WELCOME TO THE
WEDNESDAY AFTERNOON LECTURE.
TODAY WE HAVE 
DR. ANGELA
CHRISTIANO, WHO WILL BE TALKING
ON GENETICS AND IMMUNOLOGY OF
ALOPECIA AREATA.
ANGELA GOT HER PH.D. IN
MICROBIOLOGY AND MOLECULAR
GENETICS AT RUTGERS AND DID HER
POSTDOCTORAL WORK AT THE
DEPARTMENT OF DERMATOLOGY THOMAS
JEFFERSON UNIVERSITY.
SHE'S HAD HER OWN LABORATORY AS
A RESEARCH ASSISTANT PROFESSOR
AT THOMAS JEFFERSON AND LATER
 BECAME PROFESSOR AT ROCKEFELLER
IN 1995, SHE MOVED TO COLUMBIA
UNIVERSITY WHERE SHE WAS
ASSOCIATE PROFESSOR AND IS
PRESENTLY THE RICHARD AND
MILDRED RHODEBECK PROFESSOR AT
THE DEPARTMENTS OF DERMATOLOGY
AND GENETICS AND DEVELOPMENT.
SHE'S THE DIRECTOR OF THE CENTER
FOR HUMAN GENETICS AND THE VICE
CHAIR FOR RESEARCH OF THE
DEPARTMENT OF DERMATOLOGY.
SHE IS ALSO CURRENTLY THE
PRESIDENT OF THE SOCIETY OF
DERMATOLOGY AND SERVES AS THE
DEPUTY EDITOR FOR THE JOURNAL OF
INVESTIGATIVE DERMATOLOGY.
ANGELA'S RESEARCH HAS FOCUSED ON
UNDERSTANDING THE MOLECULAR
PROCESSES THAT LEAD TO INHERITED
SKIN AND HAIR DISORDERS IN
HUMANS.
SHE'S MADE REALLY BEAUTIFUL
FINDINGS AND SEMINOLE FINDINGS
STARTING WITH THE DISCOVERY OF
GENETIC MUTATIONS THAT ARE
ASSOCIATED WITH BLISTERING SKIN
DISORDERS.
SHE HAS ALSO PIONEERED THE
RESEARCH IN THE UNDERLYING
GENETIC CAUSES OF HAIR LOSS AND
IDENTIFICATION OF POTENTIAL
THERAPIES FOR ALOPECIA AREATA,
AN AUTOIMMUNE FORM OF HAIR LOSS.
SHE WILL BE PRESENTING THIS AREA
OF HER WORK TODAY AND THE TITLE
OF HER PRESENTATION IS GENETICS
AND IMMUNOLOGY OF ALOPECIA
AREATA.
PLEASE JOIN ME IN WELCOMING
DR. ANGELA CHRISTIANO.
[APPLAUSE]
THANK YOU SO MUCH FOR THE
BEAUTIFUL INTRODUCTION AND FOR
THE OPPORTUNITY TO BE HERE
SPEAKING IN THIS AMAZING LECTURE
SERIES.
SO I'M HONORED TO ATTEND AND
IT'S WONDERFUL TO SEE SO MANY
FRIENDS AND COLLEAGUES OUT HERE
IN THE AUDIENCE AS WELL AS SOME
OF THE PEOPLE WHOSE WORK WE
FOLLOWED FOR QUITE SOME TIME
NOW, AND I HOPE THAT I CAN DO
JUSTICE TO ACKNOWLEDGING
EVERYONE APPROPRIATELY ALONG THE
WAY.
SO THANK YOU FOR HAVING ME.
I'M GOING TO TALK TO YOU TODAY
ABOUT AN AUTOIMMUNE FORM OF HAIR
LOSS CALLED ALOPECIA AREATA.
IT IS WITHIN THE DETERMINE TOE
LOGIC DISEASES SO THIS FALLS
WITHIN THE NIAMS MISSION HERE AT
NIH.
I'M A PH.D. GENETICIST SO I'M
JOINED IN THIS WORK BY TWO
CLINICAL COLLEAGUES, JULIAN
MACKAY-WIGGAN WHO AND RAFAEL
CLYDES,
HE REALLY HELPED US MOVE THIS
PROGRAM INTO PRE-CLINICAL MODELS
AND WITH JULIAN'S HELP INTO THE
CLINIC.
OUR WORK REALLY STEMS FROM A
REGISTRY THAT WAS ESTABLISHED BY
NIAMS IN ABOUT YEAR 2000 OR SO
CALLED THE NATIONAL ALOPECIA
AREATA REGISTRY, AND IT WAS THAT
GROUP OF PATIENTS THAT REALLY
FORMED THE BASIS OF ALLOWING US
TO DO THE GENETIC STUDIES THAT
I'LL TALK ABOUT TODAY, AND I'M
JOINED HERE BY MY COLLEAGUES AT
THE OTHER REGISTRY SITES.
THIS WAS FOUNDED AND THE
HOMESITE WAS AT MD ANDERSON IN
HOUSTON FOLLOWED BY SITES AT
THESE INSTITUTIONS AND AT OUR
OWN AT COLUMBIA, SO WITHOUT THIS
IMPORTANT PATIENT REGISTRY, A
LOT OF WHAT YOU'RE GOING TO HEAR
TODAY PROBABLY WOULD NOT BE ABLE
TO HAPPEN, SO AGAIN I HAVE LOTS
OF GRATITUDE TO THANK FOLKS UP
FRONT FOR HELPING US DO THIS.
SO JUST TO INTRODUCE YOU TO THE
PHENOTYPES, SO ALOPECIA AREATA
IS A VERY COMMON AUTOIMMUNE FORM
OF HAIR LOSS AFFECTING ABOUT
6 MILLION PEOPLE IN THE UNITED
STATES, ROUGHLY 1 TO 2% LIFETIME
RISK.
IT CAN SOMETIMES START AS SMALL
PATCHES OF HAIR LOSS ON THE
SCALP, SOMETIMES ON THE BEARD IN
MALES, IT CAN PROGRESS TO COVER
THE ENTIRE SCALP, SOMETIMES
OCCURS IN UNUSUAL PATTERNS.
ONE THING THAT WE THINK WE KNOW
ABOUT IT IS THAT IT
PREFERENTIALLY ATTACKS PIGMENTED
HAIR SO IT SPARES THE WHITE
HAIRS, OFTEN LEAVING BEHIND A
PATCH LIKE THIS, AND IT COULD
EVENTUALLY PROGRESS TO COVER THE
ENTIRE SCALP, IN WHICH CASE IT'S
CALLED AL PIZZA T ALOPECIA
TOTALIS.
WHEN IT PROGRESSES TO THAT LATE
STAGE IT TENDS TO BE RESISTANT
TO CONVENTIONAL THERAPIES.
WHEN WE BEGAN THIS WORK, THERE
HAD BEEN 20 OR SO YEARS OF
LITERATURE IN THE FIELD
DESCRIBING AN AUTOIMMUNE
INFILTRATE SURROUNDING
FOLLICLES, IN A PATTERN CALLED A
SWARM OF BEES.
FOR MANY YEARS, THE COMPOSITION
AND NATURE OF THIS SWARM OF BEES
WASN'T WELL UNDERSTOOD, SO
THINKING ABOUT WAYS TO TARGET
THIS SPECIFICALLY WAS STILL A
LITTLE BIT OUT OF REACH SO THE
STANDARD OF CARE OF TREATMENT
FOR ALOPECIA AREATA STILL TODAY
IS STEROIDS, EITHER INJECTED
INTERLEAGUESLY
INTERLESIONLY INTO THE SCALP OR
OCCASIONALLY ORAL STEROIDS, BUT
AGAIN, WITHOUT KNOWLEDGE OF THE
DETAILS OF THIS PROCESS, IT WAS
VERY DIFFICULT OVER THE YEARS TO
COME UP WITH WAYS TO TARGET
THIS.
I'LL ALSO MAKE ONE OTHER
DISCLOSURE AT THE BEGINNING THAT
MY INTEREST IN ALOPECIA IS
PERSONAL AS WELL AS
PROFESSIONAL, SO THE TOP MIDDLE
PANEL HERE IS MYSELF.
I DEVELOPED ALOPECIA AREATA IN
1996, SHORTLY AFTER ARRIVING AT
COLUMBIA, AND THIS IS REALLY
WHAT SPARCED OUR INTEREST IN
TRYING TO DISSECT THE GENETICS
OF THIS COMPLEX DISEASE.
AND SO LET ME TELL YOU A BIT
ABOUT OUR BASIC BIOLOGICAL
CONTEXT OR PROBLEM, AND THAT IS
THAT IN NORMAL CONDITIONS, THE
HAIR FOLLICLE EXISTS IN A STATE
OF RELATIVE IMMUNE PRIVILEGE,
WHERE IT REMAINS CLOAKED IF YOU
WILL GUARDIANS OF THE IMMUNE
SYSTEM THAT KEEP IT FROM BEING
RECOGNIZED BY IMMUNE CELLS,
THAT'S PART OF ITS SPECIAL
PRIVILEGE IN THE SITE.
AND SO FOR REASONS WE DON'T YET
UNDERSTAND ENTIRELY IN TERMS OF
TRIGGERING EVENTS, THIS HAIR
FOLLICLE LOSES THAT IMMUNE
PRIVILEGE AND BEGINS TO EXPRESS
SIGNS OF DANGER SO IT
UPREGULATES MHD CLASS 1 AND 2,
OTHER DANGER SIGNALS, THAT BEGIN
TO RECRUIT IN THIS MIXED
INFLAMMATORY INFILTRATE.
OVER THE YEARS, THIS HAS BEEN
SHOWN TO CONTAIN CD4 CELLS,
CD8 CELLS, BUT THIS PROCESS,
ONCE IT BEGIN, SORT OF BECOMES A
VICIOUS CYCLE.
THE HAIR FOLLICLE SECRETES MORE
AND MORE DANGER, RECRUITING
AGAIN THIS INFILTRATE AND IT
KEEPS THIS PROCESS GOING.
SO EVEN THOUGH IT'S A COMPLEX
PROBLEM MODEL TO THINK ABOUT, IT
ALSO PRESENTS OPPORTUNITY AT TWO
LEVELS.
ONE IS TO THINK ABOUT WAYS OF
TREATING THE IMMUNE INFILTRATE
AND SORT OF DAMPENING DOWN THAT
RESPONSE, BUT THE SECOND
INVOLVES TRYING TO RESTORE THIS
RELATIVE IMMUNE PRIVILEGE STATE
OF THE HAIR FOLLICLE.
SO IF WE THINK ABOUT
INTERVENTIONS, WE CAN
POTENTIALLY THINK ABOUT DOING
BOTH OF THOSE THINGS, BOTH
RESTORING THE IMMUNE COMPONENTS
AND ALSO RESTORING THE HAIR
FOLLICLES.
SO WHEN I SHOW YOU LATER SOME OF
OUR TREATMENT WORK IN MICE AND
TO THIS MODEL AND TALK ABOUT HOW
WE'VE MANAGED TO TRY AND DO SOME
OF THIS.
SO OUR WORK REALLY BEGAN AS MANY
OTHERS HAVE IN COMPLEX DISEASE
GENETICS, AND THAT WAS TO TRY
AND BUILD AN UNBIASED GENETIC
MAP OF ALOPECIA AREATA FOR THE
FIRST TIME.
AGAIN THIS WAS COMING ALONG AT
THE TIME IN HISTORY WHEN GWAS
GENOME WIDE ASSOCIATION STUDIES
WERE JUST BECOMING POPULAR, SO
AGAIN, BECAUSE THIS IS A COMPLEX
DISEASE INVOLVING BOTH GENES AND
ENVIRONMENTAL TRIGGERS, WE
FOLLOWED THE FOOTSTEPS OF OTHER
DISEASES BEFORE US THAT HAD
REALLY PAVED THE WAY FOR USING
THIS APPROACH AND THINKING ABOUT
WAYS TO USE THE GENETIC MAPS TO
FIND POTENTIALLY NEW TARGETS
THAT COULD BE USED POTENTIALLY
WITH ALREADY FDA-APPROVED DRUGS
AND TESTING THOSE IN CLINICAL
TRIALS.
