUALLY VARY BECAUSE
OF THE MOLECULAR MECHANISMS THAT
MAY BE DRIVING DISEASE?
AGAIN TO ANSWER THE QUESTION
WE'VE BEEN FOCUSES ON K RAS
RELATED ANOMALIES.
SO ONE THING THAT WE KNOW IS
THAT THESE VARIANTS ACTUALLY
IMPAIR THE GTP HYDROLYSIS AND
THE VARIANT LEADS TO RAPID
CYCLING ESSENTIALLY OF THE DOWN
STATES OF K RAS.
AND SO WE WONDERED IF PERHAPS
THESE PATIENTS MAY NEED
DIFFERENT TREATMENTS.
SO TO DO THIS, WE DEVELOPED
NOVEL ZEBRAFISH MODELS FOR THE
DIFFERENT ALLELES SEEN IN THE
PATIENT POPULATION.
HERE'S IMAGES OF THE CONTROL IN
HEALTHY ZEBRAFISH YOU HAVE TO
COMPARE AND THESE DIFFERENT
ZEBRAFISH MODELS.
I REALIZE IT'S A LITTLE BIT HARD
TO SEE ON THE SCREEN BUT WHAT WE
KNOW IS THERE'S PERICARDIAL
EDEMAS AND ACYTIC MALFORM S AND
HERE WE CAN LOOK AT THE
PERCENTAGE OF LARVAE ON THE Y
AXIS AND PHENOTYPE ON THE X AXIS
HERE WE SEE A SIGNIFICANT
INCREASE OR THE MALFORMATIONS
COMPARED TO THE CONTROL IN ALL
THREE OF THE PATIENT-BASED
MODELS.
WE ALSO LOOKED AT THE
VASCULATURE.
HERE WE HAVE FOUR IMAGES OF THE
VASCULATURE AND QUANTIFIED THE
FACIAL LYMPHATIC IN THE THREE
MODELS.
SO THE DIAMETER IS HERE ON THE Y
AXIS AND THE DIFFERENT MODELS
ARE HERE ON THE X AXIS AND WHAT
WE SAW IS THERE IS A SIGNIFICANT
INCREASE IN THE DIAMETER OF THE
LATERAL FACIAL LYMPHATIC
COMPARED TO THE CONTROLS.
WE ALSO WANTED TO LOOK AT THE
THORACIC DUCT AND THE VESSEL IN
THE ZEBRAFISH SIMILAR TO THE
HUMAN.
YOU CAN SEE IN THE MODELS WE CAN
HAVE DILATION, WE CAN HAVE
SEGMENTS AND PUT ALL THESE
TOGETHER TO CHARACTERIZE THEM AS
THORACIC LYMPH DUCT
MALFORMATIONS AND SEE HERE ON
THE Y AXIS.
ALL THREE MODELS ABOUT 75% HAD
THORACIC DUCT MALFORMATIONS A
SIGNIFICANT INCREASE COMPARED TO
CONTROLS.
THEN WE WANTED TO THINK ABOUT
THE MOST EFFICACIOUS THERAPIES
AND TO DO THIS WE'RE USING WHAT
WE IDENTIFIED IN OUR FIRST STUDY
AS CONTROLS.
BECAUSE WE DID NOT TEST THEM IN
ALL THE VARIANTS INITIALLY AND
THEN WE'RE LOOKING AT MORE
DIRECT RAS INHIBITORS.
SO THERE'S BEEN THE DEVELOPMENT
OF THE SMALL MOLECULE AND ALLELE
SPECIFIC INHIBITORS FOR K RAS
FOR THE G12C MUTANT AND THEN
THERE'S BEEN WORK DONE TO
DEVELOP K RAS INHIBITORS.
SO WE'RE USING THE SAME
PROCEDURE WE USED BEFORE WHERE
ESSENTIALLY WE HAVE OUR
ZEBRAFISH MODEL AND SCREENING TO
UNDERSTAND WHETHER OR NOT THE
ZEBRAFISH ARE HEALTHY OR SICK.
