HELLO EVERYBODY. THIS AFTERNOON WE WILL BE DISCUSSING THE BIOLOGY OF OF -- CHIEF SCIENTIFIC OFFICE OF -- CLINICAL AND TRANSFORMATION. >> THANK YOU ALL FOR BEING SUCH GOOD HOSTS TODAY AND FOR INVITING ME TO SPEAK. I'M GOING TO GIVE YOU KIND OF A SMORGASBORD IF YOU WILL OF CORD BLOOD TRANSPORTATION AND BANKING AND THEN TALK ABOUT SOME NEW WORK AND SOME CHALLENGES THAT I THINK ARE IN THE FIELD AS WE THINK ABOUT THESE CORE BLOOD AS A SOURCE OF CELL FOR CELL THERAPY AND REGENERATIVE MEDICINE. JUST IN CASE THERE'S SOMEBODY WHO DOESN'T KNOW CORD BLU BLOOD IS THE BLOOD LEFT OVER IN THE PLACENTA AFTER BIRTH AND IT COULD BE COLLECTED AND STORED FOR FUTURE USE. CORD BLOOD CONTAINS STEM CELL -- AND IT'S IMMUNE LODGE CLAY CURRENT JUST LIKE PREGNANCY IS A STATE OF TOLERANCE. AND IT CAN BAY TRANSPLANTE BE TRANSPLANTED AND THAT'S INCELLSED EXCESS TO TRANSPLANTATION FOR PATIENTS WHO MATCH ADULT OWNERS. THE STORY STARTED BACK IN 1988 WHEN THIS YOUNG MAN WHO HAD -- ANEMIA WAS BECOMING A PLASTIC. HIS MOTHER WAS PREGNANT WITH ANOTHER BABY WHO WAS TESTED IN UTERO AND FOUND TO BE AFFECT AND NOT AFFECTED WITH IT. THROUGH A SERIES OF INTERNATIONAL COLLABORATIONS, THE CORD BLOOD WAS COLLECTED INTO A BIG BOTTLE THAT HAD SOME HEPARIN THAT WAS STERILE BY A OBSTETRICIANS IN NEW YORK. THEN SHIPPED TO -- WHO STORED IT IN HIS RESEARCH FREEZER AFTER MIXING IT WITH 10% DMSO. THE WHOLE FAMILY WENT TO FRANCE WHERE ELLEN BLUKMAN IN THOSE DAYS PROBABLY HAD THE BEST RESULTS FOR PATIENT WITH -- AWE KNEEL YEAH AND WAS THE FIRST PERSON TO USE REDUCED INTENSITY CONDITIONING FOR PARTIAL -- SHE DID THE TRANSPLANT ON THIS YOUNG MAN USING HIS SISTER'S CORD BLOOD. IT WAS SUCCESSFUL. HE'S SHOWN HERE 20 YEARS LATER AT THE ANNIVERSARY WE HAD IN FRANCE OF HIS TRANSPLANT WITH HIS WIFE AND HIS ADOPTED SON. HE IS HELPING, NOW HE'S 24 YEARS OUT AND HE'S STILL FULLY CONSTITUTED WITH HIS SISTER'S CORD BLOOD CELLS AND HIS HEMATOMA.IHEMOPOIETIC SYSTEM. I JUST WANT TO POINT OUT THIS WAS THE FIRST IN MAN EXPERIMENT. THERE WAS VERY LITTLE TO NONE PRECLINICAL WORK. IT WAS IN A CHILD WHICH I KNOW IS CONTROVERSIAL AND HAD IT NOT BEEN SUCCESSFUL PROBABLY THE FIELD WOULD NOT HAVE DEVELOPED. BECAUSE IT WAS, IF YOU FAST FORWARD NOW, YOU CAN SEE THAT MANY THINGS HAVE HAPPENED. SO AFTER THAT FIRST TRANSPLANT IN FRANCE, PABLO RUBEN STEIN -- AND WE PERFORMED THE FIRST UNRELATED TRANSPLANT USING A UNIT FROM THAT BANK IN 1993. OUR PEDIATRIC TRANSPLANT PROGRAM AT DO YOU RECOLLECT OPENED IN 1990. -- AT DUKE OPENED IN 1990. YOU CAN IS A TODAY THERE HAVE BEEN OVER 30,000 UNRELATED DONOR CORD BLOOD TRANSPLANTS PERFORMED WORLDWIDE. THERE ARE PROBABLY ABOUT 5,000 A YEAR PERFORMED AROUND THE WORLD IN THE NOD YOU WERE TIME. THERE'S MORE THAN 140 BANKS WORLDWIDE. THERE'S NO OFFICIAL COUNT THAT THE UNRELATED UNITS IN THE WORLD WAS 180,000 WITH ABOUT 180,000 IN THE UNITED STATES. FDA LICENSURE IS NOW REQUIRED FOR UNRELATED DONOR CORD BLOOD BANKS AND MOST OF THE BANKS INCLUDING OUR OWN ARE IN THE PROCESS OF APPLYING FOR LICENSURE. THE NEW YORK BLOOD CENTER HAS BEEN AWARDED THEIR LICENSE AND THEY WERE THE FIRST BANK TO DO THAT. IN 2005, THERE WAS A LAW SIGNED, A BILL SIGNED BY PRESIDENT BUSH INTO LAW ESTABLISHING THE CW BILL YOUNG CELL TRANSPLANTATION PROGRAM WHICH ESSENTIALLY UNITED THE NATIONAL DONOR IT'S WITH THE KOSHECORD BLOOD REGISTRY AND CREATED COORDINATING CENTERS FOR BOTH ADULT AND CORD BLOOD DONORS, A SINGLE DONOR REGISTRY WHICH LISTS BOTH AN OUTCOME