--WITH BASIC SCIENCE AND
CERTAINLY THIS PARTICULAR
INSTALLMENT WILL DO JUST THAT.
THE SERIES GOES ON TUESDAY
AFTERNOONS FROM 4-6:00 P.M.
EASTERN TIME FROM JANUARY
THROUGH MAY.
AND YOU CAN WATCH IT ON THE LINK
SHOWN HERE ON THE SLIDE.
CME CREDIT IS AVAILABLE, YOU
HAVE TO USE THE CME CODE WHICH
TODAY IS 52092.
IF YOU HAVE QUESTIONS, DURING
THE COURSE OF THE 2
PRESENTATIONS, YOU CAN SUBMIT
THEM VIA THE SEND LIVE FEEDBACK
BUTTON ON THE VIDEOCAST DISPLAY.
ALL OF THE PREVIOUS SESSIONS ARE
ARCHIVED AT THE LINK SHOWN HERE
ON THE SCREEN.
AND FOR ADDITIONAL INFORMATION,
YOU CAN GO TO THE WALS OFFICE
E-MAIL ADDRESS SHOWN THERE.
IN ANY CASE, IF WE COULD HAVE
THE NEXT SLIDE, IT SIMPLY GIVES
US THE CME INFORMATION AGAIN,
AGAIN THE CME CODE IS 52092.
YOU HAVE TO TEXT THAT CODE TO
18449801555.
YOU WILL SEE THAT NEITHER OF THE
SPEAKERS TODAY HAS ANY FINANCIAL
CONFLICKS TO DISCLOSE.
IF WE GO GO ON THOUGH TO THE
NEXT SLIDE, I WILL TELL YOU A
LITTLE BIT ABOUT TODAY'S
PRESENTERS.
SO THE TITLE OF TODAY'S
PRESENTATION IN CASE YOU HADN'T
GUESSED IS SICKLE CELL ANEMIA, A
GLOBAL PERSPECTIVE.
AND AS OUR FIRST SPEAKER, WE
HAVE THE GOOD DR. COURTNEY
FITZHUGH WHO IS A LASKER
CLINICAL RESEARCH SCHOLAR AND
SHE CHIEF OF THE EARLY SICKLE
MORTALITY SECTION OF THE
CELLULAR AND MOLECULAR
THERAPEUTIC BRANCH OF THE
NATIONAL HEART, LUNG, AND BLOOD
INSTITUTE.
SHE GOT HER BACHELOR'S DEGREE IN
BIOLOGY MAGNUM CUM LAUDE AT UCLA
AND COMPLETED HER MEDICAL
TRAINING AT UCSF, AND COMBINED
RESIDENCY IN INTERNAL MEDICINE
AND PEDIATRICS AT DUKE AND
COMBINED FELLOWSHIP IN ADULT
HEMEATOLOGY, AND SHE IS THE
MEMBER OF THE AMERICAN SOCIETY
OF HEMEATOLOGY AND AMERICAN
TRANSPLANSATION AND CELLULAR
THERAPY EMPLOY HER RESEARCH
INCLUSIONS ARE NONMILE ABLATIVE
TRANSPLANTATION AND SICKLE CELL
ANEMIA, HALF MATCHED
TRANSPLANTATION IN SICKLE CELL
ANEMIA, AND LONG-TERM ORGAN
FUNCTION IN PATIENTS UNDERGOING
CURIAATIVE THERAPIES FOR SICKLE
CELL DEC, AND GENETIC RISK
FACTORS FOR MYELOID MALIGNANCY
DEVELOPMENT AFTER CURATIVE
THERAPIES FOR SICKLE CELL
DISEASE.
IF YOU COULD HAVE THE NEXT
SLIDE, I WILL TELL YOU ABOUT THE
SECOND PEEKER WHO IS
THE--SPEAKER WHO IS THE GOOD
AMBROISE WONKAM, HE IS WITH THE
DEPARTMENT OF GENETIC MEDICINE
AND PROFESSOR OF GENETIC
MEDICINE AT JOHNS HOPKINS
UNIVERSITY.
HE GOT HIS MEDICAL DEGREE IN
CAMMA ROON AT THE UNIVERSITY OF
YAOUNDE, AND HE GOT HIS DEGREE
AT UNIVERSITY OF GENEVA AND GOT
A Ph.D. AT HUMAN GENETICS AT
THE UNIVERSITY OF CAPE TOWN.
HE HAS HAD HUMAN GENETICS
FACULTY APPOINTMENTS AT THE
UNIVERSITY OF YAOUNDE AND THE
UNIVERSITY OF CAPE TOWN AND HE
ROSE TO THE RANK OF DEPUTY DEAN
FOR RESEARCH AT THE UNIVERSITY
OF CAPE TOWN.
HE IS THE RECIPIENT OF A NUMBER
OF PRESTIGIOUS AWARDS AND PRIZES
INCLUDING THE DENBER-PIN ARD
PRIZE AT THE UNIVERSITY OF
GENEVA FOR HIS DOCTORAL
DISSERTATION AND THE ALAN PIFER
AWARD FROM THE UNIVERSITY OF
CAPE TOWN.
HE IS CURRENTLY THE PF THE
AFRICAN SOCIETY OF HUMAN
GENETICS AND CHAIR, STEERING
COMMITTEE OF THE H3 AFRICA
CONSORTIUM.
AND HIS RESEARCH INCLUDES
PSYCHOSOCIAL BURDEN AND GENOMICS
MODIFIERS OF SICKLE CELL
DISEASE, GENETICS OF HEARING
LOSS AND ETHICAL AND EDUCATIONAL
ISSUES IN HUMAN GENETICS IN
AFRICA.
HOWEVER, WITHOUT FURTHER ADO, I
GIVE YOU THE GOOD DR. FITZHUGH
AND THAT RHYMES, TOO.
>> GOOD AFTERNOON AND THANK YOU
FOR THE WONDERFUL INTRODUCTION,
I DON'T KNOW HOW I CAN FOLLOW
THAT.
MY TALK IS ENTITLED AN UPDATE ON
HEMEAT O PETRESSABLEETIC
TRANSPLANTATION FOR SICKLE CELL
DISEASE.
SO I'M GOING TO START BY
INTRODUCING YOU TO 1 OF MY
PATIENTS THAT I WILL REFER TO AS
MISSIAC SON, 26 YEAR-OLD AFRICAN
AMERICAN WOMAN WITH HOMOZYGOUS
SICKLE CELL DEE, SHE HAD A
REGURNLGENT VELOCITY AS SHOWN BY
ECHO CARDIOGRAM, HE HAD RIGHT
HATTER CATHETERIZATION,
PULMONARY TENSION, CHRONIC RENAL
INSUFFICIENCY.
SHE WAS EASILY FATIGUED, SHE HAD
SHORTNESS OF BREATH AFTER
WALKING ABOUT 2 BLOCKS SHE HAD
INTERMITTENT PALPITATIONS WEEKLY
LASTING A FEW MINUTES OF WITH NO
KNOWN HISTORY.
NO HISTORY OF PASSING OUT.
SHE HAD 3 PILLAR ORTHOPNEA, AND
NO PARO SIMIAL NOCTERERNAL.
SHE HAD TRANSFUSION ASSOCIATED
IRON OVERLOAD, SHE HAD BEEN
TRANSFUSED MORE THAN 50 UNITS OF
RED BLOOD CELLS IN HER LIFETIME.
SHE HAD A LIVER BIOPSY WITH
INFLAMMATION, SHE HAD FIBROSIS
AND LIVER SCARVING AND
CONCENTRATION AT 5.4-MILLIGRAMS
PER GRAM.
SHE HAD REATURENT PAINFUL
CRISIS, 16 HOSPITALIZED IN THE
PREVIOUS YEAR AND 20 IN THE
PREVIOUS 3 YEARS.
SHE HAD CHRONIC BACK PAIN, ACUTE
CHEST SYNDROME, JEIMER TENSION
AND AS I MENTIONED SHE HAD
PULMONARY HYPERTENSION WITH THE
MAIN PRESSURE OF 30-METERS OF
MERCURY AND A [INDISCERNIBLE]
AND BECAUSE THAT SHE HAD BEEN
STARTED IN AMBRISENTAN SINCE
2012.
I'M TRYING TO FIND THE--AND IT
LEADS TO, THE ORGANS NOT GETTING
ENOUGH OXYGEN, SO SICKLE CELL
DISEASE AND ALSO ASSOCIATE WIDE
HYPOXIA POLYMERIZATION,
SHORTENED RED SURVIVAL LEADING
TO STRESS, DAMAGE TO THE BONE
MARROW MICROENVIRONMENT,
INFLAMMATION ANDOXIDATIVE
STRESS.
SO THE GLOBAL BURDEN OF SICKLE
CELL DISEASE AND ENORMOUS, THE
ESTIMATED NUMBER OF NEWBORNS
WITH SICKLE CELL DISEASE
GLOBALLY WILL INCREASE FROM
305,000 IN 2010 TO OVER 404,000
IN 2050 AND IN 2010 AN ESTIMATED
79 NEWBORNS OF SICKLE CELL
DISEASE WERE IN SUB-SAHARAN
AFRICA AND 3 COUNTRIES, NIGERIA,
INDIA AND THE DEMOCRATIC
REPUBLIC OF CONGO REPRESENT 57%
OF THE ANNUAL NUMBER OF NEWBORNS
WITH SICKLE CELL DISEASE
GLOBALLY, SO YOU CAN SEE FROM
THIS FIGURE HERE--LOOKING FOR
THE POINTER.
THAT THIS BURDEN OF SICKLE CELL
DISEASE IN THE U.S. IS VERY
SMALL COMPARED TO SUB-SAHARAN
AFRICA AND INDIA.
SO PATIENTS WITH SICKLE CELL
DISEASE EXPERIENCING EXTENSIVE
MORBIDITY, THE MOST COMMON
COMPLICATION IS SEVERE
DEBILITATING PAINFUL RICE
CRISIS, PATIENT CAN HAVE
STROKES, LIVER DISEASE, YOUNG
PATIENTS REQUIRING HIP
REPLACEMENT, INFECTIONS AND
INFARCTIONS IN THE BONE, RETINAL
LOCATION NUMBER OF PATIENTSATHY
AND THE PATIENTS CAN BECOME
BLIND, THEY CAN HAVE CARDIO
PULMONARY COMPLICATIONS AND IN
THE SEVERE NONHEALING LEG ULCERS
AND MULTIPLE STUDIES INCLUDE
STUDIES THAT HAVE SHOWN THAT
PATIENTS WITH SICKLE CELL
DISEASE HAVE LIVER DAMAGE, HEART
AND LUNG DAMAGE, KIDNEY DAMAGE
ARE AT RISK OF DYING EARLY.
SO THIS FIGURE SHOWS THE
CUMULATIVE SURVIVAL AND THE
X-AXIS SHOWS AGE AT FOLLOW UP AT
DEATH OR IN YEARS AND THEY
FOLLOWED 225 PATIENTS MOST OF
THEM HAVING THE MOST SEVERE TYPE
OF SICKLE CELL DISEASE AND THEY
FOLLOWED THEM FOR A MEDIAN OF 6
AND HALF YEARS.
IMPORTANTLY 60% OF THE PATIENTS
WERE HYDROXY URIA WHICH IS THE
BEST DRUG FOR IT AT THE TIME BUT
THE MEDIAN SURVIVAL AGE AND ONLY
48 YEARS WHICH HAS NOT REALLY
CHANGE INDEED THE LAST 20 YEARS
SO ADULTS WITH SICKLE CELL
DISEASE HAVE A SHORTENED LIFE
SPAN.
THEY ALSO WANTED TO KNOW, THIS
IS OUR INVESTIGATORS AT
VANDERBILT, THEY WANT TO KNOW
WHAT HAPPENS IF YOU HAVE MORE
THAN 1 ORGAN INROFULLED SO THEY
DEFINE HEART DAMAGE AS A TRI
CUSPID OF AT LEAST 2.5-METERS
PER SECOND, BLOWING DAMAGE OF
THE 1% PREDICTED ON PULMONARY
FUNCTION TESTING OF 70% AND
THERE'S MULTIPLE DEFINITIONS FOR
KIDNEY IMPAIRMENT INCLUDING AN
ESTIMATED FILTRATION RATE OF
LESS THAN 60 AND YOU CAN SEE
THAT PATIENT WHO IS HAD NO
ORGANS, OR 1 ORGAN IMPAIRED HAD
A MEAN TIME TO DEATH OF 14
YEARS, AND THIS WAS
SIGNIFICANTLY SHORTER IN
PATIENTS WHO HAD MORE THAN 1
ORGAN IMPAIRED AT 7.8 YEARS SO
BECAUSE MISSIAC SON HAD BOTH
HEART AND KIDNEY IMPAIRMENT SHE
WAS AT RISK FOR DYING EVEN
EARLIER.
SO MILE ABLATED TRANSPLANT
OFFERS A POTENTIAL CURE FOR
PATIENTS WITH SICKLE CELL
DISEASE, MILE ABLATIVE MEANS YOU
GIVE THE PATIENTS CHEMO THERAPY
TO COMPLETE PLEA WIPE OUT BONE
MARROW OR WIPE OUT THAT WITH THE
DONEAR, HLA MATCH SIBLING MEANS
THAT THE TISSUE IS A DIRECT
MATCH, SO IT WAS REPORTED THAT
MATCHING SIBLING BONE MARROW
TRANSPLANT BETWEEN 1986 AND
2013, THEY FOWBD THAT THE 5 YEAR
OVERALL SURVIVAL IS 93%, AT 5
YEARS 93% OF THE PATIENTS WERE
ALIVE AND EVENT FREE SURVIVAL
WAS 91% AND THEY FOUND THAT THE
5 YEAR OVERALL SURVIVAL WAS
SLIGHTLY HIGHER IN CHILDREN,
LESS THAN 16 YEARS OF AGE AT
95%, AND PRESURVIVAL IS 93%,
THIS IS NOT SURPRISING SINCE
MANY OF THE PATIENTS RECEIVE THE
HIGH DOSE CHEMOTHERAPY I WAS
TALKING ABOUT.
THEN THEY FOUND THAT THE
INCIDENCE OF ACUTE GRAFT VERSUS
HOST DISEASE WAS END CHRONIC
GRAFT VERSUS HOST DISEASE, AND
THIS MEANS THAT THE DONOR IMMUNE
IS ATTACKING THE PATIENT AND IT
CAN CAUSE HARDENING AND SCARRING
OF THE LUNGS AND COULD BE DEADLY
SO I DON'T WANT TO INTRODUCE
SOMETHING WORSE THAN SICKLE CELL
DISEASE.
SO THE FIRST MAJORB STACKLE FOR
CARING FOR MISS JACKSON IS THAT
MANY ADULT WHO IS RECEIVE THE
STANDARD THERAPY WILL DIE
BECAUSE OF PREEXISTING ORGAN
DAMAGE.
SO THERE WERE DATA AT TIME TO
SUGGEST YOU DON'T NEED TO
COMPLETELY REVERT THE PATIENT'S
BONE MARROW IN ORDER TO REVERSE
SICKLE CELL DISEASE, WE WANTED
TO KNOW WHAT PERCENTAGE WAS
SUFFICIENT TO REVERSE SICKLE
CELL DEC AND WE WERE MOST
IMPORTANT BECAUSE IN THE BONE
MARROW THE MYELOID COMPART
TRACKS WITH THE ERYTH ROADWAY
DEPARTMENT, AND OF COURSE WE
WERE INTERESTED.
SO ON THE Y-AXIS YOU SEE THE
CHIMERISM WHICH IS THE BLACK
LINE AND THE SINGLE HEMOGLOBIN
WHICH IS THE RED LINE, THERE
WERE 67 PATIENTS WHO UNDERWEPT
TRANSPLANTSA THE NIH, AND
NONOBLADIVE MEANS YOU'RE GIVEN
DRUGS TO SUPPRESS THE IMMUNE
SYSTEM.
AND 3 OF THESE PATIENTS HAD HIGH
DONOR LEVEL ANDS THIS SLOWLY
FELL OVER TIME.
ALL 3 OF THE DONORS HAD SICKLE
CELL TRAITS, YOU EXPECT THOSE TO
BE 40%.
AS LONG AS THE DONOR MYELOID WAS
ABOVE 20%, THE SINGLE CELL
SICKLE SEAL DISEASE WAS FREE
BBUT AS THE CHIMERISM DECREASED
BELOW TWEBT%, THE SICKLE CELL
LEVEL INCREASE INDEED ALL THROW
PATIENT ANDS THEY HAD A RETURN
TO SICKLE CELL DISEASE, SO
SEEING THE LEVELS LESS THAN 20%
WAS ASSOCIATED WITH THE RETURN
OF SICKLE CELL DISEASE, AND WE
HAVE WORKED TO DEVELOP A
MATHEMATICAL MODEL, WHICH SHOWS
THAT THE VAST DIFFERENCES IN THE
RED CELL HALF LIFE OF THE DONOR
RED CELLS WHICH IS ABOUT 3
MONTHS VERSUS THE RECIPIENT RED
CELLS WHICH IS OHM ABOUT 5-20
DAYS.
SO THIS IS A REGIMEN THAT
NONMILE ABLATIVE REGIMEN, DONORS
AND THE PATIENTS RECEIVE
ALEMTUZUMAB, AND IT STAYS AROUND
FOR ABOUT A MONTH, WE ALSO GIVE
300 CENTIGRADE TOTAL BODY
IRERATIONIATION AND THIS ALLOWS
MORE SUPPRESSIVENESS AND CREATES
SPACE IN THE BONE MARROW, AND SO
THIS IS A DRUG THAT REEDUCATES
THE IMMUNE SYSTEM SO THAT
HOPEFULLY THE DONOR AND
RECIPIENT CELLS WILL NO LONGER
RECOGNIZE EACH OTHER AS BEING
FOREIGN.