FIRST WE USED THE MTOR INHIBITOR
AND YOU'LL SEE THE FRACTION OF
EDEMA OR THE PERCENTAGE HERE ON
THE Y AXIS AND EACH OF THE
MODELS ON THE X AXIS AND MINUS
AND PLUS SIGN REALLY JUST
DELINEATES WHETHER OR NOT THERE
WAS DRUG OR NOT SO WHAT WE SAW
IN THE MODEL IS IT LED TO A
REDUCTION FOR THE A146 ZEBRAFISH
MODEL AS A METRIC OF
IMPROVEMENT.
ANECDOTALLY IT'S SUPER
INTERESTING TO US BECAUSE ONE OF
OUR PATIENTS HAD ACTUALLY
IMPROVE
IMPROVEMENT ON THIS PRIOR TO THE
EMBOLIZATION.
WHEN WE LOOKED AT THE MEK
INHIBITORS WHAT WE FOUND IS
THERE WAS A SIGNIFICANT
REDUCTION IN ALL OF THE
DIFFERENT VARIANTS.
AND THEN WHEN WE LOOKED AT THE K
RAS INHIBITORS VI2493, WE SAW
THAT REALLY THERE WAS A TREND
TOWARDS IMPROVEMENT IN BOTH THE
G12C AND THE G12D MODEL BUT YOU
CAN SEE IN THE EXPERIMENTS THERE
WAS MORE VARIABILITY WHICH MAY
EXPLAIN THE FACT THIS WAS ONLY A
SIGNIFICANT REDUCTION IN THE
A146T MODEL.
AND THE INHIBITERS LED TO A
SIGNIFICANT REDUCTION OF EDEMA.
THEN WE SAW THIS LED TO A
SIGNIFICANT REDUCTION OF EDEMA
IN OUR 12D MODEL.
EXCITINGLY I THINK WE'VE NOW
IDENTIFIED NOVEL INHIBITORS THAT
HAVE SHOWN EFFICACY IN THE
PRECLINICAL ZEBRAFISH MODEL BUT
ARE INTERESTED IN OUR FUTURE
WORK TO UNDERSTAND HOW THE
THERAPIES ARE AFFECTING THE
MALFORMATIONS AND THIS
MECHANISMS DRIVING DISEASE WHICH
HOPEFULLY I'LL GET TO TELL YOU
ABOUT IN FUTURE WORK.
SO TODAY I HAVE TALKED TO YOU A
LITTLE BIT ABOUT THE STEPS MY
GROUP HAS BEEN TAKING TOWARDS
PERSONALIZED MEDICINE FOR
VASCULAR MALFORMATIONS.
THE STEPS WE'RE TAKING TO
IMPROVE DIAGNOSIS THROUGH
GENETIC TESTING INCLUDING SOME
OF THE NOVEL GENETIC CAUSES
WE'VE IDENTIFIED AND THE
DEVELOPMENT OF THE CELL-FREE DNA
TESTING AS WELL AS THE
DEVELOPMENT OF THE NATURAL
HISTORY STUDY.
I SPOKE TO YOU TODAY ABOUT THE
WORK WE'VE DONE ON K RAS RELATED
LYMPHATIC ANOMALIES BUT WE
WORKED ON OTHER LYMPHATIC
ANOMALIES AND THERE'S FOLKS IN
MY LAB AS WELL AS OTHERS THAT
ARE WORKING ON CANDIDATE GENES
FOR THESE LYMPHATIC ANOMALIES
AND THEN FINALLY I SHOWED YOU
HOW SOME OF THESE STUDIES CAN
LEAD US TO IMPROVED TREATMENT
FOR PATIENTS AND WHY WE NEED TO
ACTUALLY LOOK FURTHER TO
CONTINUE IDENTIFYING NOVEL
THERAPIES FOR THESE PATIENT
POPULATION.
SO REALLY THIS BEDSIDE TO BENCH
AND BACK PROGRAM FOR LYMPHATIC
ANOMALIES FUNCTIONS AS AN
ITERATIVE CIRCLE.