DATA BASE WHICH IS A CONTRACT TO THE CIB IN MILL WALK AND BANKING NETWORK CALLED THE NATIONAL CORD BLOOD INVENTORY AND THAT'S MANAGED, ALL OF THAT IS MANAGED THROUGH HERSA AND THE BANKING NEW YORK IN THE U.S. HAS 13 BANK MEMBERS. WHICH WAS A PUBLIC BANK WAS ESTABLISHED IN 1997, AGAIN WITH SUPPORT THROUGH A PROGRAM CALLED COBALT. AND I'M JUST GOING TO SHOW YOU A FEW OF THE ASPECTS OF PUBLIC BANKING THAT I THINK ARE IMPORTANT. I THINK THE TAKE HOME MESSAGE IS THAT THIS IS NOW A CONTROLLED SUBSTANCE WHICH IS SCREENED APPROPRIATELY PER FDA REGULARS AND COMING CLOSE TO GMP MANUFACTURING. WE JUST HAD OUR FDA/PAI INSPECTION LAST WEEK SO IT'S VERY MUCH IN MY MIND. WE COLLECT IN UTERO BY TAKING THE PLACENTA OUT OF THE DELIVERY ROOM, PUTTING IT IN A TRUCK AND BRINGING THE CORD DOWN SO WE CAN CLEAN IT AND PUT SOME TENSION ON IT. WE PUNCTURE THE CORD WITH A 17-GAUGE NEEDLE THAT'S ATTACHED TO A COLLECTION BAG MANUFACTURED BY PAUL IMMEDIATESA CHZ HAS 35 MILL OF CPD, A COAGULANT IN IT. WE LET THE CORD BLOOD FLOW IN BY GRAVITY LOCKING ON SCALE ANYWHERE TO NINE MINUTES. BY A TRAINED COLLECTOR IS 10 MILLS TO 1.1 TO 1.5 BILLION CELLS. ALTHOUGH YOU CAN GET LARGER COLLECTIONS IF YOU HAVE A GOOD LARGE PLACENTA. BETTER COLLECTIONS ARE CAUCASIAN BABIES AT TERM BORN TO MOMS BETWEEN ABOUT 20 AND 35 YEARS OF AGE WHO ARE NOT POST TERM AND WHO DON'T HAVE COMPLICATIONS IN PREGNANCY. AND IN OUR CASE THE CORD BLOOD IS BROUGHT BACK TO OUR LABORATORY WHERE IT'S MIXED WITH -- AND IT QUALIFIES BY COUNTING FOR POSITIVE THING WHICH IS A PRE PROCESSING KIND OF A BILLION CELLS. IT'S PROCESSED ON SOMETHING CALLED THE C PAX WHICH ESSENTIALLY DOES PARTIAL RED CELL DEBLEATION AND PARTIAL PLASMA DEPLETION. THE CELLS OF INTEREST END UP IN CELL BAG AND A PLASMA BAG. THOUGH COMPONENTS ARE STORED. THIS IS THE PICTURE WHAT THE CRYOBAG LOOKS LIKE. IT'S A TOTAL VOLUME OF 25 MILL. FIVE IN THIS COMPARTMENT AND 20 IN THIS. THEY'RE ADDED TOGETHER AFTER DMSO IS MIXED WITH THE CORD BLOOD IN A CONTROLLED WAY. THERE ARE THREE SEGMENTS ATTACHED WHICH CAN BE DETACHED FOR TESTING LATER, AND THEN THESE TWO COMPARTMENTS CAN BE USED TOGETHER OR SEPARATELY DEPENDING ON WHAT TYPE OF THERAPY YOU'RE ADMINISTERING. I THINK THAT'S IMPORTANT FOR CELL THERAPY GOING FORWARD AND IT MAY BE THAT WE WANT BEDS WITH MORE COMPARTMENTS THAN THIS. BUT THIS IS KIND OF WHAT'S USED IN THE INDUSTRY RIGHT NOW. THESE BRIDGES ARE SEALED BEFORE FREEZING AND THE CORD BLOOD IS OVERAPT AFTER THE DMSO IS ADDED AND PUT IN A CASSETTE IN AN RK STORE IN WHAT'S CALLED A BIO ARCHIVE WHICH DOES CONTROL THE FREEZING SINGLE UNIT MONITORING AND SUBMERGE UNDER THE NITROGEN FOR LONG TERM STORAGE. THIS SHOATZ YOU TH SHOWS YOU THE REASONS W HY WE DO NOT KEEP CORD BLOODS. WE ONLY KEEP SOME OF WHAT WE COLLECT BECAUSE WE CAN'T AFFORD TO KEEP THEM ALL AND OUR DECISIONS ARE BASED ON WHAT'S LIKELY TO BE USED FOR TRANSPLANT TODAY. MOST TRANSPLANTERS ACCEPT OR SELECT UNITS THAT HAVE 1.7 OR MORE BILLION CELLS. AND SO WE ARE NOT KEEPING THE SMALLER UNITS AND YOU CAN SEE THAT ESSENTIALLY ALMOST 85% OF WHAT WE THROW AWAY IS SMALL VOLUME OR LOW CELL COUNT. WE DO HAVE OTHER REASONS WITH UNITS INCLUDING PROCESSING COMPLICATIONS OR POSITIVE HEMOGLOBIN APATHY OR POSITIVE SAW RILLITY BUT THESE NUMBERS ARE RATHER LOW. AND IT'S THE MAJOR REASON THAT WE EXCLUDE IT IS BECAUSE OF THE LOW VOLUME LOW CELL COUNT. AND I'LL SAY AND I'LL COME BACK TO THIS AS OF THE 800,000 THAT ARE IN INVENTORY RIGHT NOW, ONLY