SO THIS MAP OF FUNCTIONAL
GENOMICS IS BORROWED FROM MY
COLLEAGUE AT COLUMBIA, WHO I
THINK HAS DONE ALSO A GREAT JOB
OF HELPING US TO THINK ABOUT
WAYS TO LINK OUR GENETICS TO
SOME OF THE MECHANISMS AND THINK
ABOUT NEW DRUGS.
SO I'M GOING TO TALK IN FOUR
AREAS TODAY, A LITTLE BIT ABOUT
THE GENETICS, SOME WORK ON OUR
IMMUNOLOGY IN ALOPECIA AREATA,
AND THEN FINALLY TALK ABOUT OUR
WORK TO DEVELOP NEW BIOMARKERS
SO WE COULD TRACK THE PROGRESS
AND RESPONSE OF PATIENTS TO SOME
OF THE NEW DRUGS AND THEN
FINALLY, AT THE END, SOME WORK
FROM OUR CLINICAL TRIALS.
SO THE RESULTS OF OUR GENOME
WIDE ASSOCIATION STUDY, THIS WAS
FROM ABOUT 2000 OR SO PATIENTS
ROUGHLY 1500 CASES, 3500
CONTROLS, THIS IS VERY SMALL
GENOME WIDE ASSOCIATION STUDY,
SO NOW DAYS YOU SEE NUMBERS IN
SOME DISEASES WELL OVER 100,000
CASES AND CONTROLS, SO THIS IS A
VERY MODEST SIZE STUDY.
WE TAKE A FEW THOUSAND CASE,
SPARE THEIR MARKERS TO A FEW
THOUSAND CONTROLS AND WE LOOK
FOR AREAS OF THE GENOME WHERE WE
SEE SKEWING OR
OVERREPRESENTATION OF CERTAIN
GENETIC MARKERS IN THE CASES
RELATIVE TO CONTROLS, AND WHEN
WE DO THAT, THIS RED LINE IS
STATISTICAL SIGNIFICANCE,
ANYTHING THAT RISES ABOVE THAT
LINE SUGGESTS TO US THAT THERE
IS A LOCUS THERE THAT MAY BE
CONTRIBUTING TO DISEASE.
SO THE HLA IS A NICE POSITIVE
CONTROL TO HAVE FOR ANY
AUTOIMMUNE DISEASE, BUT
PARTICULARLY IN ALOPECIA AREATA,
THERE HAD BEEN MANY CAPPED DATE
GENE ASSOCIATION STUDIES HERE IN
THE PAST, AND SOME OF THESE
OTHER GENES IN BLACK ARE ONES
THAT ARE SHARED AMONGST OTHER
AUTOIMMUNE DISEASES, SO AGAIN,
NICE CONTROLS THAT WE'RE HITTING
UPON GENES THAT SHOULD HAVE
INTEREST IN THE DISEASE.
BUT WHAT EVERY CAN GENETICIST
REALLY WANTS IS THE SMOKING GUN,
THE GENE THAT'S UNIQUE TO YOUR
DISEASE THAT HAS THE GREATEST
POTENTIAL USUALLY OF GUIDING YOU
TOWARDS A MECHANISM THAT MIGHT
HELP UNDERSTAND PATHOGENESIS.
SO IN OUR CASE, THIS JEAN GENE,
THE ULBP3 AND 6 CLUSTER IS THE
MOST SIGNIFICANT HIT IN
ALOPECIA, AND IMPORTANTLY IT'S
ALSO UNIQUE TO ALOPECIA AREATA,
SO TO DATE, THERE ARE STILL NO
OTHER AUTOIMMUNE DISEASES THAT
HAVE THIS GENE AS A CANDIDATE
GENE, SO SIMILAR TO INSULIN IN
DIABETES, FOR EXAMPLE, IT'S
USUALLY THE GENES THAT ARE
UNIQUE TO YOUR DISEASE THAT ARE
THE ONES THAT ARE THE MOST
INSTRUCTIVE ABOUT PATHOGENESIS.
THE OTHER REASON THIS GENE WAS
EXCITING IS BECAUSE IT HAPPENS
TO BE A DANGER SIGNAL.
IT'S A LIGAND FOR A RECEPTOR
CALLED NKG2D THAT'S EXPRESSED ON
ACTIVATED CD8 EFFECTOR CELLS AND
WHEN THOSE TWO ENGAGE, THE
CD8 EFFECTORS CAN TARGET AND
KILL CELLS THAT ARE EXPRESSING
THIS LIGAND.
SO FOR BOTH OF THOSE REASONS,
THIS GENE BECAME QUITE AN
INTEREST FOR US IN THE LAB.
ONE OF THE OTHER SURPRISES THAT
CAME OUT OF THIS WORK EARLY ON
WAS THE ALIGNMENT OF ALOPECIA
WITH SOME UNEXPECTED GENETIC
DISEASES.
SO WE AS I THINK MANY PEOPLE
EXPECTED ALOPECIA AREATA TO
CLOSELY RESEMBLE VIE PSORIASIS
IN
TERMS OF ITS GENETIC MAKEUP.
YOU'LL SEE THAT'S NOT THE CASE
AND INSTEAD WHAT WE SEE IS A
STRONG ALIGNMENT WITH THIS CLASS
OF AUTOIMMUNE DISEASES.
SO THIS WAS AGAIN A SURPRISE, IT
TOOK US A WHILE TO SORT OF GET
OUR MINDS AROUND THIS, BUT WHEN
WE WENT TO THE LITERATURE, IT
TURNED OUT THAT THERE WAS A RICH
HISTORY IN THIS CLASS OF
DISEASES FOR UNDERSTANDING WHAT
MAKES THEM SIMILAR AND MOST OF
THAT CONVERGES ON THIS NKG2D
AXIS.
SO AGAIN SOMETHING GENETICISTS
LOVE TO DO IS REPLICATE OUR
INITIAL GWAS STUDIES AND
OFTENTIMES WE HAVE TO COMBINE
COLLEAGUES AROUND THE WORLD ALSO
DOING GWAS STUDIES TO GET EVEN
MORE CANDIDATE GENES, SO WE'RE
VERY LUCKY TO COLLABORATE WITH
REGINA BETZ AND MARKUS NOTHEN TO
COMBINE OUR GWAS WITH THAI WE
NOW HAVE 10,000 CASES AND
CONTROLS, AND WHAT WE SEE IS AN
IMPROVEMENT IN OUR HLA SIGNAL
HERE AS WELL AS ULBP3 AND 6 AND
SOME OF THE OTHERS, SO WE FULLY
REPLY DATED OUR INITIAL GWAS IN
THIS META-ANALYSIS IN ADDITION
TO FINDING SEVERAL OTHER NEW
CANDIDATE GENES.
YOU CAN SEE THE COMPILED LIST
HERE.
SO SOME OF THE STATISTICS ON
THIS ARE GETTING IMPRESSIVE, THE
ULBP GENES YOU SEE HERE AGAIN
ARE HOLDING UP AT 10 TO THE MY
MINUS 24, SUGGESTING ONCE AGAIN
THAT THIS MIGHT BE A PLACE TO
FOCUS FOR MECHANISM.
WAVE ALSO RESOLVED OUR HLA
SIGNAL TO A FEW PARTICULAR AMINO
ACIDS WITHIN HLDRB1, SO AMINO
ACID 13 AND 37 AS WELL AS A QTL
SNP HERE, SO MOST OF OUR SIGNAL
IS COMING FROM DRB1.
THIS COMPARES NICELY TO REUM
TIED OR THRIETS, TO PSORIASIS,
WHICH HAVE ALSO DONE THIS TYPE
OF ANALYSIS WITH THE HELP OF
PAUL DEBAKER TO REALLY RESOLVE
THESE SIGNALS DOWN TO A VERY
SMALL NUMBER OF AMINO ACIDS AND
AGAIN THESE ALSO ALIGN CLOSELY
WITH THOSE IN CELIAC DISEASE AND
THOSE IN TYPE 1 DIABETES.
SO WE PUT THIS ALL TOGETHER AND
OUR GOAL NOW IS TO CONTINUE
ALONG THE GENETICS.
WE'RE NOW DOING WHOLE EXOME
SEQUENCING WITH CUSTOM CAPTURE
IN OUR GWAS READINGS TO IDENTIFY
THE FUNCTIONAL VARIANCE AND THE
GOAL IS TO ADVANCE THIS TO WELL
OVER 10,000 INDIVIDUALS.
SO I'M NOT GOING TO GO MUCH
FURTHER ON THE GENETICS TODAY,
BUT SOMETIMES MY FRIENDS LIKE TO
SAY THAT WE'VE GOTTEN SO
DISTRACTED BY THIS FIVE YEARS OF
I MEU NOLG THAT WE'RE FINALLY
COMING BACK TO DOING WHAT WE
STARTED, WHICH WAS TO GO FURTHER
INTO THE GENETICS, BUT I WON'T
GO ANY FURTHER THERE TODAY
EXCEPT JUST TO -- I'VE PUT IN
CONTEXT A LITTLE BIT, THIS IS
ALOPECIA AREATA AND THESE ARE
SOME OF THE OTHER AUTOIMMUNE
DISEASES.
THIS IS A LITTLE BIT OUT OF DATE
NOW.
THESE ARE NUMBER OF PATIENTS IN
GWAS STUDIES AND AGAIN MANY OF
THESE ARE OVER 100,000 NOW.
WHAT HAPPENS IS AS YOU MOVE TO
THE LEFT HERE, YOU BEGIN TO PICK
UP MORE AND MORE AND MORE
SUSCEPTIBILITY GENE, SO YOU CAN
SEE THAT YOU BEGIN TO GET MANY
MORE GENES WITH SMALL EFFECT
SIZES HERE AS YOU ADD PATIENTS
TO THESE GWAS STUDIES.
SO WE'RE AT THIS LEVEL, BUT I'M
HOPING WHAT I CAN SHOW YOU TODAY
IS THAT EVEN WITH KNOWLEDGE OF
THE VERY LOWEST HANGING FRUIT,
THE GENES THAT ARE EASIEST TO
FIND HERE, THAT EVEN WITH THAT
INFORMATION, WE'VE BEEN ABLE TO
MAKE SOME INTERESTING FUNCTIONAL
OBSERVATIONS.
SO WHAT I HOPE TO AGAIN SEND YOU
HOME WITH TODAY IS A LITTLE BIT
OF APPRECIATION HOW THE GENETICS
HAVE OPENED UP A NEW WINDOW INTO
UNDERSTANDING THEIR DISEASE
PATHOLOGY AND THEN ALSO HOW
WE'VE TRIED TO LEVERAGE THAT TO
CHOOSING AND REPURPOSING SOME
EXISTING DRUGS TO TRY IN THIS
DISEASE.
SO AGAIN, TAKING A PAGE FROM
WHAT'S COME BEFORE US, WE'VE
STUDIED WITH GREAT CARE THE
BEAUTIFUL WORK OF THOMAS WALDMAN
WHO'S HERE IN THE AUDIENCE --
WHO WORKS ON CELIAC DISEASE --
OWE SHEA WHO'S HERE IN THE
AUDIENCE, AND MANY OF THE FOLKS
WHO HAVE COME BEFORE US HAVE
DONE SEMINOLE WORK IN THESE
PATHWAYS IN THE ROW LATED
AUTOIMMUNE DISEASES AND WE'VE
BEEN INSPIRED BY THEIR
COLLECTIVE SCHOLARSHIP TO TRY
AND BORROW SOME OF THESE
PRINCIPLES AND APPLY THEM TO
ALOPECIA AREATA, OF COURSE WITH
THE GOAL OF FINDING SOME SHARED
TREATMENT.