SO WE'VE PHENOTYPED AND
GENOTYPED THESE PATIENTS AND
USED THE MODEL TO DEVELOP
THERAPIES AND BROUGHT THESE BACK
TO THE PATIENTS BUT FOUND WE
COULD STILL USE IMPROVEMENT SO
NOW WE'RE GOING BACK TO THE
MODEL TO IDENTIFY MORE WE CAN
HOPEFULLY THEN BRING BACK TO OUR
PATIENT POPULATION.
THOUGH I'VE FOCUSSED ON
LYMPHATIC MALFORMATIONS WE KNOW
OTHER TYPES OF VASCULAR
MALFORMATIONS HAVE GENETIC
CAUSES IN THE SAME PATHWAY AND
KNOW PROBLEMS IN LYMPHATIC
DEVELOPMENT AFFECT OTHER PATIENT
POPULATIONS SUCH AS LYMPHEDEMA
AFTER BREAST CANCER SURGERY AND
KNOW THERE'S DEVELOPMENTAL
DISORDERS FOR OTHER RASOPATHIES
AND WE KNOW THERE'S MANY CANCERS
THAT SHARE SOME OF THESE SAME
GENETIC CHANGES IN SAME GENETIC
DRIVERS.
SO REALLY THE INSIGHTS MY
PROGRAM IS GETTING AT MAY REACH
FURTHER THAN JUST OUR PATIENT
POPULATION.
AND THIS INCLUDES OUR
PARTICIPANTS AND OUR FAMILIES
AND THE INDEX PATIENT'S MOTHER
WHO IS BECOMING AN INCREDIBLE
COLLABORATOR AND MY ENTIRE
RESEARCH GROUP WHO HAS DONE A
PHENOMENAL JOB IN HELPING ME
DEVELOP THE PROGRAM.
ALL THE INCREDIBLE PEOPLE AT
NICHD AND OUR CLINICAL CENTER
COLLABORATORS WHO ALSO WOULD NOT
HAVE BEEN POSSIBLE TO ESTABLISH
ALL THIS WITHOUT THEM.
MY COLLABORATORS AT CHOC
ESPECIALLY DR. SNYDER AND SMITH
WHO IS NOW LEADING A SECONDARY
SITE OF OUR NATURAL HISTORY
STUDY WHICH WE ESTABLISHED NOW
AT CHOC AND OUR PATIENT AND
FAMILY FOUNDATION AND
COLLABORATORS AS WELL WHO
PROVIDE INSIGHT AND FEEDBACK
ABOUT OUR STUDIES.
AND ALL OF THE INCREDIBLE NIH
CLINICAL CENTER COLLABORATORS
HERE.
THANK YOU SO MUCH FOR YOUR
ATTENTION.
I REALIZE I WENT THROUGH THIS
AND SPOKE VERY FAST.
WE HAVE A LOT OF TIME FOR
QUESTIONS.
THANK YOU SO MUCH FOR YOUR
ATTENTION.
>> THANK YOU.
YES, WE HAVE SOME TIME FOR
QUESTIONS SO IF YOU HAVE THEM,
PLEASE.
I'LL START OFF.
SO YOU WERE SHOWING THE PATIENT
S HAVE THESE CENTRAL ANOMALIES
BUT WE DON'T SEEK THAT OUT
OBVIOUSLY.
ONE THING I APPRECIATE IN YOUR
WORK IS SHINING A SPOTLIGHT ON
SOMETHING WE DON'T GIVE MUCH
ATTENTION TO.
SHOULD WE BE PURSUING THIS IN
SOME FASHION?
I DON'T KNOW HOW EASY IT IS TO
DO LYMPHATIC IMAGING.
>> THAT'S A GREAT QUESTION.
NOT EVERYONE HAS LYMPHATIC
IMAGING FIRST OF ALL.
I THINK PEOPLE ONLY HAVE
LYMPHATIC IMAGING IF THEY HAVE A
PROBLEM, FOR EXAMPLE, IF THEY
HAVE EFFUSIONS OR HAVING ACYTIS
AND ONE OF THE THINGS MY
COLLABORATORS IN IMAGES
DR. SMITH AND DR. DORI HAVE DONE
WORK ON IS TRYING TO TEACH OTHER
PEOPLE THE PROCEDURE.