PROBABLY 100,000, IF THAT, HAVE THE HIGHER CELL COUNTS THAT PEOPLE ARE SELECTING FOR TRANSPLANTS SO THERE'S THIS HUGE RESERVOIR WHICH WAS EXPENSIVE TO PROCURE OF WELL-TESTED UNITS THAT JUST HAPPENED TO BE SMALLER THAT ARE AVAILABLE FOR OTHER USES. IN OUR LAB, WE DO, WE STORE EXTENSIVE SAMPLES FOR FUTURE TESTING SO WE HAVE TWO REP CAN YOU TELL SAMPLES OF THE CELLS IN THE MSO AND WE HAVE SAMPLES OF MATERNAL RED CELLS AND OR WHOLE BLOOD THAT CAN BE MADE INTO DNA PLASMA SERUM AND LIQUID BLOOD DNA PLASMA AND ALSO SEGMENTS. THERE'S A BUNCH OF TESTING THAT'S DONE AND THE MAJORITY ARE LISTED ON THIS SLIDE. WE TEST ALL THE USUAL THINGS THAT IN TODAY'S PRACTICE YOU WOULD WANT TO KNOW ABOUT THE CORD BLOOD INCLUDING VIABILITY, CD34 CELL, CD3 CELLS, FORMING UNITS. WE MEASURE ALDH BLOOD CELLS WHICH CORRELATE WITH FORMING STIR RILLITY TYPING -- USING THE NEWBORN SCREENING RESULTS FROM THE STATE, NEWBORN SCREENING LAB ON THE BABY AND THEN INFECT SHUTTLE DISEASES FOINFECTIOUSDISEASES FOR THE MOTHER PERTHE REGULARS SURGULT SURROGATES THE BY. WE DO THAT BECAUSE THE ANTIBODIES FROM MOM CROSS THE PLACENTA ANYWAY AND THIS ENABLE US NOT TO HAVE TO TAKE A LOT OF THE CORD BLOOD AWAY TO BE USED FOR TESTING. IN OUR HANDS, WE HAVE CRITERIA FOR ELIGIBILITY FOR BANKING. WE HAVE A COMPUTER SYSTEM WHICH KEEPS ALL OUR DATA WHICH WAS MADE BY THE -- CORPORATION AND ASSISTS WITH COMPUTER SIGNOUTS. ONCE IT PASSES A TRIPLE ALGORITHM, THE UNIT IS ELECTRONICALLY UPLOADED TO THE PROGRAM TO BE LISTED ON THEIR REGISTRY AND FOR OUR BANK, WE ONLY DISTRIBUTE IN IT THROUGH THE MDP NETWORK. THAT'S IMPORTANT FOR US BECAUSE WE'RE A TRANSPLANT CENTER AND A BANK AND WE DIDN'T REALLY WANTED TO HAVE A CONFLICT OF INTEREST SO WE TREAT OUR OWN TRANSPLANT CENTER JUST LIKE WE WOULD ANYONE ELSE'S. AND IT'S NOT. THERE'S NO KIND OF SPECIAL DEALS BECAUSE WE HAVE A BANK. ALTHOUGH I WILL SAY SOMETIMES WE WISH THERE WERE. WE SEND THEM ONCE THE SHIPPER -- THE UNIT IS GENERALLY SHIPPED BEFORE THE PATIENT'S THERAPY STARTS. SO IT WILL BE RESIG RESIDING AT THE TRANSPLANT CENTER. THESE RETAIN TEMPERATURES BELOW MINUS 150 FOR UP TO EIGHT DAYS BUT THE TRANSPLANT CENTER SNLDZ TO TRANSFER THE UNIT INTO THEIR OWN FREEZER. THERE'S A DAY LOGGER IN THE LID OF THE SHIPPER WHICH THEN ATTACHES TO THE UNIT AND SPRINLTS OUT PRINTSOUT A TRACING OF THE TR IP TO KNOW THE TEMPERATURE WAS MAINTAINED THROUGHOUT THE SHIPPING. AT OUR SITE WE HAVE ALWAYS WASHED CORD BLUE UNITS BEFORE ADMINISTRATION SO ON THE DAY OF TRANSPLANT, THE UNIT IS THAWED, IT'S MIXED WITH DISK TERRAIN AND AALBUMIN AND THEN CENTRIFUGE AND IT IS REEXPANDED ON WHATEVER VOLUME DESK TERRAIN AND ALBUMIN IS FOR THE PATIENT AGAIN. BECAUSE WE DO TRANSPLANTS IN VERY SMALL INFANTS. WE HAVE TO CONTROL VOLUME LOAD AND DMSO LOAD. THIS IS A CHASER BAG WE STORE BACK ON TO THE TRANSPLANT BAG. IT'S JUST A NORMAL SALINE BUT IT ALLOWS US TO RINSE THE BAG AND MAKE SURE ALL THE CELLS MAKE IT INTO THE PATIENT. CHILDREN GENERALLY UNDER GOING -- TRANSPLANT HAVE CENTRAL LINES. WE HAPPEN TO TRANSPLANT A LOT OF YOUNG INFANTS AND WE ARE TOO CENTRALIZED BECAUSE THE REIGNS AREN'T BIG ENOUGH FOR A TRIPLE CATHETER SO THIS IS A DOUBLE AND SINGLE ONE IN THE SAME CHILD. THEY ALLLY GO IN UNDER THE CLAVICLE AND INTO THE SUBCLAVIAN VEIN AND INTO THE FIRST CHAMBER OF THE HARD, THE RIGHT ATRIUM. BUT WE BRING THEM OUT TO THE SKIN TO A PLACE WHERE THE CHILD ONLY HAS TO HAVE ONE DRESSING BECAUSE DRESSING CHANGES ARE NOT A POPULAR THING