SO TO COME BACK TO OUR FAVORITE
CANDIDATE GENE, ULBP3, AGAIN
WHEN WE FIRST FOUND THIS, WE
WEREN'T QUITE SURE HOW TO
INTERPRET IT, WHAT TO MAKE OF
IT, SO WE BEGAN TO GO THROUGH
THIS LITERATURE AND WHAT CAME
THROUGH WAS THAT IN THE OTHER
THREE RELATED DISEASE STATES,
THERE WAS THE SIMILAR
UPREGULATION OF A -- IN THE END
ORGAN OF THE OTHER DISEASES, SO
IN RHEUMATOID ARTHRITIS -- IN
THE NOD MICE, THE NOMENCLATURE
GETS A LEL MESSY ABOUT -- ARE
RELATIVES OF THE SAME CLASS OF
ULBP3 LIGANDS.
SO OUR QUESTION WAS DO WE SEE
THE SAME IN ALOPECIA AREATA HAIR
FOLLICLES.
SO THE BLUE IS AN OUTLINE OF
NORMAL CELLS IN THE CONTROL HAIR
FOLLICLE.
THE RED IS STAINING FOR ULBP3.
WE ALWAYS SEE A LITTLE BIT OF
STAINING EVEN IN CONTROLS, BUT
IN ALOPECIA AREATA PATIENTS, WE
SEE A MASSIVE UPREGULATION OF
ULBP3 IN THE OUTER MOST PART OF
THE HAIR FOLLICLE IN THIS CASE,
IN THE DERMAL SHEATH,
POSITIONING IT AT THE RIGHT
PLACE IN THE ANATOMY OF THE HAIR
FOLLICLE TO INTERACT WITH THE
NK -- RECEPTOR COMING IN FROM
THE SURROUNDING IMMUNE CELLS.
SO THIS CHARACTERISTIC REALLY I
THINK BEGINS TO GIVE SOME
FUNCTIONAL SIGNIFICANCE TO OUR
CANDIDATE GENE.
SO IF WE HAVE THE LIGAND ON THE
HAIR FOLLICLE, WE EXPECT TO SEE
THE RECEPTOR ON THE INFILTRATE,
SO THIS IS CO-STAINING FOR
CD8 AND NK IM. 2DKG2D -- LIKELY
INVOLVED
IN DISEASE.
SO REMEMBER AT THE BEGINNING I
MENTIONED THIS SORT OF SWARM OF
BEES PATHOLOGY THAT WAS KNOWN UP
UNTIL NOW, AND IT WAS REALLY AT
THIS POINT THAT I WAS ABLE TO
ENLIST THE HELP OF MY CLAB
COLLABORATOR TO REALLY HELP
FIGURE THIS OUT.
WHEN RAFAEL LOOKED AT THIS
PICTURE HE SAID THIS LOOKS LIKE
TYPE 1 DIABETES OF THE HAIR
FOLLICLE, SO THAT SORT OF BECAME
OUR WORKING MODEL FOR TRYING TO
BUILD OUT OUR STUDIES ON THE
IMMUNOLOGY.
OH SO LET ME INTRODUCE YOU TO
THE MOUSE MODEL USED THROUGHOUT
OUR WORK.
SO THIS IS AN INBRED STRAIN OF
MICE CALLED C3H/HEJ.
THIS IS A STRAIRN STRAIN THAT'S
KEPT AT
JACKSON LABS, THEY DEVELOPED
SPONTANEOUS ALOPECIA AREATA IN
ABOUT 15% FEMALES AT ABOUT A
YEAR, SO IT'S NOT A VERY
TRACTABLE MODEL TO DO EITHER
PREVENTION OR TREATMENT STUDIES
WAITING AROUND ALL THIS TIME.
SO THEY DEVELOPED A GRAFT MODEL
WHERE THEY CAN TAKE SMALL BITS
OF SKIN FROM AFFECTED AA MICE
AND GRAFT THEM ON THE BACK OF
C3H RECIPIENTS, THEY START TO
LOSE HAIR ON THE BELLY FIRST,
AND THEN IF YOU LET THIS
PROGRESS TO THREE OR FOUR
MONTHS, THEY'LL LOSE HAIR
EVERYWHERE ON THE BACK, AND ON
THE REST OF THE BODY.
SO THIS MODEL IS VERY
STEREOTYPICAL, IT'S EASY TO USE
FOR TESTING, AND SO WE CAN DO
TWO THINGS WITH IT, WE CAN GIVE
DRUGS AT THE TIME OF THE GRAFT
AND WE CAN TRY TO PREVENT THE
ONSET OF ALOPECIA, THAT'S THE
EASIER MODEL, OR WE CAN LET THE
MICE LOSE THEIR HAIR, EITHER
EARLY OR LATE DISEASE, AND THEN
GIVE DRUG AND TRY TO REVERSE THE
MODEL AND ACTUALLY SET UP A
TREAT M-TYPE
TREATMENT-TYPE STUDY AND THAT'S
OF COURSE MORE CHALLENGING.
SO TO TRY AND PROVE THAT THE
MOUSE WAS A GOOD MODEL FOR HUMAN
ALOPECIA, JUST A FEW QUICK
STUDIES, SO THIS IS AT THE GENE
EXPRESSION LEVEL.
THIS IS HUMAN COMPARED TO MOUSE
ALOPECIA AREATA.
YOU CAN SEE UPREGULATION OF SOME
OF THE INTERFERON CYTOKINES
HERE, SOME MARKERS OF
CD8 CYTOTOXIC CELLS, CD8 HERE,
WE'LL GO THROUGH THIS IN A LOT
MORE DETAIL LATER BUT ROUGH
SIMILARITIES IN TERMS OF GENE
EXPRESSION.
DO WE SEE SIMILAR UPREGULATION
OF AN NK LIGAND IN THE MOUSE?
SO THIS IS HUMAN ULBP3 IN THE
STRESSED FOLLICLE, AND THIS IS
C3H MOUSE BEFORE GRAFTING.
YOU CAN SEE THAT THIS LIGAND,
H60, IS ALREADY UPREGULATED AT
BASELINE COMPARED TO BLACK
6 MICE AND HERE IT IS AFTER
TRANSFER OF THE SKIN GRAFT
SHOWING EVEN MORE UPREGULATION,
SO GOOD CONSISTENCY THERE.
DO WE SEE THE SIMILARITIES AT
THE LEVEL OF THE T-CELLS?
SO IN HUMAN AGAIN CD8, NKG2D
CELLS, HERE IN THE MOUSE, THE
SAME MARKING INFILTRATE WITH
THIS TWO MARKERS IN THESE KILLER
CELLS.
INTERESTINGLY, THIS PHENOTYPE OF
CD8 NKG2D CELLS MAKES UP A FULL
20% OF THE T-CELLS IN THE SKIN
OF LESIONAL ALOPECIA IN THE MIKE
SO THIS BECOMES A VERY
CONVENIENT BIOMARKER IF YOU WILL
IF WE CAN MEASURE THE
DISAPPEARANCE OF THESE CELLS
FROM THE SKIN, IT WOULD SUGGEST
TO US THAT WE'RE HITTING THE
RIGHT TARGET, AND WE'LL SEE THAT
AGAIN LATER.
SO THE CRITICAL EXPERIMENT
REALLY WAS TO SHOW THAT THE CD
CD8 -- WERE NECESSARY AND
SUFFICIENT.
SO HERE WE'RE TRANSFERRING
TOTAL -- INTO AN UNAFFECTED
RECIPIENT AND THAT MOUSE LOSES
ITS HAIR.
IF WE ACCEPT SEPARATE THE NKG2D
NEGATIVE FROM POSITIVE CELLS,
YOU CAN SEE HE DEPLETED CELLS,
THE MICE RETAIN THEIR HAIR AND
IT'S ONLY THE POSITIVE CELLS
THAT LOSE THEIR HAIR, SO THIS
GAVE US REALLY THE FIRST WINDOW
OF TRYING TO UNDERSTAND AGAIN A
LITTLE BIT MORE SPECIFICALLY
WHAT'S IN THAT INFILTRATE AND IF
WE COULD SELECTIVELY TARGET
THOSE CELLS MAYBE GIVE US A
CHANCE TO INTERYOU WANTINTERRUPT
THE DISEA
SE
PROCESS.
THERE ARE MANY, MANY WAYS TO
THINK ABOUT DOING THAT.
AGAIN, THIS IS A RICH LITERATURE
IN TERMS OF TARGETING THESE
CELLS, BUT HERE WE START TO
THINK ABOUT THE RISK-BENEFIT FOR
A DISEASE LIKE ALOPECIA AREATA
WHERE THESE PATIENTS DON'T HAVE
LIFE-THREATENING COMPLICATIONS
FROM THEIR DISEASE, IN MANY
CASES, IN MOST CASE, IN FACT,
HAIR LOSS IS THEIR ONLY MEDICAL
PROBLEM, SO THE RISK-BENEFIT OF
USING POTENT IMMUNOSUPPRESSIVE
DRUGS FOR A DISORDER LIKE
ALOPECIA AREATA BECOMES A
QUESTION THAT WE ASK AND ALSO TO
MAKE THIS INTO A VIABLE
TREATMENT FOR PATIENTS, WE NEED
ABOUT WHAT'S THE RIGHT WAY TO GO
HERE.
SO EVEN THOUGH THERE WAS A RICH
LITERATURE IN THE CYTOKINE
WORLD, OUR QUESTION REALLY BEGAN
TO FOCUS A LITTLE MORE ON HOW
COULD WE MAYBE COULD DO THIS
USING
SMALL MOLECULES.
SO AGAIN DEFINED BY DR. WALDMAN
WHO'S HERE IN THE ROOM AND HIS
COLLEAGUES, THE IL-15 PATHWAY WE
KNOW IS THE KEY COMPONENT OF
KEEPING THE CD8 CYTOTOXIC CELLS
ALIVE AND THAT WITHOUT AN ACTIVE
IL-15 SIGNAL, THESE CELLS REALLY
DON'T SURVIVE WELL.
SO I WON'T SHOW YOU THE WHOLE
STORY BUT SUFFICE TO SAY THAT WE
HAVE STRONG UPREGULATION OF
IL-15 PATHWAY IN ALOPECIA
AREATA, BOTH IN THE HAIR
FOLLICLE, SO WE NEED TWO
COMPONENTS ON THE SENDING CELL,
IN ALOPECIA AREATA, WE HAVE
EXPRESSION OF IL-15RA, THE
CHAPERONE RECEPTOR, AS WELL AS
IL-15, THE CYTOKINE ITSELF, AND
IN THE RECEIVING CELL, THE GAMMA
CHAIN AND BETA CHAIN CYTOKINE
HERE, SO WE HAVE ALL FOUR
COMPONENTS IN ALOPECIA,
SUGGESTING THAT THIS, IN FACT,
COULD BE THOUGHT OF AS TARGETING
WITH A DOWNSTREAM JACK
INHIBITOR.
AGAIN AS MANY YOU HAVE KNOW ON
THE CAMPUS, DR. ROCHET'S LAB HAS
BEEN ONE OF THE PIONEERS THE
FIELD ESTABLISHING MANY OF THE
CORE CONCEPTS, SO AGAIN, IT WAS
RAFAEL'S SUGGESTION TO THINK
ABOUT USING THESE JACK
INHIBITORS IN PLACE OF SOME OF
THESE MORE BROAD IMMUNE SPRE
SELF MOLECULES AS A WAY TO
TARGET FOR ALOPECIA.
SO HERE YOU SEE THAT IL-15
SIGNAL IN AN AFFECTED HAIR
FOLLICLE, IT'S VERY STROK, ALSO
IN.  SO OUTER LAYERS AGAIN
SUGGESTING IT'S AT THE RIGHT
PLACE TO BE ACTIVE.
I'LL SHOW YOU LATER BUT ALSO WE
HAVE THE STRONG EVIDENCE FOR THE
INTERFERON SIGNATURE THAT YOU
SAW A BIT EARLIER, SO THESE TWO
CYTOKINE PATHWAYS ARE REALLY OUR
TWO MAJOR AXES IN ALOPECIA
AREATA, INHIBITION OF JACK
1-2 OR JACK 1-3 TO TRY AND BLOCK
ONE OR BOTH OF THESE SIGNATURES.
SO AS IT TURNED OUT, THE JAK
INHIBITORS IN OUR STORY ACTUALLY
HAD A DUAL PURPOSE, SO WE CAN BE
THINKING ABOUT IT.