WE ARE SUPER FORTUNATE THAT
RADIOLOGY HELPED US DEVELOP A
PROTOCOL TO IMAGE THE CENTRAL
LYMPHATICS NON-INVASIVELY AS
PART OF OUR SCREENING PROTOCOL
WITH WHOLE BODY MRI BUT NOT ABLE
TO PROVIDE INTERVENTIONS THERE.
IF THEY THINK SOMEONE REQUIRES
IMAGING THEY CAN REFER TO A
LYMPHATIC CENTER IN THE RESEARCH
NETWORK MAINTAINS A LIST OF
CENTERS OF EXCELLENCE AND
THERE'S DIFFERENT TIERS
DEPENDING ON THE NUMBER OF
SPECIALISTS AND WHAT SERVICES
ARE PROVIDED AT THE DIFFERENT
CENTERS AND MAINTAIN THAT FOR
PLACES ALL AROUND THE WORLD.
>> AND ANOTHER QUESTION GIVEN
THE FACT WE DON'T HAVE DIRECTED
THERAPIES YET IS THERE A ROLE
FOR OTHER THINGS LIKE DIET.
I KNOW PATIENTS WHO HAVE
LYMPHEDEMA ARE THEY AFFECTED?
>> YEAH, THAT'S ALSO A GREAT
QUESTION.
YEAH, DIET IS A HUGE PART
ESPECIALLY FOR A LOT OF THOSE
PATIENTS THAT HAVE PRETTY
SIGNIFICANT PROTEIN LOSING
OPATHY AND FOR LYMPHEDEMA
SOMETHING THAT'S IMPORTANT IS
COMPRESSION AND ARE FORTUNATE TO
WORK WITH OUR COLLABORATORS
SEEING OUR PATIENTS BECAUSE AT
THIS POINT IN TIME COMPRESSION
IS THE ONE THING WE KNOW HELPS
PREVENT THE PROGRESSION OF
LYMPHEDEMA.
>> IT I'M WONDERING IF YOU SEE
OTHER MUTATIONS ASSOCIATED WITH
RAS LIKE RAS ASSOCIATED
AUTOIMMUNE PROLIFERATIVE
DISORDER.
DO THEY GET AUTOIMMUNE
PHENOMENON AS WELL?
>> THAT'S A REALLY GOOD
QUESTION.
>> IT'S NOT SOMETHING WE
COMMONLY SEE BUT WE'RE DOING
DIFFERENT RESEARCH AND DIFFERENT
PATIENT TO TRULY UNDERSTAND
WHETHER OR NOT WE ARE SEEING
THAT PHENOTYPE OVERLAPPING OR
WHETHER THE PHENOTYPES ARE DUE
TO OTHER GENETIC DISORDERS.
>> DO YOU KNOW IF THE SAME
GENETIC MUTATIONS ARE ASSOCIATED
WITH DISEASES?
>> YEAH, NRAS Q61 VARIANT YOU
SEE IN KRL AND OTHER PROLIF
PROLIFERATIVE DISEASES.
>> THANK YOU.
>> WE HAVE A QUESTION FROM A
VIEWING EVIDENCE.
GIVEN THE FDA APPROVED AGENTS
WITH NO SAFETY PROFILES WHAT DO
YOU HAVE TO PRIORITIZE FOR OFF
LABEL USE FOR DISORDERS AND HOW
DO YOU ENVISION DESIGNING
PRAGMATIC CLINICAL TRIALS AND
REGISTRIES FOR EXPANSION OF THE
THERAPIES FOR THE BROADER
PATIENT COMMUNITY.
>> THERE'S A LOT OF QUESTIONS IN
ONE.
IN TERMS OF CRITERIA AND PRE
CLINICAL EVIDENCE, MANY PATIENTS
HAD FAILED CONVENTIONAL THERAPY
IN MANY OF THESE EARLY OFF LABEL
STUDIES.