SO THIS REGIMEN WAS USED BY
PATIENTS AT THE NIH, AND ALSO,
THE UNIVERSITY OF ILLINOIS,
CHICAGO, AND OUTSIDE OF SAUDI
ARABIA, AND AT 5 YEARS POST
TRANSPLANT THE OVERALL SURVIVAL
WAS 93% WITH AN EVENT FREE
SURVERIFY AFRONS 85%.
IMPORTANTLY NONE OF THE PATIENTS
HAD ACUTESOEVER OR GRAPHIC HOST
VERSUS HOST DEC, SO OVER HERE,
YOU CAN SEE THAT THE MYELOIDISM
WAS 80-A HUNDRED% LONG-TERM AND
THIS IS THE DONOR LYMPHOID
SYSTEM, AND THIS ALLOWS
SUPPRESSION IF THE LEVEL IS AT
50%.
SO CAN YOU SEE THAT AT 5 YEARS
POST TRANSPLANT, 83% OF THE
TRANSPLANTS ARE OFF OF
SERILUMABS.
SO WE WANT TO KNOW HOW MANY
PATIENTS WERE ABLE TO HAVE
CHILDREN BECAUSE SOME OF THE
PRESCRIPTIONS CAUSE
STERILEAISEITION, THERE WERE 21
PREGNANCIES FROM 7 WOMEN AND 7
MEN, 1 MALE PATIENT RECEIVED
ASSISTED REPRODUCTIVE
MEDICATIONS FOR AZOOSPERMIA
WHICH LED TO A HEALTHY GIRL AND
THE OTHER PREGNANCIES WERE
UNCOMPLICATED AND RESULT INDEED
HEALTHY LIVE BIRTHS EXCEPT FOR 3
ELECTIVE OBORGZS.
SINCE I'VE HAD PEDIATRICS
TRAINING, I'M PROUD THIS HAS
BEEN USED AS WELL IN CHILDREN,
THIS IS A SLIDE FROM A COUPLE
YEARS AGO AND THAT THAT POINT
THEY TRANSPLANTED 24 PATIENTS
SINCE TWEBT 18, THE MEDIAN AGE
WAS 14 YEARS WITH A RANGE OF
3-22 YEARS, ALL OF THE PATIENTS
WERE ALIVE, 19 WERE FREE OF
SICKLE CELL DISEASE, SO 79%
EVENT FREE SURVIVAL OR THE PATES
REYECT THEIR GRAPH AND HAVE A
RETURN OF SICKLE CELL DISEASE
AND 1 PATIENT REQUIRED A STEM
CELL BOOST BUT AGAIN NONE OF THE
PATIENTS DEVELOPED GRAFT VERSUS
HOAFORT DEC AND THIS HADN'T BEEN
PREPORTED PREVIOUSLY AND 13 OF
19 INGRAFTED PATIENTS ARE OFF OF
SIROLIMUS.
SO THERE'S ALSO A SECOND MAJOR
OBSTACLE FOR MISSIAC SON AND
THAT'S WELL LESS THAN 15% OF
PATIENTS HAVE A FULLY HLA MATCH
RELATED DONOR.
OT OTHER HAND HAPPEN LO
IDENTICAL OR HALF MATCHED
EXPANDS THE DONOR POOL BECAUSE
MOST PATIENTS WILL HAVE A
PARENT, CHILD OR HALF MET
SIBLING THAT CAN 7 AS A DONOR SO
THIS INCREASES THE CHANCE THEY
WILL HAVE A DONOR FROM 15% TO
90% AND LESS TOXIC OR NONMILE
ABLATIVE CONDITIONING ALLOWS
THEM TO ENROLL WITH ORGAN
DAMAGE, SO THIS GREATLY EXPANDS
THE DONOR POOL TO ADULTS WITH
ORGAN DAMAGE.
AND IN 2000 MINE, THE EFFICACY
WERE NOT KNOWN AND THAT WERE
ONLY 2 SITES DOING THIS WITH
ADULT SICKLE CELL DISEASE AND
THAT WAS HOPKINS AND THE NIH.
SO FIRST I WILL TELL YOU ABOUT
THE HOPKINS REGIMEN BECAUSE THEY
PUBLISHED THEIR RESULTS FIRST,
17 PATIENTS RECEIVED A
TRANSPLANT, 14 PATIENTS THAT ARE
LAP LO IDENTICAL DONORS WAS 14,
THE RANGE WAS 15-46 YEARS AND I
WILL GO THROUGH THIS REGIMEN
BECAUSE I WILL COME BACK TO IT.
SO CAN YOU SEE THAT THE PATIENTS
RECEIVED ATG, THEY RECEIVED 2
SMALL BOWS DOSES OF CYCLOFOSTER
NURSED MID BEFORE THE
TRANSPLANT, 200 CENTIGRADE OF
TOTAL BODY RADIATION, THEY USE
BONE MARROW AS THE STEM CELL
SOURCE, THEY GET 2 DOSES OF
CYCLOFOSTER NURSED MADE POST
TRANSPLANT AND THEY GET
MICROFENNALLATE AND INITIALLY
THEY REF CEIVED TBI, BUT CHANGED
TO SIROLIMUS, EMPLOY THEY DON'T
FRACTIONATE THE MYELOID
COMPARTMENT SO THEY REPORT WHOLE
BLOOD CHIMERISM, AND YOU CAN SEE
WHEN THE CHIMERISM LEVELS ARE
HIGH, THE PATIENT SICKLE
HEMOGLOBIN AT 6 MONTHS POST
TRANSPLANT IS THE SAME AS THE
DONOR SO IF THE DONOR HAS SICKLE
CELL TRAIT, AND THE DONOR AS
SICKLE CELL TRAIT, AND THEN THE
TOTAL HEMODPLOABIN LEVELS ARE
CLOSE TO NORMAL.
WE HAD 6 PATIENTS COMPLETELY
REJECTED THIS SICKLE CELL
DISEASE, THIS IS 1 GREEN PATIENT
WHO HAD 5%, AND EVEN THOUGH THE
DONORS HEMOGLOBIN LEVEL IS ABOUT
40%, THE PATIENTS WAS 61% WITH
THE VERY LOW HEMOGLOBIN OF 6
PASSPORT 2.
WE WOULD HAVE CALLED THAT A
GRAPH FAILURE.
SO, IMPORTANTLY THIS IS THE
FIRST STUDY IN ADULTS IN ALL THE
PATIENTS THAT SURVIVED, AND A
50% FREE SURVIVAL BUT ALSO, NONE
OF THE PATIENTS HAD DEVELOPED
ACUTE OR CHRONIC GRAFT VERSUS
HOST DEC AS 75% OF THE GRAFTED
PATIENTS WERE OFF OF THE
IMMUNOSUPPRESSIVE THERAPY.
SO THIS IS THE STUDY THAT WE
WROTE.
HERE AT THE NIH AND THIS WAS
BASED ON MIEWRINE DATA, WE WROTE
IT AS A DOSE ESCALATION, ALL
PATIENTS RECEIVED ALEMTUZUMAB,
AND ALL PATIENTS RECEIVED
SIRIOLOMUS, THIS IS THE FIRST
DID NOT RECEIVE ANY CYCLOFOSTER
NURSED MID AND THEY WERE
STOPPING RULES BUILT INTO THE
STUDY SO IF TOO MANY PATIENTS
REJECT THE GRAFT, AND THEN IF
THE STOP RULES WERE MET THEY
WERE MOVED TO THE COHORT WHERE
THEY RECEIVE 2 DOSES OF
CYCLOFOSTER NURSED FOCUSED ON
MID.
SO 20 PATIENTS WERE TRANSPLANTED
AND THE TIME THE MEDIAN FOLLOW
UP WAS 6 YEARS, MOST PATIENTS AT
SICKLE CELL DISEASE, 2 OF THEM
HAD BETA THAT WILLASEMIA AND
BECAUSE OF THE TIME WE DIDN'T
KNOW WHAT THE TOXICITY WOULD BE,
WE TRANSPLANTED VERY SICK
PATIENTS THAT WE THOUGHT WERE
GOING TO DIE OTHERWISE,
SOPHISTICATEDY THEY HAD SEVERE
ORGAN DAMAGE INCLUDING HEART
FAILURE, END STAGE RENAL DISEASE
INCLUDING DIALYSIS, CIRRHOSIS
AND PULMONARY HYPERTENSION.
SO THESE ARE THE RESULTS OF THE
TODAY, THE FIRST COHORT, THE
PATIENTS DIDN'T RECEIVE ANY
CYCLOFOSTER NURSED FOCUSED ON
MID, 1 OF THEM INITIALLY
INGRAFTED BUT SHE LOST HER GRAFT
AT 7 MONTHS POST TRANSPLANT.
SO WE MOVED TO THE SECOND COHORT
WHERE THEY RECEIVED
50-MILLIGRAMS OF CYCLOFOSTER
NURSED FOCUSED ON MADE.
EIGHT PATIENTS WERE
TRANSPLANTED, SO WITH STOPPING
RULES, WE MOVER TO THE THIRD AND
FIEPAL COHORT WHERE THE PATIENTS
RECEIVED A HUNDRED MEGS OF
CYCLOPHOSPHOR MID, AND 10
INGRAFTED BUT ONLY 6 REMAIN FREE
OF SICKLE CELL DISEASE.
CAN YOU SEE THAT REALLY NONOR
VERY MINIMAL GRAFT VERSUS HOST
DEC.
SO DESPITE THESE PATIENTS BEING
VERY SICK, NONE OF THEM DIED
BEFORE TRANSPRANT AND 5 PATIENTS
REJECTED THEIR GRAPHS BETWEEN
3-AND 8 YEARS, MOSTLY FROM
SICKLE CELL DISEASE RELATED
COMPLICATIONS.
SO BEFORE MOVING ON TO THE MORE
RECENT TRANSPLANT STUDY, I WANT
TO TALK ABOUT WHAT HAPPENS TO
PAIN AFTER TRANSPLANT, THIS
STUDY WAS LED BY ALEXIS LEONARD
WHO IS NOW AT ST. JUDE, SHE
EVALUATED 163 PATIENTS WITH SICK
ELITE EXECUTIVE IS DISEASE, MOST
OF THEM MALE AND MOST OF THEM
HAD HOMOZYGOUS DISEASE, MOST
PATIENTS RECEIVED NONMILE
ABLATIVE CONDITIONING AND MOST
OF THEM UNDERWENT HLAA SIBLING
MATCH TRANSPLANT.
SO WHEN YOU LOOK AT THE Y-AXIS,
YOU SEE PAINFUL EVENTS BEFORE
CAN AFTER TRANSPLANT AND THIS
BLUE RECK TANGLE SHOWS THE
AMOUNT OF PAINFUL EVENTS WE HAD
2 YEARS BEFORE TRANSPLABT AND
THEN THE YELL O SHOWS EVENTS
BETWEEN 0 AND 12 MONTHS AND IN
THIS 1 SHOWS BETWEEN 12 AND 24
MONTHS, SO CAN YOU SEE, THAT
PAIN PRETTY MUCH RESOLVES
BETWEEN 1 AND 2 YEARS POST
TRANSPLANT IN PATIENTS THAT HAVE
SUCCESSFUL TRANSPLANTS WITHOUT
GRAFT VERSUS HOST DISEASE, AND
WHEN YOU LOOK AT THE PATIENT WHO
IS DID DEVELOP GRAFT VERSUS HOST
DEC, CAN YOU SEE THAT PAIN
RESOLVES AFTER TRANSPLANT BUT
INTERESTINGLY EVEN THOUGH
PATIENTS REYECTED THEIR GRAFTS
THEY HAD A SIGNIFICANT DECREASE
IN SEVERE PAINFUL EVENTS IN THE
YEAR OR 2 FOLLOWING TRANSPLANT.
SO WHY WAS THE GRAFT REJECTION
RATE IN THESE 2 STUDIES SO HIGH?
WE HAD THOUGHT IT WAS
IMMUNOSUPPRESSION THAT WAS GIVEN
SO I WILL TALK ABOUT MORE RECENT
STUDIES WHICH INCLUDED
ADDITIONAL UPFRONT CONDITIONING
WITH PSYCHE ON FOSTER NURSED
FACAS MIDS AND THERE ARE IMPROVE
OUTCOMES FOR HAPPEN LO RANS
PLANT.
SO THIS FIRST REPORT IS
INVESTIGATED BY THE
INVESTIGATORS AT UNIVERSITY OF
CHICAGO, THEY TRANSPLANTED
PATIENTS WITH THE AGE RANGING
FROM 8-30 YEARS AND THIS WAS
WHAT I WENT OVER EARLIER AND YOU
CAN SEE THEY MADE 2 CHANGES OVER
THE REGIMEN, THE FIRST IS THEY
INCREASED RADIATION FROM 200 TO
300 CENTIGRADE AND ALSO INSTEAD
OF USING BONE MARROW AS A STEM
CELL SOURCE, THEY USE PERIPHERAL
BLOOD CELLS, SO JUST WITH THOSE
2 CHANGES AND MEDIAN FOLLOW UP
OF 17 MONTHS, 7 OF THE 8
PATIENTS WERE ALIVE SO OVERALL
SURVIVAL WAS 88%, WITH THE EVENT
FREE SURVIVAL OF 75%, 2 OF THE
PATIENTS DEVELOPED MODERATE TO
SEVERE GRAFT VERSUS HOST DEC AND
1 CHRONIC GRAFT VERSUS HOST DEC
THE SECOND STUDY WAS THE HOPKINS
GROUP AND THE ONLY CHANGE THEY
MADE, THEY GIVE A SINGLE DOSE OF
4 CENTIGRADE TOTAL BODY
RADIATION, THEY TRANSPLANTED 17
PATIENTS, 12 OF THEM HAVE SICKLE
CELL DEC, AGE RANGING FROM 6-31
YEARS.
AND ALL PATIENTS WERE ALIVE SO
OVERALL SURVIVAL 100%, WITH 83%
PAIN FREE SURVIVAL, 6% THE MORE
MODERATE TO SEVERE, 18% HAD
CHRONIC GBHD BUT ONLY 1 WAS
MODERATE.
AND ALL GBHD WAS RESOLVED AS OF
LAST FOLLOW UP WITH NO SYSTEMIC
GBHD THERAPY AND 91% OF THE
PATIENTS WERE OFF THE
IMMUNOSUPPRESSIVE THERAPY SO
VERY IMPRESSIVE RESULTS.
AND IN THIS STUDY, IT WAS
REPORTED BY INVESTIGATORS THAT
THE UK AND VANDERBILT AND
THEY--THE ONLY CHANGE THEY MADE
WAS TO INCREASE OR TO GIVE A
SINGLE DOZE OF [INDISCERNIBLE]
SO THIS DRUG AS A BIT OF MILE O
SUPPRESSION AND
IMMUNOSUPPRESSION, THEY TREATED
15 PATIENTS AGE 12-26.
THEY DEVELOPED A LARGER GLOBAL
GROUP INTERNAL AUDIT CLUEDS 3
CONTINENTS SO 1 OF THEM WAS
EUROPE, UK AND THE NETHERLANDS
AND OF COURSE, THE US BUT PAISH
ALSO IMPORTANT THAT PATIENTS
WERE TRANSPLANTED IN BRAZIL SO
THIS BECAME MORE OF A GLOBAL
EFFORT.
AND THEY REPORTED THEIR RESULTS
IN 2002, SO FIRST I WILL FOCUS
ON THE 39 ADULTS THAT WERE
TRANSPLANTED SO THEY'RE AT LEAST
18 YEARS OF ANAL, MEDIAN AGE OF
TRANSPLANT WAS ABOUT 25 YEARS,
MOST OF THEM HAD HYM O ZYGOUS
SICKLE CELL DISEASE AND A MEDIAN
FOLLOW UP OF JUST 2 YEARS AT THE
TIME AND YOU CAN SEE THAT NONE
OF THE PATIENTS EXPERIENCED
GRAFT FAILURE, 2 PATIENTS DIED
FROM INFECT YOWZ RELATED EVENTS
AND 3 OF THE PATIENTS DEVELOPED
GRADE 3-4 ACUTE GBHD AND ONLY 1
MODERATE TO SEVERE GRAFT VERSUS
HOST DISEASE.
YOU LOOK AT THE 41 CHILDREN, THE
MEDIAN AGE TRANSPLANT WAS 12 AND
HALF YEARS, ALL OF THEM HAD
HOMOZYGOUS SICKLE CELL DISEASE,
AND THE MEDIAN WAS JUST OVER A
YEAR.
SO THEY HAD MORE PROBLEMS WITH
GRAFT FAILURE, GRAFT FAILURE
MEAN ITS NEVER TOOK, SECONDARY
FAILURE MEANS IT TOOK BUT THEY
REJECTED THE GRAFT, SO 10 OF THE
41 PATIENTS REYECTED THE GRAFT.
TWO PATIENTS DIED AND 10-15% OF
THE PATIENTS TWEPPED GRAFT
VERSUS HOST DISEASE, SO THE
STUDY RESULTS WERE MUCH MORE
IMPRESSIVE IN THE ADULT SETTING
AND THEY'RE DOING MORE TO TRY TO
IMPROVE RESULTS IN THE PEDIATRIC
STUDY.
THE BMCTN 1507 IS A MULTICENTER
HAPPEN LO IDENTICAL PULMONARY
TRANSPLANT TRIAL, FOR ADULTS
WITH SICKLE CELL DISEASE, USING
THAT REGIMEN, THEY HAVE 2
STRATA, 1 FOR CHILDREN AND 1 FOR
ADULTS AND THERE'S 40
PARTICIPANTS PER STRATA.