HERE'S OUR IL-15 SIGNAL COMING
FROM THE HAIR FOLLICLE BACK TO
THE T-CELL, HERE YOU SEE
BLOCKADE BY SOME JAK INHIBITORS,
BUT WE ALSO UNEXPECTEDLY HAVE A
SECOND OPPORTUNITY TO INTERRUPT
THE INTERFERON SIGNAL HERE THAT
ACTUALLY FUNCTIONS AT THE LEVEL
OF THE HAIR FOLLICLE, SO THIS
WAS UNEXPECTED, WE SORT OF GOT A
GIFT WITH PURCHASE HERE, AND
AGAIN WORK THAT I WON'T GO TOO
MUCH INTO, WE KNOW NOW THAT THE
J ASM K INHIBITORS HAVE A DUAL
EFFECT NOT JUST ON BLOCKING
IMMUNE RESPONSE BUT ALSO DIRECT
ACTIVATION OF FOLLICLE STEM
CELLS SO AGAIN, THAT WAS
UNEXPECTED.
AT THE TIME WE STARTED, THERE
WERE -- STILL ARE, I THINK, ONLY
TWO FDA-APPROVED JAK IMHIN TORES
HERE IN THE U.S., ONE WAS TOFA
TOFACINIB, AND -- TOFA IS CALLED
A PAN JAK INHIBITOR, TARGETS ALL
THREE, AND RUXO IS SPECIFIC TO
JAK 1 AND 2, ALSO -- JOHN TOLD
ME TODAY BEEN APPROVED IN EUROPE
FOR R.A.
SO A LOT OF ACTIVITY AND
DEVELOPMENT IN THIS AREA FOR
MANY DIFFERENT AUTOIMMUNE
DISEASES AND CANCERS.
SO AGAIN, THE WAY WE USE THESE
DRUGS IN THE MODEL, SOME WE GIVE
AT THE TIME OF GRAFTING TO
PREVENT DISEASE, AND OTHERS WE
GIVE AFTER THE MICE HAVE
ESTABLISHED ALOPECIA AREATA TO
TRY AND REVERSE IT.
SO LET ME SHOW YOU SOME
EXAMPLES.
THIS IS SYSTEMIC DELIVERY OF
BOTH RUXO AND TOFA.
SO HERE WE GIVE TOFA AT THE TIME
OF GRAFTING, AND YOU CAN SEE
THAT MICE THAT RECEIVED TOFA
RETAPED THEIR HAIR, WHEREAS THE
RETAINED THEIR HAIR, THE TREATED
MICE HAVE THICK, HEALTHY
FOLLICLES HERE, STILL IN THE
ANTIGEN OR GROWTH PHASE, WHEREAS
THE UNTREATED MICE HAVE A STRONG
IMMUNE INFILTRATE AND DYSTROPHIC
HAIRS, NOT MAKING MUCH OF A HAIR
SHAFT, THEIR LYMPH NODES STAY
SMALL, SUGGESTING THE CELLS
BASICALLY DON'T GET STARTED,
THEY REALLY DON'T GET BORN IN
THE TREATED ANIMALS.
THE SAME RESULT IS TRUE FOR
RUXO, SO THE TREATED MICE RETAIN
THEIR HAIR AND THE UNTREATED
MICE LOSE THEIR HAIR.
THESE ARE STRONG HEALTHY
FOLLICLES IN ANTIGEN AND
DYSTROPHIC FOLLICLES WITH IMMUNE
INFILTRATE SURROUNDING THE
FOLLICLE IN THE SAME RESULT
HERE.
SO IF WE COMPARE THAT TO WHAT WE
GET WHEN WE BLOCK WITH AN IL-15
BLOCKING ANTIBODY, YOU CAN SEE
THAT IN THE TOP ROW OF EACH
IL-15 BLOCKADE OR TO FA OR RUXO,
EACH CAN REVERSE THE MARKERS
START TO GO AWAY, YOU SEE THESE
BLACK INDICATORS OF HAIR
FOLLICLE REGROWTH SO THOSE ARE
THE HAIR SHAFTS GOING BACK INTO
ANTIGEN OR GROWTH PHASE, SO
WE'VE REVERSED, IF YOU WILL, OUR
DANGER SIGNALS OR RESTORING
IMMUNE PRIVILEGE AT THE HAIR
FOLLICLE LEVEL.
IN THE UNTREATED MICE, THEERS
ARE THESE ARE
OUR KILLER CELLS IN THE TOP
RIGHT QUADRANTS, BOTH IL-15 AND
JAK3 IN TOFA CONTROLS, BUT WHEN
WE LOOK AT THE TREATED MICE,
THESE QA
THESE QUADRANTS ARE BASICALLY
EMPTY, SUGGESTING THEY NEVER HAD
A CHANCE TO GET GOING, SO GIVING
US I THINK GOOD EVIDENCE THAT
WE'RE HITTING TARGET AND THAT
WE'RE BEGINNING TO AFFECT THE
CELLS AS WELL AS THE END ORGAN
PHENOTIME IN A POSITIVE
DIRECTION.
SO I'LL FAST FORWARD AND JUST
SHOW YOU, WE'VE DONE THIS NOW
WITH MANY DIFFERENT JAK
INHIBITOR, BOTH WITH SYSTEMIC
AND MORE RECENTLY TOPICAL
DELIVERY, SO THIS IS WHAT IT
LOOKS LIKE TOPICALLY, SO THESE
CONTROL MICE ARE TREATED WITH
THE VEHICLE CREAM BEFORE AND FOR
ONE MONTH AND FOR TWO MONTHS,
AND THEN THIS IS TOFA BEFORE ONE
MONTH, TWO MONTHS, AND THE SAME
FOR RUXO.
SO YOU SEE THIS IS A DRAMATIC
INCREASE IN HAIR GROWTH AFTER
JUST TWO MONTHS OF TREATMENT.
WE CAN WITHDRAW THE TREATMENT
AND SHOW IT'S DURABLE SO WHEN WE
TAKE THE DRUG AWAY, THEY ONLY
REGROW WHERE WE TREAT THEM,
THESE MICE WERE TREATED ON THEIR
BACK, THE DRUGS TO NOT SEEM TO
PASS SYSTEMICALLY WHEN WE USE IT
TOPICALLY.
WE'VE REVERTED SOME OF OUR
IMMUNE PRIVILEGE MARKERS BACK TO
THE NORMAL SITUATION, AND
IMPORTANTLY, WE'VE BEEN ABLE TO
CLEAR THESE CELLS FROM TREATED
SKIN, SO HERE'S OUR 20% OR SO OF
NKG2D POSITIVE CELLS BEFORE
TREATMENT AND THEN AFTER THE
TOPICAL TREATMENT, THESE GO BACK
TO A BASELINE LEVEL.
SO THIS IS ENCOURAGING AND
SUGGESTS THAT AGAIN FOR
DIFFERENT MODALITIES THAT WE
MIGHT BE ABLE TO THINK ABOUT
INCORPORATING TOPICAL TREATMENT
INTO THE ARSENAL FOR TREATMENT
OF ALOPECIA AREATA.
SO JUST A QUICK ASIDE, LET'S
CHANGE GEARS AND LOOK AT SOME OF
THE WORK WE'VE BEEN TRYING TO DO
TO DEVELOP A CONCOMITANT
BIOMARKER PLAN THAT WE COULD USE
IN TANDEM WITH OUR CLINICAL
TRIALS TO BEGIN TO GIVE US
BIOLOGICAL INDICATIONS OF
RESPONSE TO TREATMENT EVEN
BEFORE WE'RE ABLE TO SEE THE
HAIR GROWING.
SO AGAIN ENCOURAGED BY NIAMS,
WHO WAS BEHIND US REALLY 100% IN
THIS WORK.
WE HAD A SMALL R21 GRANT TO
BEGIN TO DEVELOP SOME OF THESE
GENE EXPRESSION BIOMARKERS.
SO IN ADDITION TO THE GENETICS,
WE'VE DONE NOW EXTENSIVE
TRANSCRIPTIONAL ANALYSIS, BOTH
IN THE BLOOD AND ALSO IN SKIN,
SO I'LL SHOW YOU SOME OF OUR
GENE EXPRESSION WORK.
THE GOAL IS SEVERAL FOLD.
ONE IS TO TRY AND THINK ABOUT
STRATIFICATION OF PATIENTS WHEN
THEY COME IN WITH ALOPECIA
AREATA FOR THE FIRST TIME.
SO THE MOST COMMON PRESENTATION
FOR PATIENTS IS JUST A SINGLE
PATCH OF HAIR LOSS, AND IT'S
REALLY -- IT'S UNKNOWN TO THE
PATIENT AND THEIR PRACTITIONER
WHETHER THAT PATIENT WILL GO ON
TO GET BETTER, GET WORSE OR STAY
THE SAME.
AND IT'S ACTUALLY A HUGE
FRUSTRATION BOTH FOR TREATING
AND ALSO A HUGE SOURCE OF
ANXIETY FOR PATIENTS TO KNOW IF
THEY'RE LIKELY TO SPONTANEOUSLY
REMIT OR LIKELY TO HAVE LONG
TERM PATCHY DISEASE OR LIKELY TO
PROGRESS.
SO IN THE LONG TERM, WE'D LIKE
TO HAVE A GENOTYPE RISK SCORE
THAT COULD HELP US AT BASELINE
KNOW HOW MANY SUSCEPTIBILITY
GENES A PATIENT WILL CARRY.
WE'D LIKE TO HAVE SOME SERUM
MARKERS SO WE COULD TRACK THESE
CHANGES NON-INVASIVELY, NOT HAVE
TO DO A SCALP BIOPSY EACH TIME,
THEN FINALLY WHAT I WILL SHOW
YOU IS A GENE EXPRESSION CLASS
FIRE TO MARK AGAIN THEIR
RESPONSE TO TREATMENT.
SO WE'D LIKE IT KNOW, AGAIN,
COULD WE USE THESE PROGNOSTICLY
AND ALSO COULD WE STRATIFY GIVEN
PATIENTS TO A PARTICULAR
TREATMENT.
SO IF WE TAKE BIOPSIES FROM
ALOPECIA AREATA SCALP, AND WE DO
SORT OF AN UNSUPERVISED
CLASSIFICATION, THESE ARE
CONTROL SCAL PS, THESE ARE MILD
PATCHY DISEASE IN THE MIDDLE,
AND THIS IS SEVERE, TOTALIS, YOU
CAN SEE THEY NICELY
úDIFFERENT STATES OF DISEASE.
IF WE ANALYZE THESE, IT'S ON ONE
END THE INTERFERON SIGNATURE AND
THE CYTOTOXIC T-CELL SIGNATURE
THAT'S MOST EXTREMELY
UPREGULATED, WHEREAS ON THE
OTHER SIDE, IT'S THE KERATINS
AND SOME OF THE OTHER STRUCTURE
HAIR GENES THAT ARE
DOWNREGULATED SO STATISTICALLY,
WE'D LIKE TO HAVE BOTH ENDS OF
THIS REPRESENTED SO WHEN OUR
INTERFERON SCORES GO DOWN, OUR
HAIR KERATIN SCORES GO UP AND WE
CAN MEASURE RECOVERY IN THESE
DIFFERENT WAYS.
SO HERE'S A CLOSER VIEW.
SO IN NORMAL CONTROL SUBJECT
SCALP, WE SEE VERY LOW
EXPRESSION OF OUR CYTOTOXIC
T-CELL SIGNATURE OR OUR
INTERFERON SIGNATURE, AND THE
RED INDICATES VERY STRONG
SIGNATURE OF NORMAL HAIR GROWTH.
IF WE CONTRAST THAT TO ALOPECIA
TOTALIS SSH/UNIVERSALIS, AND
SOME
HAIR IS STILL LEFT IN THESE
PATIENTS.
SO WE'VE TRIED TO QUANTITATE
THIS AS SORT OF WHAT WE CALL A
DISTANCE TO HEALTH CALCULATION,
WHERE WE CAN MEASURE COMPOSITE
SCORE OF ALL OF THE GENE
EXPRESSION IN AN RNA SCWEENS
SEQUENCING.