OF CHILDREN OF THIS AGE. SO IT'S A LITTLE BABY WHOSE OLDER BROTHER DIED AT TWO AND-A-HALF YEARS OF AGE. GOT A MY LOW BLAT TIVE TRANSPLANT DONOR. HE'S IN FIRST GRADE HERE. AND HE'S NOW 12 AND STILL NORMAL. THAT'S HIS YOUNGER BROTHER WHO WAS CONCEIVED AND ALSO HAD CARBAY THAT WAS TRANSPLANTED WHEN HE WAS TWO MONTHS OLD AND HE IS DOING WELL. IF YOU CATCH THIS EARLY YOU CAN SAVE THEIR LIVES AS WELL AS MAKE THEIR QUALITY OF LIFE NORMAL. THE INFUSION ITSELF IS VERY ANTI-CLIMATIC, INTRAVENOUS IS THE LINE TYPICALLY AND ACHES 15 MINUTES. AND -- AND TAKES 15 MINUTES. BECAUSE WE WASH OUT A CONSIDERABLE AMOUNT OF DMSO WE DON'T SEE REACTIONS ON A REGULAR BASIS. THIS IS A CHILD GETTING HIS INFUSION AND YOU CAN SEE THAT THE INFUSION ITSELF IS NOT PAINFUL TRAUMATIC, IT'S NOT DONE IN AN OPERATING ROOM. WE'RE NOT INFUSING CELLS INTO THE MARROW. IT GOES IN THE BLOOD AND THE CELLS KNOW HOW TO HONE BACK TO THE MARROW AND WE ARE NOT TOTAL E SURE HOW THAT HAPPENS. BUT THIS CHILD HAD TO HAVE NINE DAYS OF MY LOW BLATTIVE CHEMOTHERAPY BEFORE THIS INFUSION AND HE WILL HAVE A MONTH OF LOW BLOOD COUNT, NAUSEA VOMITING AND OTHER PROBLEM THAT HE NEEDS TO BE SUPPORTED THROUGH. IN ORDER TO SURVIVE THE TRANSPLANT. HE ALSO HAS TO HAVE PROPHYLAXIS AGAINST -- POST DISEASE WHICH TECTLY IN THIS MATCH BUT IN ANY ALOGENEIC TRANSPLANT IT IS A RISK AND MUST BE PROFESSION LAX -- PROFOE LAX. THEY ARE ON SAM SORT OF AMINO PROPHYLAXIS FOR A YEAR POST TRANSPLANT BUT THEN THEY CAN WEAN OFF. WHILE THEY'RE UNDER THE PROPHYLAXIS THEY NEED INFECTIOUS DISEASE PROPHYLAXIS AS WELL. IT'S NOT LIKE A SOLID ORGAN TRANSPLANT WHERE YOU NEED TO STAND IMMUNOPROPHYLAXIS FOR LIFE. YOU WILL REPLACE ANY IMMUNE SYSTEM AS WELL AS THE HEMOPOIETIC SYSTEM SO YOU ONLY NEED IMMUNE SUPPRESSION WHILE THAT PROCESS OCCURS. NOW WE PUBLISHED OUR FIRST 25 PATIENTS, IF THIS IS GOING TO WORK IN 1996 AFTER DOING THAT FIRST TRANSPLANT IN 1993. AND I JUST SHOW THIS BECAUSE SOMETIMES WHEN YOU THINK BACK ON THE THINGS THAT HAPPEN IN LIFE, I REALIZE THAT IT WAS 25 PATIENTS, THE CORD BLOOD UNITS WERE ALTERNATING OUT OF THE BLOOD CENTER. IT WAS FOR .7 KILO, THERE ARE THREE OF SIX MATCHES. 23 OF THE 25 PATCHES DPRAFTD IN 20 DAYS WITH GRAFTING -- AND EVEN 19 YEARS LATER THE EVENT -- 48%. THAT'S PROBABLY NOT VERY DIFFERENT THAN WHAT YOU WILL SEE PUBLISHED FOR CHILDREN TODAY GETTING CORD BLOOD TRANSPLANTS. AND I DON'T KNOW FOR ME IT'S KIND OF STRIKES A CORD TO KNOW HAT WITH A WE HAVE HEARD IN THOSE FIRST EARLY PATIENTS ACTUALLY HELD UP. WE LOOK IN THAT FIRST PAPER WHETHER OR NOT WASHINGTON MADE A DIFFERENCE FOR INGRAPHMENT AND THE BLACK BARS WERE ONLY THREE PATIENTS WHERE WE DID NOT WASH UNITS AND ENGRAPHMENT WAS SLOWER AND THEN THESE GREATER BOARDS WERE THE NEXT 23 OR 22 UNITS WERE WASHED THAT WE SAW EARLIER IN GRAPHMENT. THIS HAS NERVE BEEN STUDY IN ANY KIND OF CONTROLLED WAY OR RANDOMIZED TRIAL BUT EVERY CENTER HAS THEIR OWN LOCAL PREFERENCE BUT OUR LOCAL PREFERENCE IS TO WASH. MALL AWE IRAPAULA RUBENSTEIN PUBLISHED THE UNITS FOR TRACT TRANSPLANTATION LATERS AND THAT INCLUDES MANY OF OUR PATIENTS AS WELL. TWO POUR OBSERVATIONS WERE MADE. ONE THAT THE HIGHER NUMBER OF CELLS YOU CAN GIVE A PERSON BASED ON THEIR PARTICULAR BODY WEIGHT, THE FASTER THEIR ENGRAPHMENT WOULD BE, AND PATIENT GETTING MORE THAN 50 OR EVEN 100 MILLION CELLS PER KILO WHICH COULD ONLY BE SMALL CHILDREN GRAFTED MOST RAPIDLY. THEY ARE ALSO REALLY IS A THRESHOLD BLOW BUT 20 OR 25 MILLION CELLS PER