THEY'RE GETTING READY TO REPORT
THEIR RESULTS THIS YEAR BUT THE
PRELIMINARY REPORTS WERE VERY
SIMILAR TO WHAT I SHOWED AT THE
VINEDDER BUILT GLOBAL CONSORTIUM
GROUP.
I WILL TALK ABOUT 1 MORE BEFORE
I TELL BUT OUR MORE RECENT
STUDY.
THIS IS A PEDIATRIC STUDY, THIS
IS WHERE THEY INCLUDED 5
PATIENTS AND ALL OF THE PATIENTS
HAD DONOR SPECIFIC HLA ANTIBODY
SO THEY RECEIVE THIS INTENSIVE
PRECONDITIONING WITH RETUX MAB,
JUST ALL KINDS OF THINGS AND
THEN THEY RECEIVED AS FAR AS
CONDITIONING ATG, THESE WERE
PATIENTS BETWEEN 8-19 YEARS AGE
AND THEY HAD IMPRESS OF RESULTS
WITH THE MEDIAN FOLLOW UP OF ALL
25 MONTHS ALL PATIENTS WERE
ALIVE AND FREE OF SICKLE CELL
DISEASE, NONE OF THE PATIENTS
DEVELOPED OOH CUTE OR HOST
VERSUS GRAFT DISEASE, SO 2
PATIENTS EXPERIENCED CMV
REACTION BUT NO CMV DISEASE.
THERE'S BEEN ABOUT 153 PATIENTS
THAT HAVE BEEN REPORTED.
YOU CANEE THAT MOST OF THE
PATIENTS ARE PRETTY YOUNG BUT
86% OF THE PATIENTS ARE ALIVE
AND FREE OF SICKLE CELL DISEASE.
SEVENTEEN% OF THEM DEVELOPED
ACUTE GBHD AND IT'S MORE ON THE
GREAT 2 SIDES, AND IT'S MORE THE
MILDER SIDE AND 70% DEVELOPED
CHRONIC GBHD BUT MOSTLY THE
MODERATE SIDE AND 5% HAD DIED SO
THE RECENT HAPPEN LO IDENTICAL,
HAVE A HIGH EVENT PREVURIVAL
WITH HIGH GBHD AND MORTALITY.
SO WHAT ABOUT OUR STUDY, I
SHOWED YOU EARLIER OUR STUDY HAD
GRAFT REYEKS AND WHAT WE DECIDED
TO DO WAS BASED ON MURINE DATA
ADD PRECONDITIONING AND ORAL
BECAUSE THE 2 TOGETHER WORK
SINNER GESTICLY TO DEPLETE THE
IMMUNE SYSTEM, SO THEY GET 2
WEEKS OF PENTINE REGIMEN STATIN
AND ORAL CYCLOFOSTER NURSED
FOCUSED ON MADE BEFORE ALOE
TIEWZ MAB AND THEN THEY GET THE
400 CENTIGRADE OF TBI AND WE
DECIDE TO GIVE ONLY 1 DOSE OF
THE CYCLOFOSTER NURSED MID
BECAUSE WE PHOTTED WHEN WE GAVE
2, THERE WAS MORE VIRAL
REACTIVATION AND WE KNEW THAT
ADDING PRECONDITIONING WOULD
INCREASE RISK FOR VIRAL
REACTIVATION AND THEN ALL
PATIENTS RECEIVE SIROLIMUS, SO 2
PATIENTS HAVE BEEN TRANSPLANT
WIDE A MEDIAN AGE OF 29 AND HALF
YEARS, A RANGE OF 19-55 YEARS,
MOST OF THEM MALE, JUST ABOUT
ALL ARE AFRICAN AMERICAN, AND
MOST OF THEM HAVE HOMOZYGOUS
SICKLE DISEASE AND MOST OF THEM
HAVE THE SICKLE CELL STRAIGHT.
SO MOST PATIENTS TRANSPLANTEDAR
TRANSPLANTED FOR RECURRENT
PAINFUL CRISES OR ACUTE CHEST
SYNDROME, CAN YOU SEE PATIENTS
WE CHOOSE PATIENTS WHO HAVE MORE
ORGAN DAMAGE, SO ABOUT A QUARTER
OF THE PATIENTS HAD SOME TYPE OF
STROKE OR CEREBRAL VASCULOPATHY
AND ABOUT 30% OF THEM HAVE
ELEVATED TRV OR HYPERTENSION
THAT WE HAVE 16% WITH LIVER
DISEASE.
WE ALSO HAD 22 PATIENTS, 59% OF
THEM HAD 2 INDICATIONS FOR
TRANSPLANT AND 14% HAD 3
INDICATIONS FOR TRANSPLANT SO WE
TRANSPLANT A PRETTY SICK
POPULATION OF ADULTS WITH SICKLE
CELL DISEASE EMPLOY SO THE GOOD
NEWS IS WITH OUR FIRST PROTOCOL
I SHOWED YOU THAT OUR GRAFT
REJECTION RATE WAS HIGH, SO WE
ONLY HAD 1 PATIENT, ACUTELY
REYECT THE GRAFT, SO WE DID HAVE
A SIGNIFICANTLY DECREASED GRAFT
REYEKS RATE WITH THE SECOND
PROTOCOL COMPARED TO THE FIRST
1.
SO ADDING THE PRECONDITIONING
WITH PENTASTATIN AND
CYCLOPHOSPHOR MADE DID HELP THAT
BUT UNFORTUNATELY WE HAD MULTILE
COMPLICATIONS, SHOWEDDER EARLY
IN OF THE PATES HAVE THE
FOLLOWING CHIMERISM, WE HAD 4
PATIENTS EXPERIENCE THAT WITH 2
OF THEM EXPERIENCING LATE GRAFT
FAILURE WITH THE RETURN OF
SICKLE CELL DEC 2 AND HALF YEARS
POST TRANSPLANT.
WE ALSO HAD 2 PATIENTS DEVELOP A
SEVERE REFRACTORY EVIDENCE
SYNDROME IT'S AN - AUTOIMMUNE
PHENOMENON, IMPACTING RED BROOD
CELLS AND PLATELETS BETWEEN 7-9
MONTHS TRAB PLANT.
BOTH PATIENTS DEVELOPED SEVERE
HYPER INFLAMMA ARE TOY RESPONSE
AND MULTIORGAN FAILURE AND
PASSED AWAY.
WE ALSO HAD 5 PATIENTS DEVELOP
THE EPSTEIN BARRE DEC, IT WAS
UNCONTROL INDEED 2 OF THE
PATIENTS INCLUDING CHEMO THERAPY
AND VIRAL SPECIFIC T-CELLS, 1 OF
THE PATIENTS DIED.
SO WITH THE MEDIAN FOLLOW UP OF
0-46 YEARS, THE OVERALL SURVIVAL
IS 82% WITH THE EVENT FREE
SURVIVAL OF 68%.
SO ON THIS STUDY, THE LONG-TERM
SICKLE CELL DEC FREE SURVIVAL IS
NOT OPTIMAL.
SO MANY PATIENTS WITH OSM
COMPROIZ ARE EXCLUDED FROM THE
TYPE OF TRANSPLANT I'M TALKING
ABOUT AND WE HYPOTHESIZED THAT
OUR FIRST TRANSPLANT DID NOT
HAVE ENOUGH IMMUNOSUPPRESSION
AND OUR SECOND 1 HAD TOO MUCH
IMMUNOSUPPRESSION SO WE RECENTLY
OPENED A NEW PROTOCOL WITH A
IMMUNOSUPPRESSION AND WHICH WILL
INCLUDE PATIENTS WITH ORGAN
FUNCTION IN OUR FIRST PATIENT'S
GOING TO BE TRANSPLANT INDEED 2
DAYS SO WE'RE VERY EXCITED ABOUT
THAT.
SO I COMPARED THIS A COUPLE
YEARS AGO, THE RESULTS OF THE
STUDY WERE EXCITING AT THE TIME.
WE HAD 1 WITH MILE IMRAOF THE
VERSUS HOST DISEASE AND THIS
TIME WHEN IT PASSED AWAY, AND
YOU CAN SEE THAT MANY OF THE
FOLLOW UP WAS JUST OVER 2 YEARS
WHICH WAS LONGER THAN THE OTHER
STUDIES WE JUST PUBLISHED SO
WHILE THESE RESULTS ARE VERY
EXCITING ISSUES THE FOLLOW UP IS
VERY SHORT AND AS CAN YOU SEE
FROM WHAT I'VE SHOWN YOU, IT'S
IMPORTANT TO FOLLOW THEM FROM
WHAT HAPPENS, I'M NOT TRYING TO
REVERSE SICKLE CELL DISEASE, I
WANT THEM TO STAY ALIVE AND
HEALTHY FOR A REALLY LONG TIME.
SO I'M WORKING WITH
INVESTIGATORS, AND INVESTIGATORS
AT EMORY AND [INDISCERNIBLE], WE
WANT TO LOOK AT THE LONG-TERM
HEALTH EFFECTS OF CURATIVE
THERAPY WITH PATIENTS WITHIC
ISLE CELL DISEASE AND WAS
BECAUSE WE KNOW THAT HEART LUNG
AND KIDNEY DISEASE INCREASE THE
RISK OF MORTALITY, WE ARE
FOCUSING ON THESE ORGANS SO THE
FITTER AIM IS TO EVALUATE THE
INCIDENCE OF LUNG AND KIDNEY
DISFUNCTION, FIRST IN CHILDREN
WITH SICKLE CELL DISEASE,
RECEIVE A MILE ABLATIVE
THERAPIES AND ADULTS WEB
CONNECTED CEIVING NONMILE
ABLATIVE TRANSPLANT COMPARED TO
PREEXISTING COHORT OF CHILDREN
IN ADULTS DISEASE WHO DON'T GET
TRANSPLANTED SO WE CAN COMPARE
HUNDREDS OF PATIENT WITH SICKLE
CELL DISEASE THAT GET TRANSPLANT
THAD DON'T GET TRANSPLANTED WE
CAN COMPARE MILD APLATIVE TO
NONABLATIVE CONDIGGING AND WE'RE
EXCITED ABOUT THAT.
AND WE WANT TO DETERMINE WHETHER
THERE WAS SIN CLALLY SIGNIFICANT
IMPROVEMENT IN TRV IN ACULLS
WITH SCD, SO 40 PATIENTS WHO
UNDERWENT TRAN PLANT FOR THE NIH
WERE FOLLOWED FOR AT LEAST 1
YEAR POST TRAN PLANT AND IF YOU
LOOK AT THE WHOLE POPULATION,
THE TRV DID FOCUS ON THE CHANGE
OVER TIME BUT IF YOU FOCUS ON
THE 24 PATIENT WHO IS HAD A TRV
OF AT LEAST 2.5-METERS PER
SECOND, WE DID SEE A DECREASE IN
TRV, SO TRV AT BASE LINE WAS ON
AVERAGE 2.7-METERS PER SECOND,
SO THAT'S ASSOCIATE WIDE EARLY
MORTALITY AND BY 1 YEAR POST
TRANSPLANT, AND DECREASED AT
2.3, SO DECREASE TO THE NORMAL
RANGE, A YEAR AFTER TRANSPLANT.
SO WHAT ABOUT THE LUNGS, THIS IS
A TODAY WE'RE WORKING ON WITH
PARKER RULE WHO'S A PULL
MONITORROLOGYIST WHO, WOS WITH
US AND WE LOOKEDDA THE 97
PATIENT WHO IS WORK AT THE NIH,
53 OF THEM WERE FOLLOWED UP TO 3
YEARS AND AT BASE LINE AGE OF
THE 32 YEARS, MOST PATIENTS WERE
MALE AND ESPECIALLY THE
HEMOGLOBIN IMPROVES AFTER
TRANSPLANT FROM 8.8 TO 12.5, 3
YEARS POST TRANSPLANT.
MOST OF THE PATIENTS HAD
HOMOZYGOUS SICKLE CELL DISEASE,
AND IF YOU LOOK AT THE PERCENT
PREDICTED WHICH IS A MARKER OF
LUNG FUNCTION, YOU CAN SEE IT
REMAINS STABLE AFTER TRANSPLANT
AND YOU EXPECT IF YOU DON'T GET
TRANSPLANT THAD THE FEV 1 CAN
DECREASE OVER TIME.
AND THEN DLCO WAS ANOTHER MARKER
OF PULMONARY FUNCTION, AND YOU
CAN SEE THE UNADJUSTED DLCO
LOOKS TO UMPIRES PROVE SOME
AFTER TRANSPLANT AND IF YOU LOOK
AT THE DISTANCE THAT THE PATIENT
CANS WALK AFTER TRANSPLANT, IT
INCREASES FROM 490-METERS AT
BASE LINE TO 520-METERS AFTER
TRANSPLANT.
AND THEP LASTLY WE WANT TO LOOK
AT KIDNEY FUNCTION AND HOW MILD
APLATIVE TRANSPLANT WORKS WITH
THE KIDNEYS SO WE WORKED ON THIS
WITH EMILY LIMERICK, WE LOOKEDDA
THE 100 PATIENTS WHO UNDERWENT
THIS FOR AT WERE FOLLOWED FOR AT
LEAST A YEAR AND 63 OF THEM WERE
FOLLOWED FOR AT LEAST 3 YEAR
ANDS WE FOWBD THAT THE
PREVENTIVE LICENSE OF THE
CHRONIC KID NO DISEASE INCREASED
AT 1 YEAR POST TRANSPLANT BUT
NOT DEFINITE FROM BASE LINE 3
YEARS COMPARED TO 1 YEAR AND WE
FOUND THAT THE MEDIAN ESTIMATED
FILTRATION RATE DECLINED
ANNUALLY AND THE BASE LINE ON
EGFR WAS 140 AND DECLINED AND
20.9 AT 3 YEARS, BUT THE MEDIAN
EGFR REMAIN NORMAL WITHIN THE
NORMAL RANGE AND IT'S
INTERESTING BECAUSE THE EGFR WAS
ACTUALLY ABNORMALITIES NORMALLY
HIGH BEFORE THE TRANSPLANT.
SO IT DECREASED TO THE NORMAL
RANGE BUT WE HAVE TO HAVE LONGER
FOLLOW UP TO SEE WHAT HAPPENS
AFTER 3 YEARS.
SO IN CONCLUSION, HLA MAX
SIBLING TRANSPLANT WITH MILD
ABLATIVE CONDITIONING HAS HIGH
EFFICACY, WITH NONMILE ABLATIVE
CONDITIONING AND THERE'S A LOWER
RATE OF GRAFT VERSUS HOST
DISEASE DESPITE THE USE OF STEM
CELLS.
NONMILE OABLAISIVE CONDITIONING
AIMED AT TOLERANCE INDUCTION HAS
LOWER RATE OF GVHD AND DESPITE
THE USE OF PBS Cs AND REEBT
STUDIES WITH PT-CY AND 2 YEARS
POST TRAN PLANT OR CHIMERISM IS
88% AND HER LYMPHOID CHIMERISM
AND WAS 32%, HER HEMOGLOBIN WAS
LOW BUT WE WERE DOING
THERAPEUTIC FLEBOT ME TO GET RID
OF THE IRON.
HER DONOR HAD SICKLE CELL
STRAIGHTS AND SO DID SHE.
SHE WAS OFF OF NARCOTIC THERAPY
AND SHE WAS OFF OF OTHER MEDS
WITH HER PULMONARY HYPERTENSION,
SO CAN YOU SEE THE TRV WAS
REALLY ELEVATED AT 3.9-METERS
PER SECOND.
HER EJECTION FRACTION WAS NORMAL
AT 60, 6 MINUTE WALK DISTANCE
WAS 324-METER WHICH IS IS LOW,
DECREASED OXYGEN LEVEL WHEN HE
WALKS, THIS IS ALSO ABNORMAL AND
MAIN PULMONARY ARTERIOLE
PRESSURE AND ABNORMAL WAS 25 AND
HIGHER, HER CARDIAC OUTPUT WAS
HIGH SO SHE STARTED ON ABERR SIN
TAN IN AUGUST 2012.
AND AFTER A YEAR LATER HER TRV
HAD DECREASED TO 3.1, HER WALK
DISTANCE DID INCREASE FROM 324
TO 359.
SHE STILL HAD AN ABNORMAL
DECREASE IN HER OXYGEN
SATURATION WHEN SHE WALKED, AND
BECAUSE SHE HAD A PAIN CRISIS AT
THE TIME WE WERE NOT ABLE TO DO
A RIGHT HATTER CATH RIGHT BEFORE
THE TRANSPLANT.
SHOW SHE UNDERWENT TRANSPLANT IN
AUGUST 2013 AND HER AMBER SAN
TAN WAS DISCONTINUED IN APRIL OF
2014.
AND YOU CAN SEE IN AUGUST, A FEW
MONTHS LATER HER TRV HAD
DECREASE AT 2.8-METERS PER
SECOND, HER 6 MINUTE WALK
DISTANCE HAD GONE UP TO 456, HER
OX GENERATEDDATION NORMALIZED
AND HER CARDIAC OUTPUT IS NOW
NORMAL BUT IMPORTANTLY, HER
ARTERIOLE PRESSURE IS NOW NORMAL
SO HER PULMONARY HYPERTENSION
WENT AWAY AND 2 YEARS AFTER
TRANSPLANT NOW HER TRV IS DOWN
TO THE NORMAL RANGE STILL WITH
NORMALIDES OF HER OXYGEN GIGZ,
SO IF YOU LOOK AT A SURVIVAL
CURVE, BECAUSE HER TRV WAS 3.1
BEFORE THE TRAN PLANT, BUT AFTER
THE TRANSPLABT WITH THE TRV OF
2.4, SHE'S ON THIS SURVIVAL
CURVE SO SHE'S OPENING THAT THIS
WILL IMPROVE SURVOOFAL.