THIS IS OUR MOST SEVERE
PHENOTYPE, THIS IS PATCHY
DISEASE IN THE MIDDLE, AND THESE
ARE CONTROLLED SO THE GOAL IS
WHEN WE TREAT WITH A DRUG THAT
HITS THE TARGETS, WE EXPECT TO
SEE THESE GENE EXPRESSION
SIGNATURES MOVE THIS WAY TO SORT
OF RESOLVE TOWARDS THE NORMAL
QUADRANT WHICH WE SEE DOWN HEERY
GRES
REGRESS TO NORMAL.
ONE THING THAT WAS SURPRISING TO
US,
US, WE ACTUALLY AS YOU SAW
EARLIER SEE AN EXAGGERATED
PROFILE IN THE SEVERE DISEASE
COMPARED TO PATCHY.
SO NOW THAT WE LOOK PACK BACK ON
T
MAYBE THIS MAKES SENSE, BUT FOR
A LONG TIME IN OUR FIELD, IT'S
BEEN SUGGESTED THAT THESE
PATIENTS ACTUALLY HAVE WHAT THEY
CALL BURNED OUT DISEASE, MEANING
THEY'RE REALLY NOT TREATABLE
BECAUSE THE THINKING WAS THAT
THIS IMMUNE INFILTRATE HAD LONG
DISAPPEARED FROM THE SCALP.
BUT IN FACT OUR BIOPSY STUDY
ACTUALLY INDICATES THE OPPOSITE,
THAT THESE PATIENTS HAVE THE
HIGHEST LEVELS OF INFILTRATE
SIGNATURES SO THIS SUGGESTS TO
US THAT EVEN THOUGH FOR
CONVENTIONAL THERAPIES LIKE
STEROIDS, THESE PATIENTS WERE
RESISTANT, BUT FOR THE JAK
INHIBITORS OR OTHERS, THEY MAY
ACTUALLY BE TARGETABLE.
SO IN THE LAST SECTION, I'LL
JUST TELL YOU ABOUT OUR TWO OPEN
LABEL STUDIES THAT HAVE BEEN
DONE AGAIN LED BY JULIAN AT
COLUMBIA.
WE STUDIED A SMALL STUDY OF 10
TO 12 PATIENTS AS WELL AS A VERY
SMALL SERIES OF 10 TO 12
PATIENTS IN AN OPEN LABEL STUDY.
SO I'LL SHOW YOU SOME OF OUR
RESULTS.
SO AGAIN THESE ARE SINGLE ARM
PILOT STUDIES.
IN THIS STUDY, RUXO, WE STARTED
WITH 10 MODERATE TO SEVERE
PATIENTS AND ADVANCED THIS TO
TWO TOTALIS PATIENTS, THESE ARE
20 BID FOR THREE TO SIX MONTHS
AND WE FOLLOWED THEM WITH
PHOTOGRAPHY AND REPORTING AND
BIOMARKERS DURING THIS STUDY.
SO OVERALL, 9 OUT OF OUR 12
PARENTS ACHIEVED 12
PATIENTS ACHIEVED THEIR PRIMARY
OUT COME OF AT LEAST 50% OF
REGROWTH MEASURED BY SALT SCORE.
THE RESPONSE WAS SEEN AS EARLY
AS ONE MONTH.
THE REGROWTH WAS PROGRESSIVE,
ONE PATIENT WAS A LITTLE BIT
SLOWER THAN THE OTHERS BUT
EVENTUALLY CAUGHT UP.
SO I'LL JUST SHOW YOU SOME
EXAMPLES.
HERE'S A PATIENT WITH MODERATE
IF YOU WOULD TO SEVERE PATCHY
ALOPECIA, THIS IS AFTER 20 WEEKS
ON STUDY.
THIS IS ANOTHER PATIENT AT
BASELINE AFTER ABOUT FOUR
MONTHS, SHE GOT SOME HAIR
EXTENSIONS BECAUSE SHE WAS VERY
EXCITED TO HAVE HER HAIR BACK SO
THIS RUINED OUR PICTURES A
LITTLE BIT, BUT NONETHELESS, SHE
WAS VERY HAPPY.
THIS GENTLEMAN HAD LONG-STANDING
ALOPECIA AREATA.
THIS IS A TATTOO OF HIS EYEBROW
AND HE HAD LOST ALL OF HIS
FACIAL HAIR AS WELL AS THE HAIR
IN THE BACK OF HIS HEAD, AND
THIS IS HIM AFTER SIX MONTHS ON
RUXO SO HE REGAINED ALL OF HIS
FACIAL AND BODY HAIR AS WELL AS
HIS SCALP HAIR, SO COMPLETE
ESSENTIALLY COMPLETE RESPONSE.
THIS GENTLEMAN ALSO NICE
RESPONSE, THIS IS SHOWN IN
SERIES HERE BECAUSE YOU CAN SEE
HIS HAIR IS COMING BACK IN GRAY,
HERE ON TOP BUT HE DID MEET OUR
END POINT AND IF YOU'RE LOOKING
CAREFULLY, THE DERMATOLOGISTS IN
THE ROOM ARE NOTICING HIS
FOREHEAD IS ALSO REPIGMENTING,
SO THIS GENTLEMAN HAD -- AS WELL
AS ALOPECIA AREATA, CAME TO US
FROM JOHN HARRIS' GROUP AND HIS
VINILIGO ALSO RESPONDED WELL TO
TREATMENT WITH RUXO.
WE KNOW FROM JOHN'S WORK THAT
THE SAME TYPE OF IMMUNE
INFILTRATE IS SIMILAR AND YOU
CAN SEE IT RESPONDING.
SO THE HAIRLINE IN ALOPECIA IS
VERY DIFFICULT TO REGROW.
HERE YOU SEE NICE FILLING IN OF
THAT HAIRLINE.
HERE'S A PATIENT AGAIN
ESSENTIALLY COMPLETE ALOPECIA
TOTALIS AFTER SIX MONTHS.
THIS IS OUR SLOWER RESPONDER SO
AT BASELINE AND EVENTUALLY
CAUGHT UP TO MEET OUR END POINT
OF MORE THAN 50% AND HERE'S
ANOTHER EXAMPLE JUST SHOWING
FROM THE SIDE, AGAIN A NICE
RESPONSE AFTER SIX MONTHS.
SO THIS GENTLEMAN HAD AGAIN LONG
STANDING ALOPECIA UNIVERSEALIS
FOR A VERY LONG TIME AND HAD
COMPLETE REGROWTH.
SO THE -- WE DON'T HAVE A CLEAR
UNIFYING HYPOTHESIS YET.
ONE OF THEM ALSO FAILED
INTRALESIONAL STEROIDS, ANOTHER
HAD BIOPSY PROVEN ALOPECIA BUT
ALSO HAD SOME FEMALE PATTERN
HAIR LOSS AND ANOTHER ALSO HAD
MALE PATTERN HAIR LOSS BUT ALSO
CLEARLY AA SO WE'RE NOT SURE
EXACTLY WHAT WENT ON HERE.
ALL THREE OF THEM HAPPEN TO BE
FROM AFRICAN-AMERICAN OR
HISPANIC DESCENT BUT I THINK
THAT'S A COINCIDENCE BECAUSE A
LOT OF OUR RESPONDERS ARE FROM
THOSE GROUPS.
SO THIS IS AT BASELINE, THIS
LOOKS LIKE REGROWTH BUT HE
SIMPLY DIDN'T SHAVE IN THIS
PICTURE SO IT'S ACTUALLY NO
CHANGE FROM BASELINE.
HERE'S ANOTHER ONE, BASELINE,
THEN 16 WEEKS.
NO CHANGE AGAIN.
THIS PATTERN MIGHT BE A LITTLE
DIFFERENT THIS, IS A MORE
DIFFUSE TYPE.
THEN FINALLY THIS PATIENT IS THE
ONE WHO HAD FAILED STEROIDS, AND
THIS IS THE OPHIASIS PATTERN
THAT SURROUNDS THE HAIRLINE, A
VERY CHALLENGING PATTERN TO GET
TO RE-GROW.
SO THIS IS THEIR SALT SCORE SO
AT BASELINE AGAIN UP TO 100%
HAIR LOSS, SO THE HAIR LOSS
SCORE GOES DOWN.
THIS DASHED LINE IS AFTER WE
STOPPED TREATMENT, THIS IS THE
OTHER WAY, THIS IS PERCENT
REGROWTH OVER TIME.
SO THIS IS THE HAIR RETURNING,
THIS IS AT THE END OF THE
TREATMENT PERIOD, THEN THE
DASHED LINES INDICATE THE
RELAPSE AFTER TREATMENT STOPPED
AND HERE'S SOME OF THE
NON-RESPONDERS DOWN HERE.
SO RELAPSES ARE COMMON, THEY
OCCUR BETWEEN TWO AND THREE
MONTHS IF YOU WILL AFTER THE
TREATMENT HAS ENDED.
IT CAN BE SEVERE, IT CAN GO BACK
TO BASELINE, SOME SOME REPORT
MILD
SHED BUG NOT TOTALLY
SIGNIFICANT.
ADVERSE EVENTS IN OUR PATIENTS
IN THIS STUDY WERE ESSENTIALLY
MILD TO NON-EXISTENT.
NONE OF THE THINGS THAT WE WERE
AFRAID OF LOOKING OUT FOR REALLY
SHOWED UP HERE.
ONE PATIENT DROPPED THEIR
HEMOGLOBIN JUST A LITTLE BIT, WE
ADJUSTED THE DOSE AND IT
RECOVERED ON ITS OWN.
SO FOR THE BIOMARKERS, AGAIN WE
WANTED TO LOOK AND SEE IF WE
COULD NOTICE THE RESPONSE TO
TREATMENT EVEN BEFORE THE HAIR
WAS GROWING BACK.
SO HERE'S OUR TWO EXAMPLE
PATIENTS AT BASELINE, SO THE RED
BEGIN GWEN VERY HIGH INTERFERON
SCORES AND ESSENTIALLY NO HAIR
SIGNATURE.
IF WE COMPARE THOSE TO THE THREE
NORMALS HERE ON THE RIGHT,
AGAIN, LOW IMMUNE INFILTRATES
AND A LOT OF HAIR.
THIS WAS THEM AFTER 12 WEEKS.
SO YOU CAN SEE THE IMMUNE
INFILTRATE IS LARGELY RESOLVED
AND THE HAIR HAS BEGUN TO
RECOVER, AND IF WE LOOK AT OUR
BIOMARKERS, THESE ARE BEFORE
TREATMENT AND THESE ARE AFTER
TREATMENT, AND WE'VE SEEN A NICE
CORRECTION OF OUR MARKERS AND
THE BLACK AGAIN INDICATES THAT
THESE HAIRS HAVE GONE BACK INTO
THEIR GROWTH PHASE.
SO IF WE EXPAND THAT TO LOOK AT
THE WHOLE COHORT, THOOS ARE OUR
RUXO RESPONDERS IN THE MIDDLE SO
THESE ARE NINE RESPONDERS AT
TIME ZERO, HERE THEY ARE AFTER
12 WEEKS.
SO AGAIN AT BASELINE, A HIGH
IMMUNE SIGNATURE, NOT MUCH HAIR,
THEN AFTER TREATMENT, A MUCH
LOWER IMMUNE SCORE AND THE RED
INDICATES THE RETURN OF THEIR
HAIR MUCH LIKE THESE CONTROLS.
BUT HERE'S TWO NON-RESPONDERS.
SO INTERESTINGLY, I THINK THESE
TWO NON-RESPONDERS ACTUALLY DID
NOT HAVE A STRONG INTERFERON
GAMMA SCORE OR CYTOTOXIC --
SCORE AT BASELINE SO THIS GIVES
US A HINT, I THINK, THAT
SOMETHING MUST BE GOING ON WITH
THESE NON-RESPONDERS THAT'S
DIFFERENT, THEY EITHER HAVE A
DIFFERENT FORM OF ALOPECIA
AREATA OR THE FORM THAT THEY
HAVE IS DRIVEN BY A DIFFERENT
SET OF CYTOKINES BUT AS WE GET
MORE AND MORE OF THESE
COLLECTED, I THINK THIS WILL BE
INFORMATIVE FOR US TO -- HOW TO
APPROACH THESE IN THE FUTURE.