KILO WHERE CORD BLOOD ALONE DOESN'T WORK VERY WELL. AND TUMOR RELATED MORTALITY INCREASE WITH INCREASING MATCHING AND PEOPLE GETTING SMALL UNITS WITH TWO OR MORE MISMATCHES DID NOT DO WELL. PEOPLE GETTING LARGER UNITS REGARDLESS OF MATCHED AS WELL AS PATIENTS GETTING A SUCCESSIVE MATCH. BUT THESE ARE SMALL NUMBERS IN THOSE EARLY DAYS. NHLBI IS PART OF A STUDY, PROSPECTIVE STUDY IN CHILDREN WITH LEUKEMIA USING SINGLE CORD BLOOD DONORS AFTER MY LOW CHEMOTHERAPY AND THIS WAS A VERY HIGH RISK GROUP OF 191 PATIENTS WITH LEUKEMIAS. THIS SHOWS YOU AT FIVE YEARS AND THIS HAS STILL HELD UP THE OVERALL SURVIVAL WAS ABOUT 57%. AND THAT PATIENTS WHO WERE POSITIVE FOR CMV PROVED TRANSPLANTS. SO JUST POSITIVE PRETRANSPLANT. THIS IS WHERE THEY DID NOT DO AS WELL AS NEGATIVE FOR CMV. NOW THAT'S NOT SOMETHING THAT ANYONE HAS FIGURED OUT A WAY TO CONTROL. AND THESE PATIENTS DIDN'T DIE BUT SOMEHOW CMD IS A SURROGATE MARKER FOR PROBABLY IMMUNE RECONSTITUTION. PROBABLY ALSO SHOWING IN THE SUBSEQUENT PAPER THAT RELAPSE WAS LOWER IF CHILDREN WERE ABLE TO MOUNT A RESPONSE WITH THEIR T CELLS TO POST TRANSPLANT. WHEN CORD BLOOD WAS TRIED IN ADULTS IN THE EARLY DAYS, IT DID NOT HAVE VERY GOOD SURVIVAL. THE FIRST PHASE PUBLISHED IN THE U.S. HAD A 23% SURVIVAL AND YOU CAN SEE THE CELL DOSE WAS QUITE LOW IN THOSE PATIENTS. ANDERSON ROCHA HAD SIMILAR STUDY A FEW YEARS LATER WITH PATIENT WHO WERE A FEW YEARS EARLIER IN THEIR DISEASE IN EUROPE. SAME CELL DOSE A LITTLE BIT BETTER SURVIVAL. AND THEN IN JAPAN DR. TAKAHASHI IN TOKYO PUBLISHED A SIMILAR STUDY SLIGHTLY HIGHER CELL DOSE WITH A MUCH HIGHER ONE-YEAR EVENT FREE SURVIVAL. NO ONE REALLY TOTALLY UNDERSTANDS THAT EXCEPT THAT THE DIVERSITY IS LOWER IN JAPAN AND IT MAY BE BETTER MATCHING IN THESE PATIENTS. BUT ALL OF THESE SOMEWHAT DISAPPOINTING RESULTS AT LEAST IN THE U.S. AND EUROPE IN ADULTS LED THE, MINNESOTA LED BY JOHN WAGNER AND JULIET BARKER TO TRY DOUBLE CORD TRANSPLANTS MEANING TWO CORDS USED AS DONORS FOR ONE ADULT. WHEN THEY DID THAT, THEY ALSO IMPROVE THE OVERALL EVENT FREE ONE YEAR SURVIVAL TO 75%. IT'S INTERESTING BUT ONCE THAT HAPPENED IN THE COMMUNE A JUST BASICALLY ADOPTED THE PRACTICE WITHOUT ANY FURTHER PROOF THAT IT WAS NECESSARY TO USE TWO CORDS. AND WHAT'S BIOLOGICALLY INTERESTING IS THAT WHEN YOU USE TWO CORDS, MORE THAN 90% OF THE TIME ONLY ONE IS IN GRAPHS AND YOU CAN ACTUALLY PICK THE WINNER BY DAY 21-28. AND THE WINNER IS NOT OBVIOUS BY THE USUAL THINGS ONE LOOK AT LIKE CELL DOSE SO EVERYONE IS STILL TRYING TO UNRAVEL THAT PUZZLE. SOME PEOPLE THINK THE SECOND CORD'S A HELPER. THE HELPER FUNCTION. OTHER PEOPLE THINK WHEN YOU CREW TO YOU HAVE A BETTER CHANCE OF HAVING ONE GOOD ONE AND REALLY THE ANSWER ISN'T KNOWN. BUT IN 2008, BE DECIDED THROUGH THE BLOOD MARROW TRANSPLANT THAT THE QUESTION SHOULD BE ANSWERED. WE ALSO DID NOT FEEL THAT IT WOULD BE INCERTAIN IN ADULTS BECAUSE WE DIDN'T THINK THE ADULT PRACTITIONERS WOULD BE WILLING TO RANDOMIZE THEIR PATIENTS TO A LOW DOSE SINGLE CODE SO INSTEAD THE STUDY IS BEING DONE IN CHILDREN. JOHN WAGNER AND I ARE CO-PI'S AND CHILDREN WITH HEMATOMA LOGIC MALIGNANCIES WERE RANDOMIZED TO ONE OR TWO CORDS AS LONG AS BOTH CORDS COULD GIVE US CELL DOSE GREATER THAN 25 MILLION PERKILO. THE STUDY FINISHED THE ACCRUAL LAST MONTH AND THE CODE WILL FIRST BE BROKEN LATE SUMMER. AND WE'LL SEE IF THERE'S A WINNER. I THINK EVEN IF ONE OR THE OTHER WINS, ONE OR TWO, I'M NOT SURE IT'S GOING TO IMPACT ADULT