THIS IS HER, I PRESENTED HER AT
GRAND ROUNDS AND SHE SURPRISED
OUGHTIENCE, WELL, MY SON KNOWS
I'M HIS MOTHER NOW BECAUSE I'M
NOT IN THE HOSPITAL, I CAN PLAY
WITH HIM, GO TO THE PLAYGROUND,
DO NORMAL THINGS, I CAN KEEP MY
PROMISE, WHEN I SAY I WILL BE
SOMEWHERE, I CAN ACTUALLY BE
THERE.
IT'S INKRE TINSIBLE WORKING WITH
THIS POPULATION, SHE WAS LIVING
IN THE HOSPITAL BEFORE THE TRAN
PLANT, SHE WAS TALKING ABOUT HOW
WE WERE IN LIPSETT AUDITORIUM,
AND SHE SAID BEFORE THE TRAN
PLANT SHE HAD TO STOP MULTIPLE
TYPES, SO THINGS THAT WE TAKE
FOR GRANTED SHE WAS ABLE TO DO
SO I REALLY, REALLY THANKFUL I
GET TO WORK WITH THIS
POPULATION.
SO THANK YOU.
THAT'S IT.
I WANT TO THANK THE PATIENTS AND
FAMILIES ESPECIALLY, ALL THE
MEMBERS OF MY LAB AND THE
TISDALE LAB, WHO PROVIDE PROT
COLSUPPORT, THE STATISTICAL
ANALYSIS, ALL OF THE KACCTA
LESSED INVESTIGATORS IN WE WORK
WITH AND THE PEOPLE WHO
COLLABORATED ON THE HEART AND
LUNG STUDIES HERE, AND ALL THE
CLINICAL STAFF, SO THANK YOU SO
MUCH FOR YOUR ATTENTION.
>> ALL RIGHT, WELL, THANK YOU
DR. FITZHUGH FOR THAT FANTASTIC
PRESENTATION, AND HOPEFULLY AS I
STEP BACK, WE WILL HAVE LESS
FEEDBACK AND OUR SECOND PEEKER
PROFESSOR WONKAM WILL YOIN US AT
THE PODIUM.
PROFESSOR WONKAM?
>> THANK YOU.
THANK YOU.
THANK YOU FOR THE INVITATION, I
AM GRATEFUL FOR IT YOU SPOKE TO
THE WAR ON SICKLE CELL DISEASE,
THE WAY I WILL BE SPEAKING TO
THE WORLD OF SICKLE CELL
DISEASE, THE WAY IT COULD BE,
MOSTLY FROM A GENETIC RESEARCH
PERSPECTIVE.
AND FOCUSING ON AN AFRICAN
POPULATION AND WHAT COULD BE THE
MYSTERY BEHIND THE GENOME THAT
WE CAN EXPLODE, PERHAPS IN
FUTURE TREATMENT IMPROVEMENT OF
SICKLE CELL DISEASE.
AS AWE ALL KNOW THE CONDITION
WAS DESCRIBED IN THIS COUNTRY
113 YEARS AGO AND AS WAS ALLUDED
TO BEFORE, MAYBE BEFORE THAT,
AND THE MENTORSHIP OF GREAT
LEADERS ON SICKLE CELL RESEARCH
FROM MIGRATE PENTINE REGIMENNOR
[INDISCERNIBLE] SEBD ME THE
E-MAIL BEFORE HE PASSED.
I ALWAYS KEEP THIS 1, I FIRST
SPOKE TO BONE MARROW
TRANSPLANTATION, BUT IT IS
IMPORTANT TO REALIZE IT IS A
PRIVILEGE TO DO IT HERE IN
AMERICA.
IN AFRICA WHERE MOST PEOPLE ARE
FOR EXAMPLE ISSUES ON THE RIGHT
HAND SIDE THERE IS ONLY 3
CENTERS WHO ARE ABLE TO DO BONE
MARROW TRANSPLANT TISSUE, IN
NIGERIA, TANZANIA, AND AFRICA,
WE HAVE A LOT OF WORK TO DO.
THE EXPANDED CONDITION WAS
DRIEBED 113 YEARS AGO, WE KNOW
TREATMENT HAVE NOT IMPROVED
REALLY SO DRASTICALLY, ONLY 1
MEDICATION ACTUALLY HAD BEG YOUR
PARDON WIDELY USED, THE
MORTALITY DON'T HAVE NO CHANGE
IN THE UNITED STATES OVER THE
PAST 50 YEARS AS THE DIAGRAM
WILL INDICATION, BUT I WILL NOT
SEE IT IN 50% OF THE
[INDISCERNIBLE].
THAT MEANS WE HAVE TO DRAIN
[INDISCERNIBLE] GLOBAL FOR
EXAMPLE IN AMERICA TO FIND A
SOLUTION FOR THE SICKLE CELL
DISEASE PATIENT, MORTALITY IN
THE U.S. IS USUALLY DUE TO
CARDIOVASCULAR COMPLICATION SOME
OF WHICH HIGHLIGHTED HERE AND I
THINK MOST OF THOSE
CARDIOVASCULAR ARE SUBJECTED TO
GENETIC VARIATION AND I WILL TRY
TO EXPLORE FROM OUR DATA HOW WE
CAN HARNESS THAT.
WHY SHOULD YOU INVEST IN AFRICA
VARIATIONS FOR SICKLE CELL
DISEASE, THE FIRST REASON IS
THAT THE DISEASE, MUTATION
EVOLVED IN AFRICA,
[INDISCERNIBLE] 20,000S YEARS
AGO, WE WILL PROVE IT.
THE [INDISCERNIBLE] OF AFRICA
HAVE SHAPED THE COLLECTION OF
THE SPECIFIC VARIANT ASK THEY BE
IMPORTANT FOR THE COMPLICATION
AND THE CAUSE OF SICKLE CELL
DISEASE, WE JUST HAVEN'T ADDRESS
THE QUESTION OF THE
[INDISCERNIBLE].
THE OTHER REASON BESIDES SICK
CELL CELL DISEASE THAT WE ARE
ALL AFRICAN BECAUSE HUMANS LIVE
IN AFRICA AT LEAST A HUNDRED
THOUSAND YEARS BEFORE COMING OUT
OF AFRICA, THERE ARE STILL
VARIATION THAT MOVE OUT OF
AFRICA AND ARE CRITICAL TO
UNDERSTAND THE PATHING ON OF
SICKLE CELL DISEASE, I WILL SHOW
YOU A FEW EXAMPLE OF THAT.
ON THE LEFT-HAND SIDE, FOR
EXAMPLE, ON TOP SIDE, HIS NAME
IS LEE BURGER HE'S ANAN LOPOLOGY
GENETICIST, THE LOWER GUY BEFORE
AND [INDISCERNIBLE] HE IS THE
CURRENT PRESIDENT OF SOUTH
AFRICA, AND THEY'RE ENGAGE
INDEED A KISS COMPETITION
[INDISCERNIBLE] AND THAT IS
[INDISCERNIBLE] AFRICA THIS IS
THIS NEANDERTHAL OUT OF AFRICA,
WE KNOW THIS LIVES IN THEM.
THE MODEL ON THE OTHER SIDE
SHOWS THE TRUE WAVE OF
INTEGRATION OF THOSE GENOME AND
IF WE DO NOT STUDY AFRICA
POPULATION AND BE ABOUT TO
HARNESS THAT KNOWLEDGE, AND
THESE ARE THE LATE OF THE
POPULATION OF YESTERDAY, AND
THIS DATA HAVE BEEN IN REACH BY
50,000 GENOME OF PEOPLE OF
AFRICA.
BUT WE COMPARE JUST THE GENOME
ACROSS ANCESTRY WITHIN THE
UNITED STATES, WE CAN PICK FOR
EXAMPLE, THAT VARIANT THAT IS
ASSOCIATED WITH LOWER WHITE
BLOOD CELLS, PEOPLE OF AFRICAN
ANCESTRY, AGAIN THAT SHOWS THAT
SOME OF THE VARIATION THAT WE
HAVE IN AFRICAN POPULATION AND
NOT THE [INDISCERNIBLE] UNLESS
WE STUDY IS PROPERLY AND YOU
WILL SEE WHY IT'S IMPORTANT FOR
SICKLE CELL DISEASE.
WE APPROACH SICKLE CELL 3 WAYS
USING THE GENOMICS.
FIRST IS EXTENDING GENETIC
DIAGNOSTICS BEFORE BIRTH.
THIS WAS THE FIRST BABY BORN
AFTER GENETIC TESTING IN CAMMA
ROON, I AM VERY PROUD TO SAY I
DID THAT MYSELF, YOU CAN DO IT
ANYWHERE, BUT WE ALSO KNOW THAT
BEFORE BIRTH, YOU OPEN DOORS TO
VERY DIFFICULT QUESTIONS SOME OF
WHICH THAT ARE MEDICAL ABORG AND
WE KNOW IN THE CONTEXT OF--ON
THAT COUNTRY SPECIFICALLY MANY
STUDIES THAT WE PERFORM OVER
MANY YEARS, HAVE SHOWN THAT MANY
PARENT ARE OPEN TO
[INDISCERNIBLE] OF SICK ELITE
EXECUTIVE DISEASE, PLUS A VERY
HIGH BURDEN AND THAT IS
JEOPARDIZING THEIR LIVES, SOME
OF THEM ARE HOSPITAL, SOME OF
THEM ARE RELATED TO FINANCE,
SOME OF THEM ARE DISEASE BURDEN,
SOME OF THEM ARE THE DYNAMIC OF
THE CONDITION OF THE FAMILY AND
ALSO TO [INDISCERNIBLE] THE
CHILD THAT WILL PASS AWAY.
SO HOW SOCIETY IS NOT HAVING THE
SAME ATTITUDE FOR THAT APPROACH,
FOR EXAMPLE, IN THE 3 GROUP OF
STAKEHOLDERS, DOCTORS, PARENTS,
AT LEAST 1 AFFECTED CHILD AND
ALSO PATIENT, ADULT PATIENT WITH
SICKLE CELL DISEASE, WOULD
REALIZE THAT THEY
[INDISCERNIBLE] MEDICAL ABORTION
WAS VERY DIFFERENT.
FOR EXAMPLE, DOCTOR WAS LESS
OPEN TO THAT, WHILE A PARENT OR
ADULT PATIENT SURPRISINGLY WERE
OPEN TO IT, BUT JUST BECAUSE OF
THE BURREDIN OF THE CONDITION.
WHEN THAT MEANS THAT THIS WOULD
POSE CERTAINLY AN EDUCATIONAL
ISSUE, THE REASON WHY WE SHOULD
NOT BE DOING THIS, WE PROBABLY
NEED TO LOOK FOR THE KEY NUMBER
2, THAT'S HOW DO WE USE GENETIC
FOR PREVENTION, SOME OF YOU MAY
HAVE SEEN THIS SLIDE BECAUSE I
BORROWED IT WITH APPROVAL FROM
DR. GREEN, THAT SHOWS A LITTLE
BIT HOW GENETIC CONDITION,
CLASSIFIED, WE HAVE THOSE THAT
ARE AS SIMPLE AND MONOGENIC LIKE
SICKLE CELL, SOME THAT ARE
CONFLICTS MULTIGENIC, THIS IS
SINGLE DISORDER BUT IT'S ALSO
COMPLEX BECAUSE ENVIRONMENT AND
ALL THAT GENETIC MODIFIER ACTION
CHANGES THE DYNAMIC OF THE
CLINICAL EXPLANATION, 1 EXAMPLE
IS KIDNEY DISEASE IN SICKLE CELL
DISEASE.
OUR DATA FROM AFRICA AND THE
[INDISCERNIBLE] PEOPLE, HAVE
SHOWN THAT AT LEAST 3 VARIANT,
KIDNEY DISEASE IN SICKLE CELL,
THE 1 IS [INDISCERNIBLE], THE
SECOND IS APOL1, AND CURRENTLY
SOMEONE IN NIGH GROUP IS DOING
SOME GWAS ON THE POPULATION OF
SICKLE CELL AND WE ARE CONFIDENT
WE SHOW ADJUVANT SOME OTHER
VARIANT THAT IS SPECIFIC TO
SICKLE CELL DISEASE.
HAVING SICKLE CELL ACTUALLY
CHANGES, POSITIVELY THE OUTCOME
ADDING 1 EXPERIMENT THAT WE DID
MORE THAN 10 YEARS AGO WAS TO
LOOK AT THE EFFECT OF THE
[INDISCERNIBLE] TO THE CLINICAL
MANIFESTATION, AND WE FOUND THAT
IN THE CONTEXT OF THE KREEN, IF
YOU HAVE 1 DELETION, YOU HAD
THAT MORE LATER, AND HAVE YOU 2
DELETION, HAVE YOU DIAGNOSED AT
6 YEARS OLD AND WHEN WE COMPARE
THE PROPORTION OF PEOPLE OF
SICKLE CELL DISEASE, OF THIS IN
THE SAME COUNTRY, THOSE WHO DO
NOT HAVE IT, DELETION OF THIS,
ARE MORE THE POPULATION OF THE
SICKLE CELL DISEASE, BUT
[INDISCERNIBLE] COMPARED TO 20,
THAT IS A SELECTION OF THAT
VARIANT IN THE SICKLE CELL
DISEASE, FORTUNATELY FOR SOMEONE
IN KENYA, FOUND THE EXACT SAME
AND THEY FOUND FIRST OF ALL THAT
OF COURSE, THEY FOUND THAT THE
PATIENTS WITH SICKLE CELL
DISEASE WAS MUCH INDUCED IF THEY
HAVE A DOUBLE DELETION IN THE
[INDISCERNIBLE].
AGAIN, THOSE KNOWLEDGE MAY ALLOW
US FOR EXAMPLE, A NEW BORN
SCREENING TO KNOW WHAT WHICH
PATIENT, BABY, WOULD BE MORE
EXPECTED TO BE SICKER THAN OTHER
1S.
SOME OF THE STUDIES SAID THIS
WAS A DIFFICULT 1 WAS TO LOOK AT
SOME VARIANT ASSOCIATED WITH AN
EPISODE OF PAIN IN SICKLE CELL
DISEASE, WE CAN ALSO DESIGN AND
MODEL TO THIS OCCURRENCE IN THE
SICKLE CELL DISEASE, AND ALSO
USING TRANSCRIPT ORDER OF
MICRONSIC IN THE PERIPHERAL
BLOOD, SO WE CAN DECIDE WHICH
PATIENT OR NOT.
AND ALL OF THESE HAVE NOT HAD
CLINICAL APPLICATION AND/OR
IMPLEMENTATION AND WE NEED
INVEST MORE IN THOSE AREA AND WE
KNOW THAT [INDISCERNIBLE] SICKLE
CELL DISEASE MAY BE CONDITIONED
BY BLOOD PRESSURE, BUT THE ONLY
DIFFERENCE IN SICKLE CELL IS THE
DEFINITION OF BLOOD PRESSURE OR
THAT WE CALL RELATIVE BLOOD
PRESSURE, SIS SEMESTERRIC BLOOD
PRESSURE THAT IS LOWER THAN THE
GENERAL POPULATION, THESE ARE
VERY RECENTLY BACK FROM THE
GROUP WHERE WE PERFORM THESE IME
NOAM WIDE ASSOCIATION STUDIES
FROM THE [INDISCERNIBLE] AND
THAT WE ADDED G5 THAT
REASSOCIATED WITH THE SICKLE
CELL DISEASE, AND THIS IS THE
MICE MODEL, THIS IS SUGGESTED
ASSOCIATION WITH
[INDISCERNIBLE].
AND WE HAVE ANALYZED THE DATA,
FROM AFRICAN AMERICAN, AND YOU
CAN SEE THAT, THEY'RE--WE HAVE
REPLICATED AT LEAST 1 OF THE
LOCI, AT A NORMAL INTERVAL IN A
SMALL COHORT, THE
[INDISCERNIBLE] COHORT AMONG
AFRICAN AMERICAN.
THIS IS A STUDY WE FOLLOW IN BMI
WITH SICKLE CELL DISEASE AND 3
LOCI VERY PROMISING.
WE ARE CURRENTLY WORKING IN 1 OF
THE LOCI, AT THE CELL LEVEL AND
1 OF THEM ACTUALLY IN THE MOUSE
MODEL, THEY SEEM TO CONFIRM OUR
ASSOCIATION FOUND IN PATIENT
WITH SICKLE CELL DISEASE.
SO, SOME WOULD SAY WHY GWAS, IN
SICKLE CELL DEC FROM AFRICA?
IT'S IMPORTANT THAT WE PERFORM
GWAS FOR ANYTHING ELSE IN
AFRICAN POPULATION, AGAIN, 1 OF
THE REASONS IS THAT THERE ARE
SOME VARIANT THAT A ARE OUT OF
AFRICA AND HAD IS THE TYPICAL
EXAMPLE, [INDISCERNIBLE] FOR
STUDY SHOWS NOW FOR HIGH BLOOD
PRESSURE, THE VARIANT FOR
EXAMPLE, DO IN THE EXIST IN THE
EUROPEAN AND ASIAN, THAT MEANS
YOU WILL NOT FIND THOSE VARIANT
IF YOU PERFORM THE STUDY ONLY ON
ASIANS, IT IS NOT IN THAT
POPULATION.
FOR THE RESULT OF BMI, THIS IS
MORE DRASTIC, ALL THE LEAD
VARIANT WE FOUND AND
[INDISCERNIBLE].
THAT MEANS THIS VARIANT IS
AFRICA SPECIFIC.