SO HERE'S AGAIN OUR RESPONDERS
AT BASELINE AND OUR RESPONDERS
IN PURPLE AFTER 12 WEEKS, AND
THEN THE NON-RESPONDERS IN BLUE
BEFORE TREATMENT, AND IN YELLOW
AFTER TREATMENT, AGAIN SHOWING
NOT MUCH CHANGE IN THEIR
MOLECULAR SIGNATURE.
SO JUST VERY BRIEFLY, THE TOFA
STUDY, SIMILAR, 12 PATIENTS,
THIS TIME SIX MODERATE TO SEVERE
AND SIX SEVERE.
WE HAD TO ESCALATE OUR DOSE FROM
5 MILLIGRAMS BID TO 10, AND
YOU'LL SEE HOW THAT PLAYED OUT
DURING THE STUDY.
AGAIN THE SAME MONITORING WAS
DONE FOR ALL.
SO HERE'S A PATIENT AT BASELINE
AND HERE'S WEEK 40.
SO THESE ARE LONGER.
THE NUMBERS ON THE BOTTOM ARE
HOW LONG THEY SPENT AT THE LOW
DOSE, SO FIVE MONTHS AT THE LOW
DOSE, TWO MONTHS AT A MEDIUM
DOSE, AND THREE MONTHS AT THE
HIGHEST DOSE BEFORE GOING DOWN
IN A SALT SCORE FROM 100% TO
39%, SO THE STEP WISE ESCALATION
IN THEIR DOSE.
AGAIN, FIVE MONTHS AT LOW DOSE,
TWO MONTHS AT MEDIUM DOSE, TWO
MONTHS AT HIGH DOSE, AND AS YOU
PUSH THE DOSE, THEY BEGIN TO GET
A STRONGER RESPONSE.
HERE'S ANOTHER ONE EVENTUALLY
CAUGHT UP AND IS FILLED IN.
THIS WAS OUR ONLY PATIENT WHO
RESPONDED COMPLETELY ONLY AT THE
LOW DOSE, SO SHE ONLY GOT
5 MILLIGRAMS BID FOR SIX MONTHS
AND HAD A FULL RESPONSE.
THIS IS WHAT THE TIME COURSE
LOOKS LIKE, SO YOU CAN SEE THE
HAIR IS ACTUALLY BEGINNING TO
FILL IN DURING THE COURSE OF
TREATMENT.
AND IN THESE PATIENTS, AGAIN,
GROWING THE FAISHT HAIR FACIAL
HAIR IS VER
Y
DIFFICULT AND HERE YOU CAN SEE
THE EYELASHES AND EYEBROWS AS
WELL AS THE FRONTAL HAIRLINE.
SO THE SAME IS TRUE FOR OUR
BIOMARKER, THEY WORKED VERY WELL
IN SORT OF PREDICTING HOW THESE
PATIENTS WOULD RESPOND.
HERE WE'RE JUST -- RUXO FOR
COMPARISON IN THIS LANE, AND
AFTER TREATMENT, AND HERE'S A
TOFA.
BUT THE DIFFERENCE HERE IS THAT
THIS TOFA STUDY WAS DONE AT FOUR
WEEKS SO ALREADY YOU CAN BEGIN
TO SEE IN FOUR WEEKS THAT THESE
PATIENTS ARE BEGINNING TO HAVE A
MOLECULAR RESPONSE VERY, VERY
EARLY, SO THAT MEANS IF WE
TESTED EARLY, WE BEGIN TO MAYBE
PICK UP A RESPONSE SIGNATURE AND
NOW THEY WOULD EITHER, A,
RESPONDS TO THE DRUG AT ALL, B,
WOULD THEIR DOSE HAVE TO BE
ESCALATED OR C, IF THEY'RE NOT
RESPONDING, TO SWITCH THEM TO
SOMETHING ELSE.
AND HERE YOU JUST SEE THAT WE
CAN GIP TO BEGIN TO TRACK THIS
IN SERUM
SO THIS IS A FOUR-WEEK TREATMENT
LOOKING AT CLCX10 IN SERUM, SO
WE'D LIKE TO BEGIN TO MOVE THIS
TO A NONINVASIVE MARKER WHERE WE
COULD TRACK IMMEDIATE AND EARLY
RESPONSE AND FINALLY WE'VE GONE
ON TO DO THIS NOW FOR THE ENTIRE
SERIES LOOKING FROM TIME ZERO TO
TIME FOUR WEEK TO TIME 12 WEEK
AND THIS IS NORMAL SCALP ON THE
RIGHT SO YOU CAN SEE THE BLUE
CHANGING AND CHANGING OVER SO
THAT AFTER 12 WEEKS IT BEGINS TO
LOOK VERY MUCH LIKE NORMAL
SCALP.
SO AGAIN, SALT SCORES OVER TIME,
AGAIN, THIS WAS THE DOSE
ESCALATION SO THEY LOOK FLAT
UNTIL WE CHANGE THE DOSE AND
THEN THEY TEND TO RESPOND.
HERE'S THE ONE THAT RESPONDED AT
LOW DOSE.
AGAIN, THE OTHER WAY AROUND,
THIS IS REGROWTH SO THAT'S THE
PATIENT WHO RESPONDED AT LOW
DOSE, THE REST OF THEM REQUIRED
DOSE ESCALATION AROUND HERE
BEFORE THEY EFFICIENTLY CAUGHT
EVENTUALLY 
CAUGHT
UP.
SO WE'RE NOT TOTALLY SURE WHAT'S
DRIVING THAT DOSE ESCALATION BUT
WE DO HAVE SOME HYPOTHESIS.
SO AGAIN NO SERIOUS ADVERSE
EVENTS REALLY IN THIS STUDY.
ONE PATIENT HAD A LITTLE BIT OF
HYPERTENSION, ONE PATIENT HAD
INCREASED ALCOHOL INTAKE AND SO
HER LIVER FUNCTION WAS A LITTLE
BIT OUT OF LINE AND SOME
PATIENTS HAVE A FEW G.I.
PROBLEMS.
ALMOST ALL OF OUR PATIENTS
REPORT WEIGHT GAIN, BUT SOME OF
THEM SAY THAT THEY'RE JUST VERY
HAPPY TO BE OUT IN THE WORLD
WITHOUT THEIR WIGS OR WITHOUT
THEIR HATS AND THEY'RE JUST
FEELING BETTER AND SOCIAL.
SO JUST OUR STATISTICS, AND JUST
TO SAY THAT NOW MANY OTHER
CENTERS ARE USING THESE DRUGS IN
THEIR PATIENTS, SO YALE HAS DONE
SEVERAL HUNDRED PATIENTS,
STANFORD IS OVER A HUNDRED, AND
WHAT'S INTERESTING IS, THE
RESPONSE RATE IS VERY CONSISTENT
ACROSS THE DIFFERENT GROUPS THAT
ARE USING THESE DRUGS, SO 65,
70, 75% RESPONSE IS NOT
UNCOMMON.
AND SO AGAIN, THE NEXT STEP HERE
WOULD BE TO DO A PROPER PLACEBO
CONTROLLED STUDY AND I HOPE THAT
THAT WILL BE ON THE RADAR FOR
ONE OF THE GROUPS IN THE FUTURE.
SO JUST AS A COMPARATOR ABOUT
THE DOSING FOR TOFACITINIB,
PFIZER'S OWN STUDY IN 2015 ALSO
SHOWED THIS DIFFERENCE THAT WHEN
TOFA IS GIVEN AT LOW DOSE TWICE
A DAY, ONLY ABOUT 40% OF
PSORIASIS PATIENTS RESPOND AND
THAT IF YOU TAKE IT TO
10 MILLIGRAMS TWICE A DAY, IT
GOES UP TO ABOUT 60% OR GREATER,
SO THIS IS PRETTY SIMILAR, I
THINK, TO WHAT WE'RE SEEING IN
ALOPECIA AREATA SO MAYBE
SUGGESTING THAT MORE OF A DOSE
IS NEEDED TO GET THIS DRUG INTO
THE SKIN AND MAYBE A HIGHER
LOCAL CONCENTRATION IN THE SCALP
OR SKIN IS NEEDED TO TARGET SOME
OF OUR DISORDER.
SO THIS IS FROM ONE OF MY
FAVORITE REVIEWS WRITTEN BY JOHN
O'SHEA AND HIS TEAM HERE, AND SO
THIS REALLY IS SAYING FOR THE
FUTURE, WHAT'S THE THINKING IN
THE FIELD, AND I THINK UP TO
NOW, WE'VE TALKED ABOUT PAN JAK
INHIBITORS, ONE THAT TARGET JAK
1, 2 AND 3 TOGETHER LIKE TOFA,
SO THE IDEA I THINK FOR THE
FUTURE IS TO TRY AND FIND MORE
AND MORE SPECIFIC AND SELECTIVE
ISOFORMS AND FIGURE OUT IF
POSSIBLE WHICH OF THESE JAK
INHIBITORS IS CONTROLLING WHICH
PART OF DISEASE, AND AGAIN, THE
THINKING MAY COME THAT SPECIFIC
IS BETTER, BUT PERHAPS AS JOHN
AND I TALKED ABOUT THIS MORNING,
MAYBE FOR THE EARLY STAGES OF
DISEASE, HAVING SOMETHING THAT
COVERS BROADLY ACROSS MANY OF
THE CYTOKINE PATHWAYS MIGHT BE
USEFUL BECAUSE I DON'T THINK
THAT IL-15 AND INTERFERON GAMMA
ARE THE WHOLE STORY FOR ALOPECIA
AREATA, CERTAINLY NOT, AND MORE
WORK TO BE DONE THERE.
SO JUST IN THE LAST TWO MINUTES,
I'LL JUST SHARE A LITTLE BIT OF
UNPUBLISHED DATA, JUST TO SAY
WE'VE BEEN THINKING A LOT ABOUT
THE YES. TICS BUT THE JE
HE?
TICS BUT ALSO THE ENVIRONMENTAL
FACTOR, SO GIVEN ALL THE
EXCITEMENT ABOUT -- A ROLE FOR
MICROBIOME SO DON'T THINK I NEED
TO TALK ABOUT HOW IMPORTANT THIS
HAS BECOME, THERE'S A HUGE
EFFORT HERE ON CAMPUS, AGAIN,
SOME OF THE GREAT STUDIES IN
THIS FIELD IN SKIN HAVE COME
FROM HERE, FROM JEWIAN AND
OTHERS, MICROBIOME IN SKIN,
PARTICULARLY IN SOME OF THE
AUTOIMMUNE DISEASES LIKE R.A.,
DIFFERENT MICROORGANISMS AGAIN
ARE NOW SHOWING UP AS BEING
OVERREPRESENTED IN PATIENTS AT
LEAST IN R.A. AT THE ONSET OF
DISEASE, AND SO WE'VE BEGUN TO
SORT OF AGAIN MODEL OUR WORK,
OUR THINKING AFTER THE WORK OF
DAN LITMAN AND OTHERS WHO HAVE
ALREADY PAVED THIS PATH FOR
RHEUMATOID ARTHRITIS SO WE'VE
JUST DONE A COUPLE VERY SIMPLE
SPAISHTS BUT BASICALLY WE JUST
WANTED TO ASK IF WE COULD
MANIPULATE THE MICROBIOME AND
SEE IF WE COULD GET AN EFFECT ON
ALOPECIA AREATA.
SO WE USED OUR SKIN GRAFT MODEL
AND WE GAVE THE CONVENTIONAL
ANTIBIOTIC COCKTAIL THAT'S USED
TO DEPLETE THE MICROBIOME,
PRIMARILY IN THE GUT, AND SO
WHEN WE DO THAT, WE TREAT OUR
MICE BEFORE GRAFTING AND KEEP
GOING.