PRACTICE BUT WE'LL SEE BECAUSE CHILDREN INHERENTLY GET A LARGER CELL DOSE BECAUSE THEIR BODIES ARE SMALLER. EVEN WITH ONE CORD. I WANT TO JUST MENTION QUICKLY THAT CORD BLOOD TRANSPLANTATION HAS A LOT OF PEE TORTURE FOR CHILDREN WITH HEMOGLOBIN UP THESE. THESE --OPATHYS. THEY ARE RELUCTANT TO PUT PATIENTS AT RISK PARTICULARLY WITH AN UNRELATED DONOR. WHEN THERE ARE SUPPORTIVE THERAPIES THAT OKAY BUT NOT YOU'RIVE. BUT I THINK THE COMMUNITY IS MOVING MORE TOWARDS CURATIVE APPROACHES. SO THIS IS A CHILD WHO IS THE SON OF A SURGEON AT UCLA WHO GAVE ME PERMISSION TO SHOW THEIR PICTURES AND TELL THEIR STORY. HE HAD BETA MAJOR DIAGNOSED IN UTERO. FATHER DID NOT WANT THE CHILD MEDICALLY SUPPORTED WITH CHRONIC TRANSFUSIONS AND SO WE TRANSPLANTED THEM AT TWO MONTHS OF AGE AFTER -- WITH A FOUR OF SIX MATCH CORD FROM DR. RUBEN STEIN'S BANK. HE'S CURRENTLY ABOUT 12 YEARS OLD. OTHER THAN A COME OF RED CELL TRANSFUSIONS HE GOT DURING TRANSPLANT HE'S NOT REQUIRED ANY INTERVENTION. HE'S WELL, GROWING NORMALLY, HE'S OFF ON MEDICATIONS SINCE HE'S ABOUT A YEAR AND-A-HALF OF AGE. AND CURED. SO THAT'S REPRESENTATIVE OF THE BEST CASE OF WHAT COULD HAPPEN. IT'S ALSO VERY IMPORTANT I THINK TO MOVE CORD BLOOD INTO THE TREATMENT MENU I GUESS FOR SICKLE CELL ANEMIA. RIGHT NOW WE'RE TRANSPLANTING PATIENTS WHO HAVE HAD STROKES, CHEST SYNDROMES, SIGNIFICANT MORBIDITY FROM THE DISEASE AS THIS CHILD WHO HAD HAD TWO PRIOR STROKES AND WHOSE MOTHER DIED OF SICKLE CELL A FEW MONTHS BEFORE HIS TRANSPLANT. AGAIN AFRICAN AMERICAN PATIENTS HAVE HARDER TIME FINDING A MATCH DONOR AND THIS CHILD WAS TRANSPLANTED WITH A FORETO SIX CORD AFTER THERAPY AND HE IS OUTSIDE FIVE YEARS DOING WELL. THE BENEFIT WILL BE WHEN WE BRING THIS INTO THE TREATMENT OF HIS PROBABLY UNDER THE AGE OF TWO WHERE CORD BLOOD WILL PROVIDE HIGH CELL DOSES AND MORBIDITY WILL PROBABLY BE THE LEAST FROM THE TRANSPLANT AND CERTAINLY THE LEAST FROM THE DISEASE. I'M GOING TO SPEND THE REST OF THE TIME TALKING ABOUT WORK WE'RE DOING BOTH IN CHILDREN WITH GENETIC AND ACQUIRED BRAIN INJURY. THE GENETIC WORK IS PROVEN. THE ACQUIRED BRAIN INJURY WORK IS EXPERIMENTAL. BUT I'LL START WITH THE GENETIC DISEASE WORK BECAUSE THAT'S HOW WE GOT TO TRY THIS IN BRAIN INJURY. SO IT'S BEEN KNOWN FOR 20-25 YEARS THAT YOU CAN TREAT CHILDREN WITH IN BORN METABOLISM WITH ALOGENEIC TRANSPLANTATION AND THE ALSO GENERALLIC DONOR CELLS WILL SERVE AS CELLULAR SOURCE OF ENZYME REPLACEMENT. THE BAD NEWS ABOUT THIS IS YOU STILL HAVE TO ABLAT THE BONE MARROW. EVEN IN THESE CHILDREN THEIR BLOOD IS NOT THICK. BUT ONCE YOU DO THAT, THE MARROW AND THE IMMUNE SYSTEM IS REPLACED WITH DONOR CELLS THAT CIRCULATE THROUGH THE BLOOD AND PROVIDE ENZYME ANYWHERE THE BLOOD GOES BUT MORE IMPORTANTLY ENZYMES ALSO OR CELLS MIGRATE TO THE BRAIN, CROSS THE BLOOD BRAIN BARRIER, GRAFT IN THE BRAIN AND PRODUCE LOCAL CELLULAR ENZYME REPLACEMENT THERAPY. AND THROUGH THIS WORK, WE'VE ALSO SEEN EVIDENCE OF NON-HEMOPOIETIC CELL OWN GRAPHMENT. THIS WAS PUBLISHED IN BLOOD A FEW YEARS AGO FROM THE FIRST AUTHOR OF OUR GROUP BUT IT SHOWS YOU THE RANGE OF THE DIAGNOSIS OF THE FIRST 160 CHILDREN THAT WE TRANSPLANTED WITH THESE DISORDERS. AND YOU CAN SEE THERE'S A LARGE GROUP WITH -- DISEASE, DISTROPHY AND EVEN LARGER GROUP WITH IS AN FELIPE OWE -- THESE ARE THE TYPICAL LIFE STORIES THAT ARE AMENABLE TO TRANSPLANTATION. AS I MENTIONED, ALL CHILDREN GET MY LOW BLAZE CHEMOTHERAPY TO THE PROPHYLAXIS AND THEN A WHOLE HOLES