SO IT ALSO SUGGESTS THAT IF THIS
VARIANT WAS ALSO TO BE USED FOR
ANY MANIPULATION, THERE IS NO
WAY [INDISCERNIBLE] AND YOU WILL
HEAR THIS STORY AGAIN AND AGAIN
DURING THIS ECTOMYOSIN WELLURE.
SO THE KEY NUMBER 2 IS FINDING
MARKERS THAT MAY ALLOW US TO BE
TARGETED [INDISCERNIBLE].
THE [INDISCERNIBLE] WHICH IS THE
MODIFICATION OF [INDISCERNIBLE]
THERAPEUTICS.
A VERY LONG TIME AGO, IN THE
STUDY AS SHOWNOT PANEL ON THE
LEFT-HAND SIDE, IT SHOWED IF YOU
HAVE HIGH LEVEL OF
[INDISCERNIBLE], YOU WILL LIVE
MUCH LONGER, THIS QUANTITATIVE
SUBJEK, AND THERE IS MEASURABLE,
ASSOCIATED, WITH THE INHIBIT
ANTS OF THE HEMODPLOABIN WITH
THE POPULATION, AMERICAN OR SOME
CELLS WITH THIS PATIENT IN
AFRICA.
NOW THE POPULATION OF 1 OF THE
GENES CALLED BCL11 A FOR THE
TREATMENT OF SICKLE CELL
DISEASE, AND THIS WAS APPROVED
BY THE FTA ON DECEMBER 8th OF
LAST YEAR, THIS WAS THE FIRST
PATIENT VICTORIA GRAY WHO WAS
TREATED A FEW YEARS BEFORE USING
THAT,A PROACH FOR SICKLE CELL
DISEASE.
DEFINITIVE TREATMENT BY
MODIFYING THAT GENE THAT
CONTROLLED FOR THE HEMEAT O
DPLOABIN.
I WILL REPEAT THAT THE STORY
SHOULD NOT STOP THERE AND IT
NEEDS TO BE EXPANDED FOR EXAMPLE
BY INVESTIGATING THE AFRICAN
POPULATION.
BCL11 THAT'S WELL KNOWN, LOI MYB
THAT'S LESS KNOWN AND THE 1
AROUND [INDISCERNIBLE], THE
COMBINATION OF THE 3 EXPLAIN
[INDISCERNIBLE] IN THE
POPULATION IN ANCESTRY.
BUT IF YOU DO THE SAME ANALYSIS
FOR AVAILABLE DATA INCLUDING OUR
OWN DATA IN POPULATION, MAXIMUM
50% ISSUES THERE WAS INDEED FROM
NIGERIA PUBLISHED YESTERDAY OR
TODAY IN THAT POPULATION EXPLAIN
EXACTLY 14% [INDISCERNIBLE].
THAT MEANS WE STILL HAVE 80%
MISSING [INDISCERNIBLE] JUST FOR
THE LEVEL IN POPULATION OF
AFRICA ANCESTRY AND ALL OF THEM
A POTENTIAL TARGET FOR
THERAPEUTICS.
SOMEONE WILL ARGUE THAT THE GWAS
WERE PUBLISHED 10 YEARS AGO FROM
A POPULATION IN TANZANIA, AND
THIS IS FROM CHROME ON STUDIES
OF MULTIPLE ENDOCRINE 2 AND
YAWBD FROM CHROMOSOME 6,
ALLOWING THERE WAS 1 PROBLEM
WITH GWAS, THE 1 PROBLEM WAS THE
USE OF AFFYMETRIC 6, THAT WAS
DEVELOPED ON THE BACK GROUPED OF
EUROPEAN HAPLOTYPE.
NOW REMEMBER THOSE HAPLOTYPE ARE
LONGER, THAT MEANS YOU MAY NOT
HAVE ALL THE TIME THAT MAY
IDENTIFY FOR PATIENT ASSOCIATION
OF GENES.
THOSE HAPPEN LO DOZE USING GY,
BIEWSED ON THE EUROPEAN
HAPLOTYPE HAVE ALREADY BEEN
SHOWN THAT THEY DO NOT
[INDISCERNIBLE] FOR QUANTITATIVE
THREAD, AND SHOWN ON PURPLE IN
THIS SLIDE.
LET'S GO BACK, PRESENTING ON THE
POSTER GAME, [INDISCERNIBLE],
MANY THINGS HAPPEN OVER THE PAST
300,000 YEARS IN AFRICA,
MIGRATION WITHIN AFRICA,
MIGRATION OUT OF AFRICA,
MIGRATION BACK TO APRICKA.
IF YOU HAVE A CONTINENT THAT'S
ON THE SOUTH AXIS, DIVERSE LAYER
OF DIRECT CLIMATE, THE FOOD AND
INFECTION, HAVE YOU DIFFERENT
TYPE OF NATURAL SELECTION, YOU
KNOW GENOME THAT CHANGES
DRASTICALLY, WITH THAT SPECIFIC
GENOME COMPOSITION.
THESE HAVE BEEN SHOWN AGAIN AND
AGAIN BY A STUDY FROM AFRICA
FROM A COUPLE YEARS BACK AND BY
SHOWING THIS BIG DIVERSITY IN
THAT STUDY, WE TOOK THE
OPPORTUNITY TO DECIDE A GWAS
STUDY THAT [INDISCERNIBLE] VALUE
SHEET USING ABOUT 500 CHROMOSOME
AND HOPEFULLY TRY TO TAKE
ADVANTAGE OF THE SHORTER
HAPLOTYPE THAT WE ALREADY KNEW
BEFORE THAT WOULD IMPROVE THE
FINE MAPPING IN GWAS.
SO THESE ARE WHERE THE GNA WERE
TAKEN, WERE TAKEN TO DEVELOP
ALLEY, WE SAW THAT 2.5%.
WE USE THE VERY SAME
[INDISCERNIBLE] TO PERFORM
AGAINST IN POPULATION TO
DETERMINE SICKLE CELL DISEASE
FROM CAMMA ROON.
FOR THOSE THAT DO NOT KNOW WHERE
CAMEROON WAS AT, IT IS IN AFFRIC
AIT'S A HIGHLY DIVERSE
POPULATION LIVING IN CAMEROON,
THIS IS PROBABLY THE PERFECT
PLACE TO PERFORM SUCH STUDY.
SO THESE ARE THE 2 CLINIC THAT
DID THE HARD WORK ON THE GROUND
BUT WITH THE EQUIPMENT AND
[INDISCERNIBLE], DID ALL THE
ANALYSIS.
AND BEFORE WE DID AANALYSIS, WE
WANTED TO KNOW WHICH WOULD BE
THE BEST AMPUTATION PANEL OF OUR
GWAS, SO WE DID A COMPARATIVE
ANALYSIS OF ALL THIS, OF
6-AMPUTATION PANEL THAT WE KNOW,
OF AT THE MOMENT, THE FITTER
PANEL IS THE TOP MET 1, JUST
DAYS ON THE NUMBER OF VARIANT,
THE PANEL SEEMS TO BE THE BEST
TREATED FOR OUR STUDY.
WE ALSO MEASUREOT AMPUTATION,
AGAIN, THE TOP MET PANEL SEEMS
TO BE THE MOST ACCURATE BUT YOU
CANNOT [INDISCERNIBLE]
CHROMOSOME 19 ALL PANELS SEEM TO
BE LESS [INDISCERNIBLE].
THAT I THINK THAT WILL BE A
STORY OF A DIFFERENT DAY.
WHEN WE ALSO LOOK AT THE
ACCURACY BASAL MINOR FREQUENCY,
AGAIN THE PANEL SEEMS TO BE THE
BEST PANEL FOR THE STUDY IN
AFRICAN POPULATION AND LASTLY,
WHEN WE LOOK AT THE NUMBER OF
VARIANT ACROSS PANEL, ACTUALLY
WE REALIZE THAT THOSE 6 PANELS
SHARE ONLY ONE-THIRD OF THE
VARIANT, AND EACH OF THEM HAVE
SPECIFIC VARIANT THAT OTHER
PANELS DO NOT HAVE, WHAT DOES
THAT--IT MEANS IF YOU ARE NOT
DOING A GWAS BASED ON GENOMES,
IF YOU ARE WORKING ON THE
POPULATION, THAT HAVE NOT BEEN
STUDIED, YOU BETTER USE AS MUCH
PANEL AS YOU CAN BECAUSE THE
TRUTH IS NOT IN 1.
IF YOU CAN CHOOSE 1, YOU SHOULD
[INDISCERNIBLE].
IF YOU CAN, ON MANY PANEL, TRY
TO DO IT.
SO THAT MESSAGE I JUST DID NOW,
WHAT WE DID IS WE START BY STAGE
1 ON OUR DISCOVERY CARD IN
CAMEROON, WE ANALYZE THE DATA
FROM TANZANIA USING THE IMPROVED
PANEL WE HAVE NOW.
WE PERFORMED ANALYSIS ON AFRICAN
BASED COHORT, WE PAY FOR
TBLOABAL ANALYSIS BY ADDING ALL
THE DATA WE HAVE FROM AMERICAN
FROM VARIOUS COHORT, ABOUT 7
COHORT IN AMERICA, AND I MUST
SAY ALL THE THIS WE HAD FOR THE
STUDY WAS VERY [INDISCERNIBLE]
TO SHARE THE DATA, IT WAS
DIFFICULT TO HAVE THE DATA FROM
THE COHORT THAT WE REQUESTED TO
HAVE ACCESS TO.
AND THESE ARE THE DATA.
THE FIRST LINE IS THE DORPHY
COHORT, SHOWING THE B-CELL
RELEVANT THAT'S REPLICATED ON
THE THAT AND CLEARLY IN LOCI,
[INDISCERNIBLE] 1.
THE SECOND PATTERN IS THE AFRICA
BASED COHORT META-ANALYSIS, CAN
YOU REALIZE THIS ARE 7 NEW LOCI
AND THE THIRD IS THE GLOBAL
META-ANALYSIS TO THE TRADITIONAL
LOCI, AND THE WAY WE HAVE THE
ABILITY, BEFORE THE STUDY WE HAD
THE ABILITY OF LESS THAN 20%,
AFTER THIS, USING H3 AFRICAN
SPECIFIC [INDISCERNIBLE], WE
HAVE THE ABILITY OF 90%.
AND THIS 90% OF THE ABILITY IS
THE EXACT SAME THAT WAS FOUND IN
THE FIRST STUDY PERFORMED IN THE
UK POPULATION USING
[INDISCERNIBLE] STUDY, SO THAT
WE HAVE CLOSE TO WHAT THE NATURE
AND [INDISCERNIBLE] AFRICAN
SPECIFICALLY.
SO THE PAPER, IN THIS
RATEABILITY WE USE IT--IT'S
STILL ABOUT 50% COMPARED TO WHAT
WE KNEW BEFORE.
--THIS CHAIN WAS OR SEEMED TO BE
ACROSS THE PANEL THAT WE USE, IT
SEEMS TO BE THE SECOND.
AGAIN, THE VALUE WE FOUND WAS
THE FIRST GROUP OF BAD CHART,
AND BE FOUND THAT TAN SWRANNIAN,
ARE MOSTLY AMERICAN, AND WE
FOUND A FEW CATEGORY POPULATIONS
THAT MOST OF THEM ARE EUROPEAN
AND AFRICAN POPULATION, AGAIN IF
YOU DON'T DO THAT IN THE
POPULATION, YOU DON'T SEE IT, AS
SIMPLE AS THAT.
AND SOMEONE WILL SAY WHY IS THAT
THE GWAS NOT FIND IT JUST
BECAUSE THE HAPLOTYPE AROUND A
IF YOU TAKE AN AFRICAN DIET FROM
CAMEROON, GENETICALLY IT WILL BE
SO DIFFERENT FROM A GUY IN
[INDISCERNIBLE], AS FOR EXAMPLE,
SOMEONE [INDISCERNIBLE].
BECAUSE OF THE [INDISCERNIBLE]
OF THE MODIFICATION THAT
HAPPENED 300,000 YEARS WITHIN
AFRICA BECAUSE OF LIVING WITHIN
AFRICA, IT SUGGESTS THAT
REPLICATION OF GWAS STUDY, EVEN
WITHIN AFRICAN MIGHT BE
DIFFICULT BECAUSE THE DIVERSITY
IS TOO HUGE, BECAUSE THE PABLE
WILL NOT NECESSARILY CAPTURE
WHAT YOU WANT TO SEE.
SO IF WE FINE MAP, THIS HERE, WE
REALIZE THAT MOST OF THE VARIANT
THAT THE GWAS SIGNIFICANT AND
NOT ACTUALLY ON THE CORRECT LINE
FOR THE TRANSCRIPT OHM, THAT
SIDE, BEFORE THAT, WE SEE A
GROUP OF ENHANCER, TO SPARE
ABOUT 50 KB BEFORE THE
TRANSCRIPTION SITE AND THIS IS
WHERE MOST OF OUR VARIANTS ARE
FOUND.
WE TRIED TO TRACK THE RELATION
WITH TD VARIANT AND POTENTIAL
BYPASSING SITE AND THE GENES ARE
LOCATED THERE.
AND WE LOOK AT THE ATAQSEQ LOAD
AND REALIZED THAT EEIVETTIVELY
WHERE WE HAVE MOST OF THE
VARIANT THAT GWAS HAVE
SIGNIFICANT ENHANCER ACTIVITY.
AND BELOW, ON THE CHART BELOW,
WE CAN SEE THAT, AND THE 1 IN
THE MISD IS MOST INTERESTING,
THE BAND THERE IS GIF01 AND THAT
VARIANT IS SOAB WIDE UP TO 40%
OF THE [INDISCERNIBLE] THE
CUT-OFF FOR A MANIPULATION IS
USUALLY AROUND 20%.
WHAT HAPPEN FIST YOU KNOCK OUT A
GENE, IF YOU KNOCK OUT THE YEEN,
THE MICE SURVIVE, WE DON'T DO
IT, AND THE MICE DOESN'T SURVIVE
BUZZ THE MICE DOESN'T MAKE BLOOD
VESSEL AND THE MICE DOESN'T MAKE
BLOOD AT ALL.
AND THAT YEEN, ANOTHER GENE WHEN
WE LOOK AT IT, THE KNOCK OUT
AGAIN DOESN'T ALLOW THE
[INDISCERNIBLE] OF THAT MICE.
SO THAT MEANS IF WE WANT TO
EXPLORE THIS GENE AT THE
MOLECULAR LEVEL, YOU NEED TO
HAVE A CONDITIONAL KNOCK OUT.
SO BECAUSE WE WANTED TO KNOW HOW
DID THIS GENE ACTUALLY WORK, WE
JUST DID THE SIMPLE THING THAT 1
OF MY FRIEND, [INDISCERNIBLE]
AND WE REALIZE THAT
[INDISCERNIBLE] BELONGED TO THE
PATHWAY OF HYPOXIA AND THAT
PATHWAY IS DIRECTLY CONNECTED TO
THE [INDISCERNIBLE] PRODUCK, WE
ARE STARTING TO GET IN CLOSER TO
THE MECHANISM.
AND WHAT WHY IS A PATHWAY OF
HYPOXIA IMPORTANT FOR
[INDISCERNIBLE] PRODUCTION, WE
DID NOT DO THE WORK, SOMEONE
ELSE ALREADY SHOWN THAT I POXIA
INDUCIBLE FACTOR A, THAT WAS
DISCOVERED BY DR. GREG ZEPHYR
.
SO OUR CURRENT DIAGNOSIS IS THAT
1 CAN INCREASE CAN ALLOW FOR
[INDISCERNIBLE] PRODUCTION
PRODUCTION OF F-CELLS, PAIR UP
OF [INDISCERNIBLE] AND
ENHANCERS.
SO WE HAVE A MODEL WE TRYING TO
EXPERIMENTAL VERY FINAL THIS
MODEL IS COMPLEX, BUT IT'S
IMPORTANT FOR US TO HAVE A
COMPLEX, BECAUSE EACH OF THE
LINE, EACH OF THE STICK WILL BE
VERIFIED EXPERIMENTAL.
SO, THE FIRST THING TO DO FOR US
WAS TO KNOCK OUT THAT GENE, AND
UDEPRIVATION CELL LINE, AND THAT
IS THE CLASSICAL CELL LINE THAT
I USED TO EXPLORE PRODUCTION FOR
BCL11A, AND THIS BCL11A, NEW
SALE LINE ASSOCIATE AS CAN YOU
SEE HIGH PRODUCTION OF
[INDISCERNIBLE] BUT THE DELETION
OF [INDISCERNIBLE] 1 IS NOT
ASSOCIATE TD WITH IT AT ALL.
IT IS NOT EXPRESSING THIS ALIKE.
THIS MEANS IT'S NOT THE
[INDISCERNIBLE].
SO WE LOOK AT THE LITERATE AND
YOU ARE LOOK AT THE EXPRESSION
OF F LT1 BELOW AT A TIME.
THE 1 BELOW IS THE RED BLOOD
CELL, AS CAN YOU OBSERVE BLUE
MEANS IT'S NOT EXPRESSING THE
DOUBLE RED BLOOD CELLS AS WEB
CONNECTED EXPECTED.
IF YOU MOVE UPWARDS YOU RAZE
THAT THIS IS A BETA CELLS IN
EACH, IN B-CELL LINEAGE, AND
PERHAPS IN THE HEMATOPOIETIC
STEM CELL, THAT MEANS SHOULD
SHOULD BE THE MODEL THAT WE
SHOULD USE.
GOING TO [INDISCERNIBLE].