THIS WAS ABOUT TWO MONTHS AFTER
GRAFTING, AND THE CONTROL MICE
ARE LOSING THEIR HAIR RIGHT ON
TIME, BUT THE ANTIBIOTIC-TREATED
MICE RETAIN THEIR HAIR, AND THIS
IS THE COCKTAIL AGAIN, USED IN
MANY OF THE MICROBIOME STUDIES.
SO WE PUSHED IT FURTHER SO NOW
THIS IS ABOUT FOUR MONTHS AFTER
GRAFTING, THE UNTREATED MICE
HAVE LOST THEIR HAIR AND THE
ANTIBIOTIC TREATED MICE STILL
HAVEN'T LOST THEIR HAIR.
SO WE'VE DONE THIS NOW A NUMBER
OF TIMES OVER RELATIVELY
CONFIDENT THAT THERE'S AN EFFECT
HERE, A TON MORE WORK TO BE
DONE.
WE'VE SEQUENCED THE SKIN
MICROBIOME FROM THESE TREATED
MICE AND WE DON'T SEE ANY
DIFFERENCE IN THEIR SKIN AND
WE'VE NOW BEGUN TO WORK THROUGH
THEIR GUT MICROBIOME TO
UNDERSTAND IF, IN FACT, THIS
EFFECT MAY BE COMING FROM THE
GUT.
SO AGAIN HERE'S OUR CONTROLS,
HERE'S OUR TREATMENTS AND AFTER
GIVING THOSE ANTIBIOTICS, THE
TREATED MICE AGAIN RETAIN THEIR
HAIR IN 100% OF CASES.
SO MORE WORK TO BE DONE.
IS IT SKIN, IS IT GUT, IS IT
BOTH?
HOW DOES THIS WORK?
IS IT PRIMING AT A DISTANT SITE?
THIS IS JUST THE BEGINNING OF
THE STORY, BUT I JUST WANTED TO
GIVE YOU A LITTLE FLAVOR OF
EXCITEMENT FOR SOME OF THE WORK
THAT WE'RE NOW DOING TO TRY AND
COMBINE OUR GENETICS WORK WITH
BOTH NEW TREATMENTS AND ALSO NEW
WAYS OF LOOKING AT THE
ENVIRONMENTAL EFFECTS.
SO I'LL CLOSE BY JUST SAYING
THAT IT'S BEEN A REALLY EXCITING
COUPLE OF YEARS FOR JAK
INHIBITORS IN SKIN, AND HERE'S
JUST SOME OF THE EXAMPLES OF
CASES THAT HAVE COME IN THE
LITERATURE IN THE PAST FEW
YEARS.
ESPECIALLY THIS CANDLE SYNDROME
STUDY THAT'S ONGOING HERE AT THE
NIH.
I LEARNED TODAY FROM ED ABOUT
GRAPH VERSUS HOST DISEASE WHICH
I DIDN'T KNOW AT ALL, SO THIS IS
OUR WORK ON ALOPECIA AREATA AND
I THINK IN THE HAIR FIELD, THIS
WORK IS NOW EXPANDING INTO OTHER
FORMS OF INFLAMMATORY ALOPECIA
INCLUDING THE SCARRING ALOPECIAS
THAT ALSO HAVE NO SUITABLE
TREATMENTS AT THE MOMENT, ARE
EVEN LESS WELL UNDERSTOOD THAN
ALOPECIA AREATA, BUT BECAUSE OF
SOME OF THE EARLY WORK FROM
OTHERS IN THE FIELD, RALPH AND
HIS COLLEAGUES ESPECIALLY, HAVE
BEGUN TO DEFINE THIS EARLY
IMMUNE INFILTRATE, SUGGESTING
THAT A JACK INHIBITOR MIGHT WORK
HERE TOO AND WE HAVE SOME DATA
NOW THAT WILL BE PRESENTED AT
THE SID MEETING ABOUT THIS,
SUGGESTING THAT AGAIN THESE
DRUGS MAY HAVE A BROADER USE IN
THE FIELD.
SO THIS IS JUST A SUMMARY OF
EVERYTHING WE'VE TESTED IN THE
ALOPECIA AREATA MOUSE MODEL.
THE ONES IN GREEN HAVE I THINK
MADE IT ALL THE WAY INTO HUMAN
CLINICAL PROOF OF CONCEPT.
WE HAVE AGAIN 12 PATIENTS WITH
RUXO, THERE'S ONE CASE REPORT OF
RUXO TOPICAL -- ONE PATIENT HERE
IN THE NIH CANDLE STUDY WHO HAD
ALOPECIA AREATA WITH RAH FEEL
AND RECOVERED THEIR ALOPECIA
AREATA.
TOFA, THIS IS NOW WELL OVER
SEVERAL HUNDRED, AGAIN AS SOME
OF THESE ADVANCE HOPEFULLY INTO
THE CLINIC, THIS HUMAN SIDE OF
THE TABLE WILL FILL OUT MORE.
SO AGAIN, MORE WORK TO BE DONE
BUT JUST A SORT OF OVERVIEW OF
HOW THINGS ARE LOOKING.
SO I THINK COMING BACK FULL
CIRCLE, HISTORICALLY CLINICAL
TRIALS IN ALOPECIA REALLY HAVE
BEEN SORT OF, IF LU, ONE OFF
STUDIES, REPURPOSING STUDIES
FROM PSORIASIS DRUGS MAINLY, AND
THESE HAVE BEEN PARTICULARLY
UNFRUITFUL FOR ALOPECIA AREATA,
AND I THINK NOW THAT WE
UNDERSTAND THE GENETICS AND A
BIT ABOUT THE IMMUNOLOGY, WE CAN
SEE WHY.
THERE'S NOT MUCH OVERLAP IN THE
PATHWAYS THAT ARE INVOLVED IN
BOTH DISEASES, AND SO I'M VERY
GRATIFIED THAT AFTER SUCH A
SHORT TIME REALLY OF THIS WORK
COMING OUT, THAT THERE'S BEEN A
TREMENDOUS UPTAKE OF INTEREST ON
THE PART OF THE PHARMACEUTICAL
PARTNERS TO BRING THESE DRUGS
INTO STUDIES, SPECIFICALLY FOR
ALOPECIA AREATA, AND THAT REALLY
IS A CHANGE IN THE WAY THAT THIS
DISEASE HAS BEEN STUDIED IN THE
PAST.
THIS IS THE FIRST TIME
HISTORICALLY THAT ANY OF THESE
FOLKS HAVE TAKEN AN INTEREST IN
ALOPECIA FOR ITS OWN SAKE AND
NOT AS A SECOND INDICATION FOR A
PSORIASIS DRUG, SO I'M EXTREMELY
ENCOURAGED BY ALL OF THIS
ACTIVITY.
THERE'S INTEREST IN TOPICAL
DRUGS, THERE'S INTEREST IN ORAL
DRUGS, THERE'S PAN JAKS, THERE'S
SINGLE ISOFORMS.
I THINK THIS IS GOING TO BE A
REALLY EXCITING SPACE.
AND HOPEFULLY ONE THAT WILL LEAD
TO AN APPROVAL FOR THIS
INDICATION SOMETIME IN THE
FUTURE.
SO I'LL JUST CLOSE BY SAYING A
WORD OF THANKS BEING HERE AT THE
NIH.
OUR WORK HAS BEEN SUPPORTED BY
NIAMS FROM THE BEGINNING,
STARTING WITH THE FOUNDING OF
THE AA REGISTRY IN 2001, EVEN
BEFORE THAT FOR ME PERSONALLY,
BUT THIS IS REALLY THE TIMELINE
OF WORK THAT'S GONE ON LARGELY
AGAIN SUPPORTED AT DIFFERENT
TIMES BY NIAMS, HERE'S OUR
CONTRACT, HERE'S OUR INITIAL
R21, HERE'S OUR UO1, FINALLY
MUCH MORE RECENTLY, OUR CENTER
GRANT WHICH JUST STARTED, AND
THEN ON THE BOTTOM, THIS IS
AGAIN THE CLINICAL TIMELINE, BUT
THIS IS REALLY LOBBIED BACK AND
FORTH BETWEEN LAB FINDINGS AND
MOVING THEM INTO THE CLINIC, AND
I THINK AGAIN WITHOUT MY
EXTREMELY WONDERFUL COLLEAGUES
AT COLUMBIA, THIS WOULD NOT HAVE
COME TO PASS AND WE'VE HAD
TREMENDOUS FOUNDATION SUPPORT
FROM NAF AND ALSO THE LOCKS OF
LOVE FOUNDATION THAT HAVE REALLY
HELPED AGAIN JUMP START SOME OF
THOSE EARLY STUDIES.
RIGHT NOW IN 2016, AT LEAST,
THIS HAS BEEN A MILESTONE FOR
US, SO JUST THIS PAST FALL, OUR
TEAM AT COLUMBIA HAS BEEN
GRANTED A P50 GRANT FROM NIAMS
AND THIS IS THE FIRST OF ITS
KIND IN ALOPECIA AREATA CENTER
FOR RESEARCH TRANSLATION AND WE
COULDN'T BE MORE HONORED AND
MORE PROUD TO BE BRINGING THIS
WORK FORWARD.
SO I PUT THIS SLIDE IN FOR
DR. COLLINS, I HOPE THAT HE'LL
SEE IT AT SOME POINT.
THIS IS FROM A REVIEW THAT HE
WROTE IN 2011 WHERE HE WAS
TALKING ABOUT THE POTENTIAL FOR
GENOME WIDE ASSOCIATION STUDIES
TO UNCOVER NEW DRUG TARGETS, AND
YOU CAN SEE AGAIN MANY OF THESE
DISEASES WERE WELL AHEAD OF US
WITH THEIR NUMBER OF GWAS HITS
AND THE NUMBER OF DRUGS THAT
REALLY WERE ASSOCIAED AND THAT
HAVE COME THROUGH THE PIPELINE.
SO I ADDED ALOPECIA TO THIS, AND
EVEN WITH OUR EIGHT LITTLE GENES
AT THE BEGINNING, THREE OF THOSE
TURNED OUT TO BE FRUITFUL IN
IDENTIFYING DRUG TARGETS.
I DIDN'T TALK ABOUT ABATACREPT
TODAY BUT I HOPE HE KNOWS
ALOPECIA CAN TAKE ITS PLACE IN
THIS TYPE OF STUDY AND BE A
SUCCESS STORE O.A.R. FOE USING
GENETICS TO TAKE AN UNBIASED
LOOK AT A DISEASE AND BRING A
NEW UNDERSTANDING TOGETHER WITH
IMMUNOLOGY COLLEAGUES, CLINICAL
SCIENTISTS AND HOPEFULLY SOMEDAY
GET NEW APPROVALS.
SO I'LL STOP AND JUST
ACKNOWLEDGE AGAIN MY TWO
INCREDIBLE COLLEAGUES, MY TEAM
IN THE LAB THAT HAS GROWN AND
CHANGED OVER THE YEARS,
ESPECIALLY THESE FOLKS WHO HAVE
TAKEN THE LEAD ON MANY OF THESE
PROJECTS, AND ESPECIALLY AGAIN
NIAMS AND SOME OF OUR OTHER
SUPPORTERS FOR BELIEVING IN US
AND ALLOWING US TO BRING THIS
FORWARD.
THANK YOU FOR HAVING ME.
[APPLAUE]
>> WE HAVE TIME FOR A COUPLE OF
QUESTIONS.
>> YES.
I NOTICE UNDER THE AUTOIMMUNE
DISEASES YOU DIDN'T MENTION
GRAPH VERSUS HOST DISEASE IN
TERMS OF DERMATOPATHOLOGY, YOU
HAVE SOMETHING CALLED SAT LIE
PTOSIS WHICH GOES AROUND TO
SINGLE KERATIN SITE AS IT DIE,
SO YOU CAN DISTINGUISH IT FROM
ERYTHEMA MULTIFORUM.
IT'S BEEN A LONG TIME SINCE I'VE
LOOKED AT GRAPH VERSUS HOST
DISEASE BUT IT CAN BE CONSIDERED
IN ITS CHRONIC FORM MORE OF AN
AUTOIMMUNE DISEASE.
DO THEY HAVE THIS CONDITION AND
WOULD THIS BE HELPFUL IN THAT
CONDITION IN GRAPH VERSUS HOST
DISEASE SECONDARY TO BONE MARROW
TRANSPLANTATION?