OF ANTIBIOTIC AND FUNGAL ANTI-VIRAL AND PROPHYLAXIS IMMUNE SUPPORTIVE CARE WITH IBIG TO ACCELERATE HUGE ENGRAPHMENT TO INFUSIONS, TPN, PAIN MEDICINE AND LOW DOSE HEPARIN. IN OUR HANDS WITH THE MY LOW APPROACH THESE KIDS ARE AVERAGING 53 DAYS AND THEN THEY STAY NEAR OUR TRANSPLANT CENTER FOR ANOTHER FOUR TO EIGHT MONTHS DEPENDING ON WHAT THE SITUATION IS POST TRANSPLANT FOR THEM AND WHAT KIND OF SUPPORTIVE CARE THEY CAN BE GIVEN AT HOME. ENGRAPHMENT AGAIN IS RELATED TO CELL DOSE BUT HERE I JUST WANT TO POINT OUT THAT THE THING THAT MOST IMPACTED ENGRAPHMENT IN THIS KID WAS CALLING FORMING UNIT DOSE PER KILO AND IF YOU COULD GET TO A DOSE OF ABOUT 26,000 PER KILO -- I'M SORRY, YES, 26,000 OR HIGHER PER KILO AND 56,000 WAS THE HIGHEST, THEN ENGRAPHMENT OCCURRED IN ABOUT 10 OR 11 DAYS AS OPPOSED TO THOSE GETTING LESS THAN ABOUT 10 OR 11,000 PER KILO WHERE ENGRAPHMENT WAS BOTH DELAYED AND THE PORTION OF PATIENTS INGRAFTING WAS LOWER. WE ACTUALLY DO SELECT UNITS NOW BY CFU CONTENT IN A SEGMENT AND THIS IS JUST SHOWING YOU THE SIMILAR DATA WITH CD34 BUT NOT QUITE AS POWERFUL. ALL THESE PATIENTS GOT VERY HIGH CELL DOSES. THE MEDIAN CELL DOSE IN THIS GROUP BECAUSE THEY'RE YOUNG SMALL CHILDREN WAS 90 MILLION CELLS PER KILO WHICH YOU WOULD NEVER ACHIEVE IN A DOSE. BUT EVEN IN THAT HIGH CELL DOSE RANGE THAT REALLY DISSECTED THE BETTER GRAPH. ALSO IMPORTANT OBSERVATIONS WE MADE HERE WERE THAT CHILDREN WHO IN THE LEFT HAND BAR HAD A SCORE OF 80 PERCENT OR HIGHER HAD MUCH IMPROVED SURVIVAL. THIS IS 11 YEARS POST TRANSPLANTED. CHILDREN WITH A ALANSKI FOREWHICH IS A PERFORMANCE SCORE DID NOT DO AS WELL AND HAD DEATHS RELATED TO COMPLICATIONS OF DISEASE NOT OF TRANSPLANTS THREE TO FIVE YEARS POST TRANSPLANTS. BECAUSE WE KNOW THIS NOW WE ONLY FAKE CHILDREN TO A HIGHER LAN SKI AND IN TRANSPLANT WE'RE EXPLORING OTHER APPROACHES WITH THE CHILDREN FOR MORE ADVANCED DISEASE. AND AGAIN THIS IS JUST OUR DATA SHOWING THAT CFU IN THIS GROUP NOT ONLY PREDICTED ENGRAPHMENT BUT OVERALL SURVIVAL AND THAT THE HIGHER DOSES PRODUCED BETTER OUTCOME POST TRANSPLANT. NOW THESE ARE CHILDREN WITH -- SYNDROME OR -- TYPE ONE AND UNTREATED CHILD SHOWED HERE WITH A SEVERE JEANNIE TYPE. GENOTYPE. THEY DIE BECAUSE OF -- AND WITH SEVERE MENTAL RETARDATION BUT THEY ALSO HAVE DISEASE IN THE EYE. THEY HAVE HEARING LOSS, THEY HAVE JOINT DISEASE AND THEY HAVE MULTIPLE OTHER MANIFESTATIONS. AND THIS IS A CHILD WE TRANSPLANTED AT A YEAR OF AGE SHOWN ABOUT THREE OR FOUR MONTHS POST TRAGEDIES PLANT WHEN HE WENT HOME AND HIS MOTHER SENT US BUT HERE HE IS TWO YEARS LATER. I SHOW THESE PICTURES JUST SO YOU CAN SEE NOT ONLY DOES THE HEART GET BETTER AND I'LL TALK ABOUT THE BRAIN IN A MINUTE BUT THE PHENOTYPE JUST PHYSICALLY OF THESE KIDS IMPROVERS. AND A LOT OF THE FEATURES REGRESS. SOME OF THE ABNORMAL BONY FEATURES BECOME LIGHTER. THE HEARING LOSS DOESN'T PROGRESS. IN FACT WE'VE HAD CHILDREN WITH IMPROVED HEARING. THE CLOTTING DOESN'T PROGRESS SO THESE CHILDREN DON'T GO BLIND. THEIR HEARTS STAY NORMAL FUNCTIONALLY AND THEIR IQ ACTUALLY IMPROVES. AND SO THIS IS BY MARIA WHO AT THE TIME WAS AT THE UNIVERSITY OF NORTH CAROLINA, CHAPEL HILL, AND THEY ARE COLLEAGUES IN THIS WORK ALTHOUGH THEY ARE NOT OUR COLLEAGUE IN BASKETBALL. BUT SHE LOOKED AT THE FIRST 20 CONSECUTIVE CHILDREN WE TRANSPLANTED. SHE HAD A TEAM OF NEUROPSYCHOLOGISTS AND DEVELOPMENTAL SPECIALISTS, PEDIATRICIANS HEARING SPECIALISTS, PHYSICAL OCCUPATIONAL SPECIES THERAPISTS