WE NOW USE K562, WHICH IS
[INDISCERNIBLE] CELL LINE, AND
WE EXPOSE THEM TO HYPOXIA AND
FLT1, AND IT INCREASEOT RIGHT
HAND SIDE, THE BAR IN RED, WITH
EXPOSURE OF K56 TO THE HYPOXIA
AND THAT HYPOXIA ASSURES US
INCREASING OF HIERK F ALPHA,
WHICH AGAIN IS VERY REASSURING
TO US BECAUSE THAT MEANS THAT
THERE IS A RELATION BETWEEN FLT1
AND HIFA, AND WE ALWAYS REALIZE
THAT KNF 1 SPECIFICALLY AT THE
TIME OF THE [INDISCERNIBLE]
SEEMS TO BE INCREASED AT THE
SAME TIME, AGAIN, UP UNTIL THEN,
WE STILL DON'T HAVE THE
MECHANISM.
SO LET'S GO BACK TO THE MAP.
BY LOOKING AT THE AREA OF THE
FIRE MAP WHERE WE FOCUS ON 1
SPECIFIC GENE CALLED GIF1, AND
WE KNOW THE MODIFIER FOR THE
[INDISCERNIBLE].
THE ATAC-SEQ INFORMATION AGAIN,
I THINK THE EXPERIMENT WE DID
LAST WEEK, I THINK IT WAS THE
LAST TIME I PRESENT THIS
PUBLICLY, WE XOK OUT THAT
REGION, WE DID 2 EXHIBITING OUT,
THE FITTER KNOCK OUT WAS THE
WHOLE REGION, THE SECOND KNOCK
OUT WAS JUST THE AREA WHERE WE
THINK WE HAVE BINDING SIDE OF
GIF-1 AND WE HAVE A 3.74
INCREASE OF FLT1 AND 4.16
INCREASE.
SO I THINK WE ARE GETTING CLOSE
TO THE MECHANISMS.
WE BELIEVE THAT THE REGION WHERE
WE FOUND THE GY SALARY ARE SOME
PERTURBED THE BINDING SITE ON 1
OF THE [INDISCERNIBLE] OF FLT1,
SO OF COURSE WE HAVE TO HAVE 1
OR 2 OF THE EXPERIMENT TO SHOW
THAT.
WE MOVE TO THE CD34, WHICH IS A
NATURAL LINE AND CLOSER TO WHAT
WE SHOULD SEE IN ADULT BECAUSE
K562, IS THE CONTROL, SO IT
BEHAVES SOMETIME STRANGELY
INVITRO, BY TALKING OUT FLT1, IN
CD34, AND ALSO KNOCK OUT IT
BCL11 AS A CONTROL EXPERIMENT,
THE VARIABILITY UNDER THE
COVERRABILITY OF THE CELL ARE
VERY ACCEPTABLE.
AND WE NOW CULTURE AND
DIFFERENTIATE THOSE CELLS ON
THAT INHIBITION OF FLT1 AND YOU
CAN SEE THAT WHEN YOU INHIBIT
THE [INDISCERNIBLE] ON THE
VASCULAR AND GROWTH FACTOR
THERE'S NO GROWTH OF
[INDISCERNIBLE] AT ALL.
AND WE REPEAT THIS EXPERIMENT IN
A VERY DIFFERENT WAY, MEASURING
CELL, AGAIN, THERE IS NO
PRODUCTION, OF FLT-AMOUNT OF
EXPERIENCE O GLOBIN AND THAT IS
REDUCED UNDER HYPOXIA.
SO A LOT HAVE BEEN REFEIGNED WE
BELIEVE FLT 1 IS ASSOCIATE WIDE
INDUCED [INDISCERNIBLE]
POTENTIALLY, WE ALREADY HAVE 2
ON POTENTIAL GENES THAT WILL BE
INVOLVE THAD WILL GUIDE OUR NEXT
EXPERIMENT.
AND I WILL STOP THERE FOR THIS
PART.
SO THIS IS THE LIMPIFIED MODEL
THAT WE HAVE AND WE WILL TRY TO
FOLLOW ALL THE QUESTION MARKS OF
EXPERIMENT THAT WE NEED TO
DECIDE AND PERFORM TO TRY TO
UNDERSTAND WHY AND WHY FLT1 IS
THE NEXT TARGET FOR SICKLE CELL
DISEASE, FOR THERAPEUTICS AND WE
NEED TO PUSH LIKE MANY OTHERS
ARE PUSHING HERE TO FIND A NEW
TARGET BECAUSE UNLIKE VICTORIA
GRAY, THERE ARE MANY PATIENTS IN
AFRICA THAT WILL NOT HAVE ACCESS
IF YOU DON'T MAKE DOSE 30 AND TO
MAKE IT THERAPEUTABLE, THIS IS 1
OF OUR PASHTS FROM CAPE TOWN,
HE'S SICKLE CELL DISEASE, HE'S A
GRADUATE STUDENT AND BELIEVER OF
GENE EDITING OR THERAPY FOR SICK
ELITE EXECUTIVE DISEASE.
I WILL MOVE TO KEY 4 AND 5, THE
KEY 4 AND 5 LESS CLOSE AFTER
TRANSLATION, THEY ARE MORE
[INDISCERNIBLE].
I THINK 1 OF THE PERSPECTIVE OF
YEEN THERAPY OF SICK CELL CELL
DISEASE TO EXPLORE RNA, FOR
EXAMPLE HYDROXY URIA, IS
TRADITIONAL FOR SICKLE CELL
DISEASE, WE DON'T KNOW IT MAY
ACT AS TRUE MIKE ARE RNA AND
THIS IF THATIA TRUE WE CAN
PACKAGE IT IN A SPECIFIC WAY TO
MODIFY FOR EXAMPLE,
[INDISCERNIBLE] PRODUCTION
WITHOUT CHANGING THE WHOLE
TRANSCRIPT ORDER OF MICRONSIC,
WE CAN ALSO PACKAGE MICRORNA
JUST FOR HEMODPLOABIN A, ITSELF,
WE KNOW THAT WORKING FOR
COVID-19 FOR EXAMPLE, VACCINE,
WHY SHOULD IT WORK FOR EXAMPLE,
IN SICKLE CELL DISEASE?
ANOTHER UNSOLVED QUESTION IS
RARE VARIANT OF SICKLE CELL
DISEASE, THAT WAS ENTIRELY POSED
BY A PATIENT AND FRIEND AND HE'S
ABOUT 63 TODAY, HE LIVES WITH
SICKLE CELL DISEASE, HE IS THE
LEADER OF THE SICKLE CELL
SUPPORT GROUP IN
[INDISCERNIBLE].
AND HE ASKED ME WHY DID I
SURVIVE.
AND I SAID I DON'T KNOW.
HE SAID I NEVER TOOK PROPER
TREATMENT BUT WHY I DEPARTMENT
DIE LIKE MANY OTHERS.
I SAID MAYBE YOU HAVE GOOD GENES
AND THEN MAYBE YOU HAVE GOOD
JEEPS AND THEN I WAS THINKING HE
MAY HAVE GOOD GENES AND THEN I
LOOK FOR PEOPLE LIKE HIM, 25 OF
THEM THAT SURVIVE IN AFRICA
WITHOUT TREATMENT.
IT WAS HARD TO FIND IT AND I
LOOK AT THE REVERSE, THE REVERSE
SHOULD BE PEOPLE WHO HAVE THAT
TREATMENT, I COULDN'T FIND THOSE
BECAUSE [INDISCERNIBLE].
SO SECOND BASE WAS THOSE WHO
HAVE STROKE BEFORE YOU'RE 10 AND
A WHOLE SEQUENCE, WHOLE EXOHM
SEQUENCE 2 OR 3 AND WE HAVE A
MITSD GROUP LOWER THAN 50 YEARS
OLD AND WITHOUT STROKE AND BY
DOING SO REALIZE THAT ACTUALLY
THE LONG SURVIVOR, HAVE MUTATION
IN THE IMPORTANT YEEN, 1 THAT'S
CHLORIDE, CHANNEL, THE SECOND 1
THAT'S A YEEN THAT MODIFY
L-GLUTEA MIN, YOU KNOW IT WAS
APPROVED BY THE FDA LIKE IN 2017
FOR THE TREATMENT OF SICKLE CELL
DISEASE, SO SUGGESTING THAT
MAYBE SOME OF THESE PATIENTS
LONG SURVIVORS HAVE RECURRENT
VARIANT THAT ALLOWED THEM TO
HAVE PRODUCTION OF L-GLUTEA
MINE.
AND THEN AGAIN WE LOOK WHEN WE
DO THOSE THINGS YOU THINK YOU
MIGHT BE CRAZY RIGHT?
AND THEN WE WENT IN AND
LITERATURE AND LOOKAD THE
TRANSCRIPTOMIC DATA FROM
COMPLETELY DIFFERENT OTHER
PEOPLE AND THEY EXACTLY THE SAME
PATHWAY, NOT USING EXORDER OF
MICRONS DATA BUT THE BLOOD
TRANSCREPT ORDER OF MICRONSIC,
AND THESE ARE THE DATA IN THAT
PAPER.
YOU MAY NOT KNOW, THIS GUY, IS
MY
MY COUSIN OF A DIFFERENT TIME
BECAUSE OF MY NIEWBIAN ANCESTRY,
BUT [INDISCERNIBLE] MAY HAVE
DIED FROM SICKLE CELL DISEASE,
AND THE WAY WE KNOW IT IS THAT
THERE IS A WAY TO STUDY HIS
BONES AND KNOW HE HAS THE
DISEASE AND HE TIED 5000 YEARS
AGO AND IF HE HAD IT 5000 YEARS
AGO, IT SUGGEST IT SHOULD HAVE
BEEN FIXED IN THE POPULATION
LONG BEFORE THAT, IT ALSO
SUGJERTS THAT OVER THE LAST 5000
YEARS, THERE ARE MANY PEOPLE,
SICKLE CELL MAY HAVE PUT
PRESSURE ON OUR OWN GENOME AND
POTENTIALLY SELECT SOME OF THE
VARIANT IN A SIMILAR WAY MALARIA
SELECTED ENVIRONMENT IN THE
YEERN, WE SELECTED THE
HYPOTHESIS, USING THE DATA FROM
THE SICKLE CELL DISEASE, FROM
CAMEROON AND CONGO AND COMPARE
POTENTIAL SELECTION TO A
POPULATION THAT WERE
[INDISCERNIBLE].
IT WAS HOMOZYGOUS, IT IS, AND
THAT HOMOZYGOUS IS THE FESTER
MANHATTAN PLOT, ALL OTHER
MANHATTAN PLOT FROM SICKLE CELL
COHORT AND YOU CAN IDENTIFY
MUTATIONS IN CHROMOSOME 11 IN
BLUE BUT AT LEAST 2 AREA IN
VARIOUS COHORT THAT ARE SELECTED
OR NATURALLY SELECTED IN OUR
GENOME AND THE JEERNS ASSOCIATED
IN THOSE AREA OF SELECTION ARE
ON THE LOWER RIGHT.
I DON'T THINK THE DATA ARE
PUBLISHABLE, ACTUALLY THESE DATA
ARE PRELIMINARY BECAUSE IF YOU
WANT TO DO A PROPER SELECTION
AND ANALYSIS, YOU NEED TO DO THE
EXACT SAME ANALYSIS ON THE
GENERAL POPULATION, WE DID NOT
DO IT IN THIS SPECIFIC STUDY,
THIS WAS JUST PRELIMINARY BUT WE
HAVE NOW, THE POWER, THE NUMBER,
THE SEQUENCE TO PERFORM THIS
STUDIES BECAUSE WE HAVE ENOUGH
GENOMES AND ENOUGH SAMPLES FOR
THE STUDY.
ANOTHER QUESTION WE SHOULD
INVESTIGATE IS THE EVOLUTION OF
SICKLE CELL BARRIERS OR THAT
AREA.
FOR EXAMPLE, 1 OF MY STUDENTS
KEVIN HE DID THIS HEAT MAP
STUDY, SHOWING FOR EXAMPLE, THAT
SICKLE CELL DISEASE,
[INDISCERNIBLE] AND AFTER A MAP
OF THE AREA IN AFRICA, THAT
MEANS THAT THE GOOD AFRICAN
MYSELF I MAY HAVE THE 3 VARIANTS
IN MY BLOOD, WE KNOW WHAT IT
WOULD DO, IF SOME VARIANT WILL
LEAD YOU TO HAVE MORE KIDNEY
DISEASE THAN OTHERS.
AND IT ACTUALLY PROTECTIONS YOU
AGAINST KIDNEY DISEASE, WHAT IF
YOU HAVE THE COP BINNATION OF
ALL OF THEM?
SO YOUNG MIND AND CLEVER MIND
NEED TO WORK ON MODELS ON HOW
THESE ISHT ACT TOGETHER, THESE
ARE DATA FROM MARIA, A PROJECT
THAT SHOWED THAT THERE'S NOT
JUST [INDISCERNIBLE] SELECT FOR
MALARIA, THESE ARE RECENTLY
PUBLISHED FROM OUR LAB, WE FOUND
2 [INDISCERNIBLE], AND SPECIFIC,
AND THE LASTLY, THE RESULT
QUESTION IS WHERE THE SICKLE
CELL DEC COME FROM.
THE 50 POPULATION CLEANING FOR
SICKLE CELL DEC WAS NOT IN
AFFRIC AHE WAS IN GREECE AND
SICKLE SEALS IN GREECE HAVE BEEN
THERE FOR A LOCK TIME, AND
SICKLE CELL IN DEC IN PEOPLE IN
THE SOUTHERN PART OF ITALY AND
THEY HAVE BEEN THERE FOR A LONG
TIME.
SICKLE CELL DISEASE HAVE BEEN
[INDISCERNIBLE] FOR A VERY LONG
TIME.
IF WE ARE [INDISCERNIBLE] SICKLE
CELL EVOLVE IN AFRICA, LET'S SAY
20,000 YEARS AGO, HOW DOES THAT
MUTATION HAPPEN TO GO TO GREECE?
SO SOMEONE SHOULD HAVE RUN, SWAM
AND LANDED IN GREECE AND MIXED
AND LET SICKLE CELL DISEASE IN
THERE, AND THE SAME PERSON OR
SISTER OR COUSIN, PROBABLY MOVED
TO THE MITSD EAST OR INDIA AT
THE SAME TIME, ACTUALLY WE HAVE
NO IDEA, WE HAVE NO IDEA
EVOLUTIONARY POPULATION WIDE HOW
IT LANDED IN OUR PART OF THE
WORLD.
AND WE ARE UNAWARE OF WHERE IT
COMES FROM IN THE FIRST PLACE.
SO THOSE ARE SOME STUDIES WE
KNOW SHOULD BE DONE.
FOR EXAMPLE WE DID A SIMPLE
ANALYSIS LOOKING AT THE
HAPLOTYPE AND YOU SLEEP APNEA
AND OBESITYY A LOT OF DIVERSITY
WITHIN 4 OR 5 DIFFERENT GROUP IN
AFROM FRICCA.
THIS MEANS THERE HAVE BEEN A LOT
OF MIXTURE OR MOVEMENTOT
COMBINATION AROUND IN THAT AREA
ASK THATY WE HAVEN'T YET
PROPERLY CAPTURE AND WE KNOW
THAT ALL THOSE COMBINATION
LISTENED WITH SINGLE ORIGINAL
SHOWN BY [INDISCERNIBLE] AND HIS
PAPER, NOW, WE SHOULD BE ABLE TO
REFINE THE ORIGINAL SICKLE CELL
DEC BY USING [INDISCERNIBLE].
FOR EXAMPLE, THEY ARE CURRENTLY
[INDISCERNIBLE] FOR A GROUP OF
PEOPLE THAT LIVE IN SOME PLACE
TODAY, CALLED CAMEROON 8000
YEARS AGO.
IF WE STUDIED THOSE DNA PROPERLY
BETTER WE COULD KNOW BETTER WHEN
THE DISEASE IMETS SPONTANEOUS
ACTIVITY THE POPULATION IN A
CERTAIN WAY, IN A SIMILAR WAY,
WE WOULD BE ABLE TO NOX FAMILY
--NAVIGATE
THE PATH OF MIGRATION WITHIN THE
COUNTRY AND NOW THE CONTINENT.
SO I HOPE I CONVINCED YOU OF 3
THINGS ISSUES THE FIRST IS THAT
WE USE IME NATIONAL LIBRARY OF
MEDICINIC VARIATION IN AFRICA TO
DISCOVER A NEW VARIANT AT
MODIFYING THE CLINICAL
EXPRESSION OF SICKLE CELL
DISEASE ISSUE THE SECOND, THE
BEST MODIFIER OF SICKLE CELL
DISEASE AND [INDISCERNIBLE] BUT
THE MISSION IRRITABILITY OF THE
BETA GLOBIN CAN BE FOUND IN
AFRICAN GENOMES AND CAN OPEN UP
FOR MANIPULATION, THE THIRD IS
THAT THERE IS STILL AN AREA THAT
YOU CAN EXPLORE FOR THE AREA OF
SICKLE CELL DISEASE, BUT ALSO
THE EVOLUTIONARY OF SICKLE CELL
DISEASE, ESPECIALLY IN THE
GENOME, THAT CAN OPEN UP AGAIN A
NEW TARGET FOR THERAPEUTICS THAT
SHOULD GO AS THE WAY WE IMAGINE
IT AS SCIENTISTS AND WE HOPE
THAT IN A COUPLE YEARS IT WILL
BE THE WORLD THE WAY WE LEAVE IT
FOR THE PATIENTS OF SICKLE CELL
DISEASE, THANK YOU VERY MUCH.
>> GREAT.
THANKS A LOT.
WE HAVE A HAND HELD FLOATING
AROUND.
THOSE WERE REALLY FABULOUS
PRESENTATIONS FROM BOTH OF OUR
SPEAKERS TODAY AND WELL'S JUST A
WHOLE PANOPLY OF QUESTIONS THAT
HAVE BEEN SUBMITTED BOTH ONLINE
AND I KNOW THERE ARE PROBABLY
SOME INQUIRING MINDS HERE IN THE
ROOM JUST WAITING TO POSE THEIR
QUESTIONS AS WELL.