>> IS ED HERE?
WOULD YOU LIKE TO?
PLEASE.
I'M NOT AN EXPERT BUT THE WORLD
EXPERT IS HERE.
>> SO THERE'S A LOT OF INTEREST
IN ORAL AGENTS AND RUXO IS OFF
LABEL FOR THE REASONS YOU SAY,
AND THE SUCCESS RATE AT LEAST IN
SOME OF THE PRELIMINARY TRIALS
IS ON THE ORDER OF 50 TO 60%.
>> FASCINATING TALK AS ALWAYS,
ANGELA.
SO WE TALKED ABOUT -- EARLIER
TODAY, I'M WONDERING ABOUT THE
RELATIVE CONTRIBUTION OF
CD4CD8 CELLS IN ALOPECIA AREATA
MAINLY BECAUSE ALTHOUGH YOU SEE
THAT GAMMA SIGNATURE, RIGHT, YOU
DON'T REALLY SEE APOPTOSIS OF
THE CARE SITES.
AND THEN YOU SHOWED THE
BEAUTIFUL IMAGE OF CD4 ILL
FILTRATION INTO THE HAIR
FOLLICLE, SO I'M WONDERING IF
GAT MA SIGNATURE COULD BE
ACTUALLY FROM CD4 T-CELLS,
WONDERING WHETHER OR NOT YOU
PHENOTYPED THOSE CD4 T-CELLS
THAT INFILTRATE INTO THE HAIR
FOLLICLES.
>> IT'S A GREAT QUESTION.
IT'S ONE THAT WE GET ALL THE
TIME IS WHY DOES OUR MH CLASS
2 GENETICS SIGNAL AND OUR
EFFECTORS ARE CD8.
SO MY BEST ANSWER IS AT THIS
POINT IS THAT I HOPE IT'S GOING
TO TURN OUT LIKE CELIAC DISEASE,
WHERE WE HAVE A SORT OF
PRIMARYISH ROLE OF THE CD4 CELLS
AND THEN THE EFFECTORS MAYBE
BEING LESS SPECIFIC, IF YOU
WILL, SO WE HAVEN'T DONE ANY OF
THAT WORK YET, WE'RE JUST
GETTING BACK TO DOING THE
CD4 CELLS, BUT JUST TO SAY THAT
THE SAME CONUNDRUM EXISTS IN
PSORIASIS, SO THEIR MAIN GENETIC
SIGNAL IS -- 1 EVEN THOUGH A LOT
OF THEIR EFFECT COMES
DIFFERENTLY, SO I DON'T KNOW YET
WHAT IT MEANS, BUT I WILL SAY
IT'S NOT UNCOMMON AND IT DOES
MIMIC WHAT'S SEEN IN CELIAC.
SO WE'VE GOT A TON OF WORK TO
DO.
WE HAVEN'T PHENOTYPED THEM YET.
WE KNOW THAT OUR CD WILL CELLS
ARE EXPRESSING A LOT OF GAMMA
BUT WE HAVEN'T YET STARTED
DIGGING INTO THE CD4s.
>> AND THE CD4 IS NOT
INFILTRATING IN THE MOUSE MODEL?
>> YES, THEY ARE.
>> OKAY.
THAT'S GOOD.
THANK YOU.
>> HI, I JUST WANTED TO SAY YOUR
WORK VEILY COOL AND ALSO YOU
MENTIONED IN THE BEGINNING THAT
WHITE HAIRS DON'T FALL OUT AND I
WAS WONDERING IF YOU THOUGHT
THAT MAYBE THE LA KNOW SITES ARE
SOMEHOW PROTECTIVE OR ARE THEY
BEING SACRIFICED INSTEAD OF THE
HAIR FALLING OUT OR --
>> THAT'S A GREAT QUESTION.
SO HISTORICALLY, IN THE
DETERMINE DERM
LITERATURE, YOU'LL SEE SUDDEN
WHITENING OF THE HAIR, ONLY THE
WHITE HAIRS STAY BEHIND, AND
THAT'S THOUGHT TO BE SORT OF AN
ACUTE ONSET OF ALOPECIA AREATA,
SO WE DON'T KNOW WHY THEY
SPECIFICALLY TARGET THOSE
PIGMENTED HAIRS EXCEPT THAT
THERE'S BEEN THINKING IN THE
FIELD FOR A LONG TIME THAT IT
MUST BE OR SHOULD BE A ME LA
KNOW SITE ANTIGEN THAT COULD BE
ONE OF THE PRECIP TANTS, SO
THERE'S BEEN REPORTS OVER TIME
ABOUT WHAT SOME OF THOSE
ANTIGENS MIGHT BE, BUT DURING
NORMAL REMODELS OF THE HAIR,
WHEN HAIR NORMALLY GOES
THROUGH -- THE ME LA KNOW CITES
ACTUALLY EITHER GET APOP TOIZED
AND/OR YOU A TO HAVE JIEZED
WHICH IS BECOMING ANOTHER MAJOR
PATHWAY IN ALOPECIA AREATA, THEY
UNDERGO A CONTROLLED INVOLUTION,
IF YOU WILL, AND REGRESSION, SO
IF SOMETHING GOES WRONG THERE
AND THOSE ME LA KNOW CYTE
ANTIGENS AS WELL AS SOME OF THE
REST OF THE HAIR SHAFT ANTIGENS
GET EXPOSED DURING THAT NORMAL
CATAGEN, THERE'S SOME
DEREGULATION, IT'S POSSIBLE THAT
THAT COULD BE ONE OF THE
UPSTREAK TRIGGERS.
ALSO WORKS IN REVERSE, WHEN THE
HAIR BEGINS TO RECOVER FROM
ALOPECIA AREATA, WHEN IT FIRST
GROWS BACK, IT TENDS TO BE CLEAR
OR WHITE, AND THEN EVENTUALLY
THE PIGMENT SORT OF
REDEPOSITS -- THE FIRST TO GO
AND THE LAST TO RECOVER IN SOME
WAY.
SO A LOT TO BE DONE STILL, BUT
ONE OF OUR CANDIDATES -- ANOTHER
ONE THAT'S UNIQUE TO ALOPECIA
AREATA ON THE HAIR FOLLICLES,
INVOLVED IN PIGMENTATION AND
MELANOSOME YOU A TO AUTOPHAGY
DURING
PIGMENTATION, IT CAUSES THE LOSS
OF PIGMENT IN HORSE, LIPAZAANER
HORSES -- CAUSES THEIR COAT TO
CHANGE GRAY COLOR, SO THAT'S OUR
BEST -- WE'RE ACTIVELY TRYING TO
WORK ON THAT AS WELL.
>> THANK YOU.
>> SURE.
>> I THINK YOUR WORK VEILY COOL
TOO.
SO I WAS THINKING THE ONE DRUG
YOU DIDN'T MENTION WAS OWE CLA
SIT ANYBODY, AND THE ONE THING I
HEARD IS THAT'S MORE LIPOPHILIC,
WONDERING IF IT MIGHT HAVE
ADVANTAGES FOR SKIN DISEASE AND
THAT SORT OF THING, BUT
COUNTERING THAT, WHEN YOU DID
YOUR QUADRUPLE ANTIBIOTIC
EXPERIMENT, THAT -- DO YOU THINK
IT'S THE THE LESIONAL CELLS, AND
WOULD DIFFERENT TYPES OF JA
KMENT INHIBITORS MAKE A
DIFFERENCE IN TERMS OF EFFICACY?
>> THAT'S FANTASTIC.
SO WE HAVE USED THE DOGGY JAK
THANKS TO YOU AND IT WORKS
WONDERFULLY IN THE MODEL SO IT
WORKS GREAT TOPICALLY AS WELL AS
SYSTEMICALLY.
SOME OF THEM ARE ACTUALLY HARDER
FOR US TO WORK WITH TOPICALLY SO
SOME ARE LESS FRIENDLY, THAT ONE
IS VERY FRIENDLY TOPICALLY, SO
IT HAS A VERY NICE PENETRATION
AND IT WORKS VERY WELL IN BOTH
CONTEXTS.
FOR THE TRAFFICKING EXPERIMENT
FOR THE GUT PRIMING, THIS AGAIN,
WE'RE JUST AT THE BEGINNING OF
THIS, BUT WE DID TRY TO UTE
FILGOTANIB AS WELL IN THE
DIFFERENT SETTING AND WE HAD NO
LUCK BASICALLY, IT WAS VERY
INSOLUBLE, KIND OF DIFFICULT FOR
US TO WORK WITH.
SO WE HAVEN'T TRIED YET ANY
DRUGS TO BLOCK TRAFFICKING TO
TRY AND INTERFERE WITH ANY OF
THAT.
I DON'T HAVE A GUESS, MAYBE YOU
DO, ABOUT WHICH ONE OF THE JAKS
MIGHT BE THE BEST TO THINK ABOUT
THERE, BUT I HOPE THAT ONCE WE
GET THE MICROBIOME STORY
DEVELOPED, THAT WE CAN FIND SOME
INTERSECTION BETWEEN THAT AND
USING INHIBITORS THAT WILL GIVE
US AGAIN A LITTLE MORE INSIGHT.
NOTHING YET.
>> CAN I HAVE LAST QUESTION?
>> THERE'S GOING TO AB RECEPTION
IN THE LIBRARY, SO WHOEVER WANTS
TO JOIN ANGELA, YOU'RE MORE THAN
WELCOME.
>> OKAY.
>> THANKS.
>> OKAY.
SO I UNDERSTAND YOUR RATIONALE
OF STARTING WITH THE FDA
APPROVED DOSE OF TOFA AND THEN
GOING UP TO 10 MILLIGRAM TWICE A
DAY.
HOW ABOUT INSTEAD STARTING WITH
10 MILLIGRAM TWICE A DAY AND
THEN MAINTAINING 5 MILLIGRAM
ONCE A DAY SO THAT KIND OF
DIMINISH POSSIBLE SIDE EFFECTS,
HAVE YOU THOUGHT ABOUT DOING
THAT?
HAVE YOU TRIED TO DO THAT AT
ALL?
>> SO MANY OF THE SITES ARE
DOING EXACTLY THAT.
THEY'RE STARTING WITH 10, SOME
EVEN HIGHER, 15, AND SORT OF THE
THINKING IS TO GIVE THE HIGHEST
DOSE FIRST, GET THINGS UNDER
CONTROL, AND THEN MOVE TO A
LOWER DOSE.
SO THE LOWER DOSE IN MOST CASES
HAS GONE TO 5 BID.
SOME PATIENTS HAVE FLARED EVEN
AT 5 BID SO THEY'VE HAD TO GO
BACK UP TO 10 OR SO, SO THERE IS
SOME TUNING THAT TAKES PLACE,
BUT YES, I MEAN, WE DID THIS
CAUTIOUSLY AT FIRST IN THE
SETTING OF THE STUDY, BUT
PRACTICALLY SPEAKING, MANY OF
THE FOLKS USING THIS NOW ARE
STARTING HIGH AND THEN REDUCING
JUST AS YOU SAID, ONCE THEY
START TO GET REGROWTH.
I DON'T THINK YOU COULD EVER GO
TO -- AND JOHN WILL CORRECT
ME -- A SORT OF ONCE A WEEK
DOSING BECAUSE YOU NEED TO KEEP
THINGS -- HALF-LIFE AND OTHER
THINGS, BUT MAYBE A LOW
CONSISTENT DOSE OVER TIME RATHER
THAN INTERMITTENT.
SO BUT YES, THAT'S BECOME THE
WAY THAT FOLKS ARE TRYING IT
NOW.
EXACTLY RIGHT.
>> ACTUALLY WHAT'S BEEN TRIED
WITH THE DOGS AND IT WORKS VERY
WELL FOR THE DOGS.
>> THANK YOU.
>> SO I WOULD LIKE TO FINISH
INVITING YOU TO COME JOIN US FOR
A RECEPTION IN THE LIBRARY AND
TO THANK ONCE AGAIN
DR. CHRISTIANO FOR HER TALK.
[APPLAUSE]