SO THINKING ABOUT THINGS WHERE
PATIENTS ARE NO LONGER
RESPONDING TO FOR EXAMPLE,
OTRIOTIDE OR NOT ELIGIBLE FOR
PROCEDURE SIMILAR TO THE FIRST
PATIENT I TOLD YOU ABOUT,
TYPICALLY, MANY ARE OFF LABEL
DRUG TREATMENT AND HAVE TO BE
FDA APPROVED THOUGH THERE'S NEW
TRIALS OPENING UP FOR MEDICINE
FOR VASCULAR ANOMALY AND THE
KINASE SPECIFIC INHIBITOR THAT
IS CURRENTLY THE CLINICAL TRIAL
IS OPEN FOR COMPLEX LYMPHATIC
ANOMALIES DEVELOPED BY
THERAPEUTICS.
SO PEOPLE ARE STARTING TO THINK
IN THAT SPACE WHICH IS SUPER
EXCITING.
BUT BECAUSE WE'RE NOT A
THERAPEUTIC COMPANY AT THE NIH
WE'RE TRYING TO FOCUS ON THINGS
THAT ARE ALREADY APPROVED FOR
THINGS OR OTHER DRUGS WHERE WE
THINK WE MAY LEARN SOMETHING OR
THEY'RE IN THE APPROVAL PROCESS.
>> THE SECOND PART OF THE
QUESTION HOW WOULD YOU ENVISION
DESIGNING PRAGMATIC TRIALS.
>> THE THING ABOUT THE COMMUNITY
IS IT'S SMALL.
THERE'S WONDERFUL PEOPLE THAT
COLLABORATE AND I THINK
DIFFERENT PATIENT GROUPS
INTERACT WITH RESEARCHERS VERY
WELL.
THERE'S A CONSORTIUM OF VASCULAR
ANOMALIES AND HEMATOLOGISTS
ONCOLOGISTS CALLED CANVAS WHICH
IS A GROUP OF THOSE INTERESTED
IN DRIVING THERAPY FORWARD AND
SO THAT'S KIND OF A GOOD
COLLABORATIVE NETWORK THAT MY
GROUP OR MYSELF I HAVE
PARTNERSHIPS WITH INCLUDING THE
PEOPLE IN THE A SPECIAL INTEREST
GROUP SO I THINK THOSE ARE GOOD
PEOPLE TO PARTNER WITH FOR
LEADING CLINICAL TRIALS AND THE
AMAZING THING IS I FEEL
FORTUNATE TO CONNECT WITH THE
PATIENT GROUPS AND I THINK A LOT
OF THE WORD IS MANY PATIENTS ARE
CONNECTED THROUGH A LOT OF THESE
GROUPS AND EVEN STARTING THEIR
OWN SO WE HAVE TWO PATIENTS THAT
ARE LONG TERM PATIENTS OF MINE
BEFORE I CAME HERE AND JOINED
OUR STUDY AND PARTICIPATED IN
THIS VIRTUAL SUPPORT GROUP AND
ONE I DIDN'T HAVE TIME TO TALK
ABOUT TODAY AND THOUGH THE
SUPPORT GROUP HAD LOW ENROLLMENT
WHAT THE TWO PARENTS FOUND WAS
THAT THEY JUST FELT LIKE IT WAS
SO HELPFUL TO TALK TO OTHER
FAMILIES ON A REGULAR BASIS AND
SO WHAT THEY DID WAS START THEIR
OWN VIRTUAL SUPPORT GROUPS SO
THEY CAN ALL COLLABORATE AND
TALK ABOUT WHAT ARE THE NEW
INNOVATIONS.
LAST WE TALKED TO THEM IT WAS
OVER 90 FAMILIES.
SO ANYWAY, I GUESS THE SHORT
ANSWER TO THAT QUESTION IS
PARTNERING WITH OTHER CLINICIANS
THROUGH NETWORKS AND DIFFERENT
ACADEMIC SOCIETIES AS WELL AS
PARTNERING WITH PATIENTS WITH
THEIR OWN SUPPORT GROUPS AND THE
MORE FORMALIZED SUPPORT GROUPS.
>> I DON'T THINK WE HAVE ANY NOR
ONLINE QUESTIONS.
ARE THERE MORE QUESTIONS FROM
THE AUDIENCE HERE?
WELL, DR. SHEPPARD, THANK YOU
VERY MUCH.