O I'LL TART WITH 1 THAT IS TIME
HONORED, NOT TO MAKE A PUN,
QUESTION, WITH REGARD TO THE
TREATMENT OF SICKLE CELL DISEASE
IN THE UNITED STATES AND PERHAPS
THIS WOULD GO TO DR. FITZHUGH
FIRST BUT I THINK DR. WONKAM MAY
HAVE THOUGHTS ABOUT IT, TOO.
AND THAT WOULD BE WHAT IS THE
OPTIMAL AGE FOR TRANSPLANTATION
FOR SICKLE CELL DISEASE, JUST
BASED ON THE FACT THAT
HEMATOPOIETIC STEM CELL
TRANSPLANT IS SOMETHING THAT'S
BEING DONE A LOT IN PATIENTS
WITH PRIMARY IMMUNO DEFICIENCY
DISEASES AND OFTEN TIMES THE
PREFERENCE IS TO TRANSPLANT
THOSE PATIENTS AS EARLY AS
POSSIBLE BECAUSE THE OUTCOMES
OFTEN TIMES ARE A LOT BETTER,
THE EARLIER 1 INTERVENES.
SO HAVE THERE BEEN ANY STUDIES
DONE IN YOUNG CHILDREN WITH
REGARD TO TRANSPLANT AND ARE
THERE ANY DATA WITH REGARD TO
OPTIMAL AGE.
NTHAT'S A GREAT QUESTION AND THE
WAY I ANSWER IT IS IT MIGHT NOT
BE HOW EVERYBODY WOULD ANSWER IT
BUT I CAN SAY THAT THE ISSUE
WITH THIS QUESTION IN SICKLE
CELL DISEASE IS SURVIVAL IN THE
UNITED STATES IS REALLY, REALLY
HIGH.
NINETY-EIGHT% OF CHILDREN WILL
SURVIVE TO ADULTHOOD WITH SICKLE
CELL DISEASE, SO IF YOU HAVE ANY
SIGNIFICANT MORTALITY ASSOCIATED
WITH THESE, INVESTIGATIONAL
CURATIVE THERAPIES, IT'S A BIG
DEAL IN CHILDREN, AND YOU ALSO
CAN'T PREDICT WHO WILL HAVE THE
MORE SEVERE DISEASE, SO, IT'S
NOT LIKE YOU CAN--YOU CAN LOOK
AT THIS HEALTHY CHILD AND SAY
YOU HAVE THIS GENETIC RISK
FACTOR, YOU WILL HAVE SEVERE
DISEASE, YOU JUSTIFY HAVING THIS
TRANSPLANT AT SUCH A YOUNG AGE.
THERE HAVE BEEN STUDIES TO SHOW
WITH DATA GOING BACK TO THE
1980S THAT THE YOUNGER PASHTS DO
HAVE BETTER OUTCOMES BUT NOW
THAT WE HAVE NONMILE O ABLAISIVE
CONDITIONING, AND ENOUGH THAT
I'VE SHOWN THE SURVIVAL IN
ADULTS NOW, IT'S A CONTROVERSIAL
QUESTION, THE NEW GENE THERAPY,
EDITING STUDIES HAVE BEEN
ENCLOUDING CHILDREN, AND THERE
ARE SOME RISKS ASSOCIATED WITH
TRANSPLANTING ADULTS AND ALSO
ONCE PATIENTS ARE ON DIALYSIS
AND HAVE SEVERE ORGAN
DYSFUNCTION, IT'S NOT
REVERSIBLE, SO MY FREE RADICALS
FERENCE, SINCE I'M GOING FIRST
IN HUMAN STUDY SYSTEM TO INCLUDE
ADULTS BUT WHEN WE GET MORE DATA
THE GOAL WOULD BE TO START
TRANSPLANTING CHILDREN, WITH THE
EFFICACY AND TOXICITY PROFILE
LOOKS REALLY GOOD NAND FROM WHAT
YOU SAID IT MAY BE A FOLLOW UP
QUESTION THAT 1 COULD MAYBE FIND
SOME SORT OF A COMPROMISE
POSITION, SOME AGE SOUNDS LIKE
FOR VERY YOUNG CHILDREN AS WOULD
BE DONE WITH PRIMARY IMMUNO
DEFICIENCY DISEASES BECAUSE THE
CHILDREN LIVE AT LEAST THROUGH
THAT AGE GROUP, IT'S PROBABLY
NOT OPTIMAL BUT PERHAPS LATER IN
CHILDHOOD OR ADOLESCENCE, AT
SOME POINT BEFORE MAJOR ORGAN
DAMAGE OCCURS BUT AFTER THE
NORMAL AGE CURVE, THAT MAY BE
SOMEWHERE IN THERE, 1 COULD FIND
AN OPTIMAL TIME.
>> I DO THINK IT'S ALSO
IMPORTANT TO INFORM, I CAN'T
HAVE THE DOCTOR SAY THIS IS WHAT
YOU SHOULD DO FOR YOUR CHILD, SO
I THINK IT'S IMPORTANT TO LET
FAMILIES BEEN THIS AND WITH
THEIR OWN NONTRANSPLANT
PHYSICIANS, FAMILY MEMBERS TO
RESPECT COME UP WITH THE
DECISION, I CAN SAY WE DO HAVE A
PATIENT THAT WAS TRANSPLANTED AS
A CHILD AND HAD NONMILE ABLATIVE
CONDITIONING AND THE TRANSPLANT
DIDN'T WORK AND WE'RE GETTING
READY TO RETRAN PLANT HIM BUT HE
LOST HIS FERTILITY AND HIS
PARENTS FEEL VERY GUILT NOW THAT
WE WENT THROUGH THAT AS A CHILD
AND IS NOT GOING TO BE ABLE TO
HAVE CHILDREN ON HIS OWN.
SO IT'S JUST A DECISION THAT
IT'S IMPORTANT NOW THAT WE HAVE
ALL DIFFERENT TYPES OF CURATIVE
THERAPIES AND YOU KNOW TRUGS
THAT ARE BEING STUDIED, I THINK
IT'S IMPORTANT TO KEEP FAMILIES
AWARE AND LET THEM BE THAT
TRANSPLANT IS AN OPTION.
NOKAY, WELL THANK YOU VERY MUCH.
SO I HAVE ANOTHER QUESTION FROM
1 OF OUR ONLINE VIEWERS, WHO
WANTS TO JUST EXPRESS THE VIEW
THAT THIS WAS A IMRAIT
PRESENTATION FROM BOTH OF THE
SPEAKERS AND WISHING TO ASK, IF
IT IS POSSIBLE TO USE CELL FREE
DNA FOR THE DIAGNOSIS OF SICKLE
CELL DISEASE?
>> YES, I THINK THAT SHOULD BE
THE WAY OF EARLY DETECTION, CELL
FREE, SO THE ANSWER IS YES.
>> OKAY, SO THAT COULD BE
SOMETHING THAT'S OFFERED IN THE
NURSERY, IN THE NEW BORN NURSEY
NYES, CERTAINLY I HOPE THAT IT
WILL EXTEND TO PRENATAL
TREATMENT, IN UTERO TREATMENT,
SPECIFICALLY IF WE'RE ABLE TO
HAVE A MUCH MORE SAFER
[INDISCERNIBLE] APPROACH ANDS
SPECIFIC IN VIVO APPROACHES IN
WHICH CASE THE CELL-FREE DNA
WILL HAVE GREAT IMPORTANCE
BECAUSE YOU CAN IDENTIFY THE
CHILD AREA AS SOON AS POSSIBLE,
REMEMBER MY ROLE IS TO SPEAK TO
THE WORLD THE WAY IT SHOULD BE,
IT COULD BE, BUT THE WAY IT IS
NOT.
>> YES, INDEED.
INDEED.
OKAY, SO, HERE'S A QUESTION THAT
SORT OF BRINGS TOGETHER SOME OF
WHAT DR. FITZHUGH WAS TALKING
ABOUT THEN SOME OF THE MORE
GLOBAL CONCERNS THAT DR. WONKAM
MENTIONED, SO, WHAT ARE THE
COMPARATIVE COSTS OF HAPPEN LO
TRANSPLANTATION IN DIFFERENT
COUNTRIES?
>> YEAH, SO, I DON'T KNOW THAT
THE HAPPEN LO IDENTICAL
TRANSPLANTS BEING DONE IN TOO
MANY COUNTRIES ESPECIALLY NOT IN
SUB-SAHARAN AFRICA THAT I'VE
HEARD.
IT'S PROBABLY BETWEEN 2 AND
$400,000 IN THE U.S., BUT THAT
COMPARES TO GENE THERAPY AND
GENE EDITING THAT WERE JUST
APPROVED, THEIR ESTIMATED COST
IS 2-$3 MILLION, BUT EVEN THE
TYPE OF TRANSPLANT THAT WE'RE
DOING NOW WILL BE TOO EXPENSIVE
TO BE ABLE TO APPLY IT IN THESE
REGIONS IN AFRICA, SO THERE'S A
LOT THAT HAS TO BE DONE TO MAKE
IT MORE AFFORDABLE AND
APPLICABLE TO PLACES ALL OVER
THE WORLD.
>> SO JUST AS A FOLLOW UP
QUESTION, YOU MENTIONED THE
COMPARATIVE COST OF JEEP THERAPY
OR YEEN EDITING AS BEING ON THE
ORDER OF AT LEAST, I THINK YOU
SAID 10 FOLD, THE COST OF WHAT A
TRANSPLANT WOULD BE BUT YET 1
MIGHT THINK THAT THE EDITING
WOULD NOT HAVE THE SAME ISSUES
WITH REGARD TO
IMMUNOSUPPRESSION, LATER ON AND
WITH THE POSSIBILITY OF
INFECTION, AND ALL OF THE
COMPLI--MAYBE NOT ALL OF, BUT
MANY OF THE COMPLICATIONS, MOST
TRANSPLANT.
SO, WHY IS IT SO MUCH MORE
EXPENSIVE?
>> YEAH, THAT'S A GOOD QUESTION
FOR THESE COMPANIES.
I THINK A LOT OF THE WORK IS
DONE EXVERIFY O SO YOU'RE HAVING
TO DO ALL THESE COMPLICATED
THINGS TO EDIT THE YEENS AND DO
THE EDITING AND GENE THERAPY, I
CAN SAY I KNOW THAT PEOPLE ARE
WORKING ON AN IN VIVO OOH PROACH
SO THAT ALL YOU HAVE TO DO IS
JUST INJECT THE GENE AND YOU CAN
KILL THEM THAT WAY AND POTENTIA
WILY AND THAT WOULD BE A WHOLE
LOT CHEAPER THAN WHAT WE'RE
DOING NOW.
SO THIS IS JUST THE CURRENT COST
BUT FOR THE FEATURE, THE COST
WILL HAVE TO COME DOWN EVEN FOR
AMERICANS TO BE ABLE TO GET GENE
THERAPY OR GENE EDITING.
NYES, YES.
YEAH, OKAY, WELL, THANK YOU FOR
THAT.
HERE'S ANOTHER QUESTION THAT
CAME IN A WHILE AGO, C WONKAM
HAS TALKED ALET ALET--LITTLE BT
ABOUT THE POSSIBILITY OF WHETHER
SICKLE CELL DISEASE WENT FROM
AFRICA TO INDIA OR GREECE OR ALL
OF THE OTHER COUNTRIES SO ARE
THERE CLINICAL DIFFERENCES
BETWEEN SICKLE CELL THAT IS SEEN
IN SOME OF THESE OTHER
COUNTRIES, GREASE OR INDIA OR
OTHER PLACES?
VERSUS WHAT HAS BEEN OBSERVED IN
THE AFRICAN POPULATION?
>> THE SWU IS YES, IN AFRICA
THERE ARE DIFFERENTIA PLACES,
BUT AT THIS TIME, THE WAY IT'S
CLASSIFIED IS ON 4 DIFFERENT
HAPLOTYPE BACKGROUND, THE OLDEST
1 WILL BE CAMEROON, AND THEN
[INDISCERNIBLE], AND THEN
[INDISCERNIBLE] AND THEN SENEGAL
TYPE, THE TYPE FOUND IN SENEGAL,
ASSOCIATED INCREASED
[INDISCERNIBLE], SO YOU WILL BE
MUCH LESS [INDISCERNIBLE], AND
THAT VERY SAME HAPLOTYPE IS
FOUND IN SICKLE SALE DISEASE
THIS PATIENT MOSTLY FROM INDIA,
SO THE FIRST [INDISCERNIBLE]
VARIES BECAUSE OF THE GENOMICS
BACKGROUND OF SICKLE CELL DEC,
SO IT WILL ALSO VARY BECAUSE OF
THE ENVIRONMENT THAT ARE THE
STRONGEST MODIFIERS AND THAT
ENVIRONMENT IN AFRICA IS MARKED
BY THE [INDISCERNIBLE], BY THE
[INDISCERNIBLE] BY THE RATE OF
BACTERIAEREMMIA, AND BY THE
[INDISCERNIBLE] OF THE
[INDISCERNIBLE] AND MUCH MORE
SIGNIFICANT THAN OTHERS THAT YOU
WILL NOT SEE IMMEDIATELY SO NOT
NECESSARILY IMMEDIATELY BUT AT
LEAST AND OF COURSE THE
STRONGEST MODIFIER IS THE ACCESS
TO CARE, [INDISCERNIBLE] NOT YET
IMPLEMENTED ACROSS MANY AFRICAN
COUNTRY FROM THE LAST COUNT,
PENICILLIN, PROPHYLAXIS ACCESS
WHICH IS NOT WIDELY IMPLEMENTED
AND ACCESS TO HIDE ROXYUREIA IS
CONTINUING.
NSO ANY DATA WITH REGARD TO
THESE HAPLOTYPES THAT YOU
MENTIONED THAT YOU WOULD SUGGEST
IN CERTAIN PARTS OF AFRICA OR
WHATEVER, THAT THERE'S BEEN ANY
SELECTION FOR 1 OR ANOTHER
HAPLOTYPE IN TERMS EVER, I FIST
THERE HAVE BEEN JUST BY VIRTUE
OF THE PRESENCE OF MALARIA AND
THESE OTHER FACTORS THAT YOU'VE
TALKED ABOUT, BUT WITH THE FETAL
HEMODPLOABIN IT WOULD SEEM LIKE
MAYBE THAT'S SORT OF A COUNTER
VAILING PROCESS THAT WOULD BE
SELECTED FOR.
NOH, YEAH, THAT'S, MAYBE THEY
ARE TRULY TO YOUR QUESTION, THE
FIRST IS HAPLOTYPE, TO THE
GEOGRAPHY, I WOULD SAY YES,
ACTUALLY THE--1 OF THE 15--ABOUT
10 YEARS AGO WHO STUDIED THE
GLOBAL DISTRIBUTION OF
HAPLOTYPE, WHEN WE REALIZE THAT
IN A SINGLE COUNTRY AT LEAST 2
COUNTRY, CAMEROON, EI DIDN'T
WANT AND SUDAN THEY WERE ALL
THERE, IT WAS BASED ON THAT,
THAT WE PUT OUR DATA HYPOTHESIS
THAT THERE IS A SINGLE WHOLE
GENOME SINGLE SICKLE CELL
DISEASE, BUT IF WE LOOK
GROSSLYOT WESTERN PART OF AFFRIC
ATHE HAPLOTYPE IS THE MOST
COMMON, SENEGAL HAPLOTYPE IS
REALLY RESTRICTED TO THE EASTERN
PART OF AFFRIC ATHE CAMEROON IS
BETWEEN SUDAN AND CAMEROON AND
THAT SPECIFIC CORRIDOR.
THE SECONDLY OF YOUR QUESTION IS
THEN THE SELECTION THAT MAY HAVE
AND REACHED SOME VARIANT
[INDISCERNIBLE] FOR THE WORKS
FOR EXAMPLE, THE VARIANT FOUND
IN THE HAPLOTYPE, IS THERE ANY
INDICATION THAT IT HAS BEEN
SELECTED IN WEST AFRICA, BUT A
STUDY THAT SHOULD BE DONE.
>> ALL RIGHT, WELL THANK YOU
VERY MUCH FOR THAT.
OKAY, NOW HERE'S A QUESTION FROM
THE PAST, THE DISTANT PAST, I
THINK.
SO THIS IS A QUESTION WITH
HAVING TO DO WITH WHETHER THERE
ARE ANY PHARMAICOLOGGIC AGENT
COULD HAVE AN EFFECT ON THE
FLEXIBILITY OF SICKLED RED CELLS
THAT WOULD HAVE ANY CRUCIATE
LIGAMENTTILITY FOR THE TREATMENT
OF PATIENTS?
NYEAH, THERE ARE DRUGS THAT ARE
TRYING TO INCREASE OXYGEN
AFFINITY AND IF YOU'RE ABLE TO
INCREASE OX GENERATED TO THE
HEMODPLOABIN, YOU DECREASE
SICKLE, SO THE FIRST DRUG
APPROVED FOR THIS IS VOCES CELL
TOR, BUT THERE'S ALSO
[INDISCERNIBLE] AND BOTH OF
THESE ARE STUDIED AND SHOWING TO
DECREASE MARKERS OF HEME OLDER
PEOPLE SIS, AND THEN THERE'S
ANTIP-SELECTIN WHICH HAS BEEN
SHOWN TO DECREASE PAINFUL
CRISIS, THAT'S AN EFFUSION
WHEREAS THE OTHERS ARE ORAL SO
THAT'S 1 OF THE LIMITATIONS OF
THOSE BUT THERE'S ALSO ALBEAUTA
MIN, BUT IT'S THOUGHT TO
DECREASEOXIDATIVE STRESS AND
SHOWN TO DECREASE PAINFUL
CRISIS, SO DRI DROKSYUARY WAS
APPROVE INDEED 2017, SO IT WAS A
LONG TIME IT WHERE IT OHM HAD 1
DRUG AND I THINK WE HAVE 4 OR
ALMOST 5, SO IT'S EXCITE THRG'S
A LOT OF DRUGS NOW FOR THE
SICKLE CELL DISEASE.
NSO HERE'S ANOTHER QUESTION FOR
DR. FITZHUGH, FOR THE RELATED
DONORS WHAT ARE THE
HEMOGLOBIN-ESQUE STATUS WITH
REGARD TO SICKLE CELL TRAIT AND
ALSO WHAT ARE THE RECIPIENTS
ANTIBODY PROFILES?
>> SO THOSE ARE 2 DIFFERENT
THINGS SO LIKE I SAID LESS THAN
15% PATIENTS HAVE AN HLA-MATCHED
SIBLING BUT YOU KNOW MOST OF OUR
PATIENTS HAVE SICKLE CELL TRAITS
SO AS I SAID, IN THE HAPPEN LO
STUDIES THERE ARE 3-QUARTERS OF
A PATIENTS HAD SICKLE CELL
TRAITS,IME NOT SURE EXACTLY WHAT
THE HLA MATCH SIBLING BUT I
WOULD SAY A GOOD PROPORTION OF
THEM ALSO HAD SICKLE CELL TRAIT
AND AS FAR AS ANTIBODY AT THAT
TIMEUS, WE HAVE PATIENT WHO IS
HAVE [INDISCERNIBLE] SO FROM THE
FREQUENT RED CELL TRANSFUSIONS
THEY CAN DEVELOP ANTIBODY WHICH
IS CAN MAKE IT MORE AND MORE
DIFFICULT TO TRANSFUSE THEM AND
INVOLVE THESE THE SEVERE
HEMOLYTIC TRANSFUSION REACTION
SO WE DO HAVE PATIENTS WHO ARE
IMMUNIZED WHO HAVE THESE SO WE
WORK CLOSELY WITH OUR
TRANSFUSION MEDICINE DEPARTMENT
AND IF THEY HAVE REALLY
CHALLENGING ANTIBODIES THEY CAN
GET BLOOD AND FREEZE IT SO THAT
THEY CAN PREPARE OUR PATIENTS TO
GET TRANSFUSED AFTER TRANSPLANT.
NALL RIGHT.
SO LET'S SEE.
HERE'S ANOTHER QUESTION WITH
REGARD TO DR. FITZHUGH SPOKE
ABOUT POST TRANSPLANT
CYCLOFOSTER NURSED FOCUSED ON
MID THAT SEEMS TO BE AN
IMPORTANT PART OF THE EVOLVING
REGIMEN FOR HAPPEN LO IDENTICAL
TRANSPLANT DISP SO THE QUESTION
IS ARE THERE ANY OTHER AGENTS
BEING TRIED INSTEAD OF
CYCLOFOSTER NURSED FOCUSED ON
MADE THAT MIGHT ALSO HAVE A
BENEFICIAL EFFECT IN TERMS OF
THESE REGIMENS.
>> YEAH, I MEAN WE'RE STUDYING
ABACITIB, IT'S A CTL4A, SO IT
ACTS WHERE IT ALLOWS, THERE'S 2
DIFFERENT SIGNALS THAT OCCUR IN
IMMUNE RESPONSE AND THE FIRST 1
IS THE ANTIGEN ENGAGING THE
T-CELL RECEPTOR BUT THEN THERE'S
A SECOND CO STIMLATTORY REACTION
THAT LEADS TO IMMUNE RESPONSE,
SO THE FIRST THAT OCCURS WITHOUT
THE SIGNAL, THAT CAN LEAD TO
TOLERANCE OR ENERGY, WHERE THE
CELL BECOMES ENERGIC OR
UNRESPONSIVE TO THE ANTIGEN, SO
CTLA 4 ACTUALLY PLOKS THE IG,
BLOCKS THAT, INTERACTION FOR
SIGNAL, TOO, SO THAT'S A DRUG
THAT'S BEEN SHOWN TO DECREASE
GRAFT VERSUS HOST DISEASE IN
PATIENT WHO IS HAVE HEMEAT O TO
LOGIC MALIGNANCIES AND USE
STARTING TO BE USED MORE WITH AN
UNRELATED DONOR STUDY WHERE THEY
HAD A HIGH RISK OF IT AND REALLY
DECREASE THE RISK FOR GRAFT
VERSUS HOST DISEASE AND SINCE
OUR PROBLEM HAS BEEN MORE GRAFT
REJECTION, OUR NEW STUDY, DOES
INCLUDE ABACITINIB TO TRY TO
DECREASE THE GRAFT REJECTION
RATE NOKAY, ALL RIGHT.
WELL, THANK YOU.
SO THIS IS A QUESTION THAT
PERHAPS BOTH OF YOU MIGHT WANT
TO ADDRESS, IT'S SORT OF RELATED
THAT SOMETHING THAT DR. WONKAM
TALKED ABOUT A LITTLE BIT BUT
ARE THERE ANY PROGRAMS FOR
POPULATIONS SCREENING OF SICKLE
CELL TRAIT FOR MARRIAGE
COUNSELING?
>> YES, THERE ARE.
THERE ARE 3 LAYER OF SCREENING,
THE FIRST 1 IS NEW BORN
SCREENING, THE SECOND IS THE
SCREENING FOR PREGNANCY BECAUSE
IT'S WHERE YOU MAY ANTICIPATE
PERHAPS IF THERE'S NEW BORN
SCREENING, THERE MIGHT BE
SCREENING FOR AT-RISK PREGNANCY
AND THEN THERE'S POPULATION
SCREENING THAT INVOLVE AN
EFFICIENT WAY TO DO IT, 1 IS
THAT THE HIGH SCHOOL, IS THE
MOST RECOMMEND ASKED THERE IS
PREMARITAL SCREENING THAT
SOMETIME SYSTEM SUGGESTED BY THE
LAW OR ACTUALLY RECOMMENDED BY
THE LAW BUT VERY HARD TO
IMPLEMENT ALMOST IN PRACTICE.
IT'S HARD BECAUSE THE CONCEPT OF
MARRIAGE INVOLVE [INDISCERNIBLE]
PATHOLOGICAL, SOME PEOPLE CALL
IT LOVE, IT'S QUITE HARD TO MEET
SOMEONE AND JUST SAY, OKAY, I
LIKE YOUR EYES BUT WHAT IS YOUR
HEMOGLOBIN, SO YOU CAN DO THAT.
BUT BY EXPERIENCE, A LOT OF
PATIENT I SAW IN MY CLINIC IN
YAONDE FOR EXAMPLE, ENCLOUDING A
COUPLE DOCTORS, THEY KNEW THEY
WERE HETEROZYGOUS BUT THEY CHOSE
TO GET MARRIED.
SO WILL W. H. O. WILL COME IN TO
DO THE SCREENING AT THE
UNIVERSITY BECAUSE PEOPLE SHOULD
KNOW THEIR STATUS AND THENAR P
HARES THEY CONDITION THE WAY
THEY CHOOSE THEIR PARTNER BUT
INFORMATION IS HARD WHERE 1
PERSON OUT OF 4 SOMETIMES IS
CARRIER.
>> OKAY, ALL RIGHT.
SO THEN HERE'S ANOTHER QUESTION
THAT PERHAPS BOTH OF YOU WOULD
BE INTERESTED IN, AND THAT IS
DR. WONKAM TALKED ABOUT VARIOUS
MODIFIER LOCI THAT ARE INVOLVED
IN THE NATURAL HISTORY OF OR THE
PROGRESSION OF SICKLE CELL
DISEASE, ARE THOSE MODIFIER LOCI
BEING CONSIDERED IN THINKING
ABOUT CANDIDATES FOR
HEMATOPOIETIC STEM CELL
TRANSPLANTATION, YOU KNOW OR
EITHER FROM THE RECIPIENT OR THE
DONOR.
>> SURE.
I REALLY--I DON'T KNOW I'M THE
RIGHT PERSON BECAUSE I DON'T SEE
PATIENTS FOR SICKLE CELL DEC,
YOU ONLY THING I CAN IMAGINE IF
THE MODIFIER IS STRONG ENOUGH TO
HAVE A HIGH LEVEL OF BETA
FLOABIN, YOU WON'T SEE THE
DOCTOR BECAUSE [INDISCERNIBLE]
IN THE STUDY 50 YEARS AGO, THE
BAR FOR HAVING OR LOWERING, OR
TO INCREASE SURVIVAL, IS USUALLY
IN GENE EDITING, AND YEEN
THERAPY IS THE TARGET IS 20% OF
THE HEMOFLOABIN, SO IT SUGGEST
FIST YOU ARE A MODIFIER LIKE
HAPLOTYPE, I DON'T KNOW, HAVE
THE TYPE OF SENEGAL HAPLOTYPE,
THAT ALLOW AN ANIMAL THAT IS
MORE THAN 20% CERTAIN, YOU MAY
NOT NEED TRANSPLANTS.
BUT [INDISCERNIBLE] STUDY FROM
SENEGAL, WE HAD A COHORT FROM
SENEGAL, THEY ALL HAVE HIGH
LEVEL OF BETA TBLOABIN, BETA
ALSO HAVE KIDNEY MALFUNCTION
TSUGGESTS THAT THE BETA TBLOABIN
DOESN'T DO IT ALL, IT IS
POSSIBLE THERE IS SOME CLINICAL
COMPLICATION, THAT WILL STILL
HAPPEN IF EVEN IF YOU HAVE THE
ANIMAL AND THEIR DATA FROM WHERE
PEOPLE HAVE [INDISCERNIBLE]
COMPLICATION.
I THINK THERE'S AN AREA OF
INVESTIGATION WHERE WE NEED MORE
PERSPECTIVE COHORT FOR THAT.
>> OKAY.
ALL RIGHT.
SO LET ME SEE IF THERE ARE ANY
OTHER QUESTIONS.
ARE THERE ANY QUESTIONS FROM THE
GROUP HERE WHO WOULD LIKE TO
POSE A QUESTION?
>> OH AND I THINK THAT DR. ARIAS
WOULD LIKE TO POSE A QUESTION SO
LET ME TURN IT OVER TO HIM FOR A
MOMENT.
>> WELL, THANK YOU BOTH FOR A
VERY EXCITING PRESENTATIONS.
IT'S A LOT TO THINK ABOUT.
SO MY QUESTION HAS TO DO WITH
URIA, WHICH YOU'RE FROM A
PHYSICAL CHEMICAL POINT OF VIEW,
SHOULD BE A VERY EFFECTIVE
COMPOUND TO USE TO MODIFY THE
HEMOFLOABIN.
BUT YET, A VERY LARGE PROPORTION
OF PATIENTS ARE LISTED AS
UNSUCCESSFUL WHEN TREATED OR I
DON'T KNOW WHETHER IT'S THEY
STOPPED RESPONDING OR WHETHER
THEY WEREN'T RESPONDING IN THE
FIRST PLACE, SO MY QUESTION IS:
ARE THERE ANY STUDIES
ASSOCIATING THE HAPLOTYPES WHEN
YOU DESCRIBED TO THE PHENOTYPE
OF THE RESPONSE OR LACK LIFE OF
URIA, AND THE SECOND FOR
DR. WONKAM IS, IS SICKLE DISEASE
FOUND AMONGST THE
[INDISCERNIBLE] IN AFRICA?
>> THE SECOND QUESTION, CAN YOU
REPEAT, PLEASE?
>> IS SICKLE DEC FOUND AMONGST
THE [INDISCERNIBLE] IN AFRICA.
>> YES, THAT'S A GOOD 1.
>> YEAH.
>> THE FIRST 1, IS THERE ANY
MODIFIER THAT IMPROVE THE
RESPONSE TO HYDROXIA, YES, MOST
OF THE VARIANT THAT ACTUALLY
CHANGES THE ROLE OF HEMEAT O
FLOABUE LYNN WITH HYDROXURIA,
BUT THE I THINK HYDROXURIA
DOESN'T ACT ONLY BY IPT GREATER
CREASING LEVEL OF GLUTEA MINE,
BUT ALSO BY REDUCING THE AMOUNT
OF WHITE BLOOD CELL REDUCING
INFLAMMATION, SO IN SOME
PATIENT, RESPONSE IS NOT
NECESSARILY MEASURED BY THE BETA
GLOBIN BUT BY THE COMPLICATION
LIKE PAIN COMPLICATION THAT ARE
SOMETIMES ASSOCIATED WITH THE
INFLAMMATION.
SO I DON'T THINK THE MECHANISM,
HYDROXIA, FOR THE BETA GLOBIN IS
STILL--WE BELIEVE IT'S TRUE POST
TRANSCRIPTIONAL CHANGES IN THE
MICROARE, NA, AND THE
EXPERIMENTAL DATA AND ALSO DAT
PRODUCED BY [INDISCERNIBLE] AND
HIS GROUP.
BUT WE STILL ARE THE SUBJECT OF
AN INVESTIGATION.
THE SECOND QUESTION DO
[INDISCERNIBLE] I GUESS YOU ARE
SPEAKING TO THE ETHIOPIAN,
SPECIFIC THAT GROUP OF ETHIOPIAN
WHO ARE JEWS, I CAN'T GIVE YOU A
DISEASE.
BUT THE ANSWER I CAN GIVE IS
THAT GENERALLY IN ETHIOPIA,
SOUTHERN PART OF ETHIOPIA, STILL
HAVE MALARIA AND EVERYWHERE YOU
HAVE MALARIA, ANYTIME YOU HAVE
SICKLE CELL, THE NORTHERN PART
OF ETHIOPIA, HAVE LESS, AND
PEOPLE THAT THAT PART OF
ETHIOPIA, WHO HAVE SICKLE CELL
TRAIT IS MUCH LOWER.
[INDISCERNIBLE], HISTORICALLY,
IS SUBJECT OF A LOVE STORY
BETWEEN KING SOLOMON AND THE
QUEEN OF SABBA.
IT ALL DEPENDS ON WHERE THE
DESCENDANT LIVES, IF THEIR
DESCEND ANTILIVE IN THE SOUTHERN
PART, I THINK SOME OF THEM WILL
HAVE SICKLE CELL DISEASE, 1 OF
THE WAYS TO QUICKLY KNOW THAT IS
PERHAPS TO WORK WITH ISRAEL AND
THE BIOREPOSITTORY THAT HAVE
BEEN COLLECTED NOW.
I KNOW THE JEWS IN ISRAEL NOW,
THEY WILL BE CALLED BETA-ISRAEL
POPULATION, JUST REALLY DOJ SOME
SCREENING IN THAT POPULATION,
BUT I WILL PERHAPS MOVE ON A
DIFFERENT POPULATION BUT IT'S
JUST A DIVERSE BUT A AN
IMPORTANT DIVERSION.
THE PEOPLE WHO ASSOCIATE SICKLE
CELL DISEASE, YOU KNOW IN THE
POPULATION WHO INITIALLY EVOLVED
IN CENTRAL AFRICA, IN A TRIANGLE
BETWEEN NIGERIA, CAMEROON AND
CONGO, AND MIGRATED, EXPANSION
ACROSS AFRICA.
AFTER YEARINGS LATER, THERE'S
SOME IN AFRICA WHO DON'T HAVE
SICKLE CELL, ALSO
[INDISCERNIBLE] DO NOT HAVE
SICKLE CELL DISOAZ SO ZULU, AND
[INDISCERNIBLE] PEOPLE DO NOT
HAVE SICKLE CELL DEC.
BECAUSE AFTER AT LEAST 1000
YEARS OR 1000 AND A HALF YEARS
LIVING IN MALARIA ENVIRONMENT,
THERE WAS NO NEED FOR OUR GENOME
TO MAINTAIN THE VARIANT.
SO I WOULD SUPPOSE THAT SUCH
DYNAMIC WOULD PROBABLY HAPPEN IN
PLACES LIKE ETHIOPIA, IF YOU ARE
LIVING IN A HIGH MOUNTAIN OF
ETHIOPIA, WHERE THEOXIEN IS
LOWER AND MALARIA WILL NOT
SURVIVE, OVER TIME, PERHAPS AT
LEAST 1000 YEARS YOU WILL
NONAPOPTOTIC THE NEED TO HAVE
THE SICKLE VARIANT AND THE
VARIANT WILL BE MUCH LOWER AND I
GUESS, IN POPULATION LIKE IN THE
POPULATION, THE SICKLE CELL DEC
IS RESISTANT AND IT COULD BE
RELATED TO THAT.
>> THANK YOU.
>> ALL RIGHT, ARE THERE ANY
OTHER QUESTIONS FOR OUR
SPEAKERS?
IF NOT, I THINK THAT WE'RE JUST
ABOUT AT THE END OF OUR TIME
ANYWAY, SO I WOULD LIKE TO THANK
YOU BOTH, AGAIN, VERY, VERY
MUCH, THIS HAS BEEN REALLY JUST
A VERY STIMULATING TERRIFIC
THOUGHT PROVOKING SET OF
PRESENTATIONS AND I WANT TO
THANK YOU AGAIN VERY, VERY MUCH
FOR JOINING US THIS AFTERNOON.
ALL RIGHT AND WITH THAT, I THINK
THAT WE WILL CALL IT TO A CLOSE
AND WE LOOK FORWARD TO SEEING
EVERYONE AGAIN NEXT WEEK FOR
ANOTHER INSTALLMENT, THE EIGHTH
IN THE SERIES.
SO, ANYWAY, THANK YOU VERY MUCH