AND THEY ALL ASSESS THE KIDS PRETRANSPLANT AS WELL AS EVERY THREE MONTHS FOR THE FIRST TWO YEARS POST EVERY SIX MONTHS FOR THE NEXT FEW YEARS MOST AND THEN YEARLY THEREAFTER. WHAT YOU CAN SEE IN THIS FIRST GROUP OF FIRST 20 KIDS IS THAT IN THE BLACK DOTTED LINE THEIR DEVELOPMENTAL QUOTIENT WHICH IN A YOUNG CHILD IS EQUIVALENT TO IQ WAS FALLING OFF AT THE TIME OF TRANSPLANT. YOU'RE COMPARING IT TO THE RED LINE WITH THE GRAY AIR ARCS WHICH IS THAT OF TYPICALLY DEVELOPING CHILDREN. YOU CAN SEE THEY'RE FALLING OFF THE CURVE. FOR THE FIRST YEAR OR SO THEY CONTINUE TO FALL OFF THE CURVE. BY THE TIME THEY'RE SIX TO SEVEN YEARS OF AGE, THEY CATCH UP. AND THEIR VELOCITY OF INCREASING COGNITIVE FUNCTION ACTUALLY INCREASES OVER THE MEAN OF THE GENERAL POPULATION. AND WE NOW HAVE A WHOLE SERIES OF THESE KIDS WHO ARE IN MIDDLE SCHOOL AND EARLY HIGH SCHOOL AND THEY'RE STILL PERFORMING NORMALLY. SO THIS SEEMS TO BE DURABLE IN TERMS OF A RESPONSE. I DIDN'T BRING THIS SLIDE BUT I CAN TELL YOU THAT THE CHILDREN TRANSPLANTED UNDER SIX MONTHS OF AGE ACTUALLY HAD THE BEST IQS WHEN YOU LOOK AT THEM TEN YEARS LATER. SO TIME IS IMPORTANT AND THE YOUNGER THE DISEASES, THE CHILD IS WHEN THE DISEASE IS CORRECTIVE, THE BETTER THE OUTCOME. WE ALSO NOTICED IN THESE KIDS THAT IF THE CHILD HAD A CARDIO -- THIS IS THE HEART OF A CHILD WITH IS AN FELIPEO WHO HAD A CLINICAL -- AND WAS BIOPSIED SIX MONTHS POST TRANPLANT SHOWING THE GRAFT OF DONOR CELLS. SO THIS WAS A BOY WHO RECEIVED A FEMALE DONOR. THIS IS A -- STAIN AND A MYOSIN STAIN AND THIS IS A -- SHOWING STACKING JUST TO SHOW THIS IS NOT FUSION OF DONOR AND WHOLESALE. BUT YOU CAN SEE THIS IS THE NUCLEUS AND THEN COMING BACK ON TOP OF THAT. ANYWAY WAY YOU SEE FEMALE CELLS YOU KNOW THOSE ARE DONOR. AND ABOUT 14% OF THE CELLS IN THIS CHILD'S HEART WERE FEMALE AND WERE FROM HIS DONOR AND WERE DIFFERENTIATED INTO THE CARDIO I DON'T KNOW NOW I'M GOING TO SHOW YOU OUGHT SIMILAR SLIDES AND OTHER ORGANS BUT I'M NOT PROPOSING THAT THESE HEMOPOIETIC CELLS TRANSDIFFERENTIATED INTO CARDIAC MYO SITES OR OTHER LINEAGES. I THINK CORD BLOOD HAS A MIX OF CELLS THAT SOME OF WHICH ARE PREGENERAL TURS OF NON-HEMATOMA -- PROGENITORS AND WHEN NEEDED THEY COULD BE CALLED TO ACTION WITH AN INFLAMMED ORGAN AND CAN DIFFERENTIATE IT INTO THE CELL OF INTEREST. THIS IS A CHILD WITH HUNTER SYNDROME. IT'S BEEN SAID THAT YOU CAN'T TRANSPLANT A CHILD WITH HUNTER SYNDROME OR THEY WON'T DERIVE BENEFIT I GUESS WOULD BE THE BETTER WAY TO PUT IT. THIS CHILD WAS ARE TRANSPLANTED AT TWO MONTHS OF AGE BECAUSE OF A FAMILY HISTORY OF A BROTHER WHO HAD BEEN DIAGNOSED AT AGE FIVE AND DIED AT AGE 10. THIS CHILD'S SHOWN AT AGE SIX AND-A-HALF HERE. HE'S NOW TEN WHICH IS THE SAME AGE AVENUE HIS BROTHER'S DEATH AND HE'S STILL COMPLETELY NORMAL. YOU CAN SEE HE'S PHENOTYPICALLY NORMAL. HIS IQ IS NORMAL. HE HAS NOT HAD ANY MANIFESTATIONS OF HUNTER'S. AND I THINK AGAIN, GETTING THESE CHILDREN TO TRANSPLANT EARLIER, WHATEVER THERAPY TURNS OUT TO BE BEST IS KEY TO SEEING MAXIMAL RESPONSES. THAT ALSO IS A PITCH IN AN INDIRECT WAY FOR NEWBORN SCREENING BECAUSE IF WE CAN PICK THESE KIDS UP EARLY, WE CAN DEFINITELY MAKE A DIFFERENCE. THESE ARE CHILDREN WITH -- DISEASE THEY ALL HAVE THE EARLY INFANTILE FORM WITH A 30KB HOMOZYGOUS DELETION. THAT DISEASE IS FATAL BY ONE TO TWO YEARS OF AGE. CHILDREN PRESENT WITH IRRITABILITY AND SEATING PROBLEMS IN THE FIRST FEW MONTHS OF LIFE. GENERALLY BY SIX MONTHS OF AGE THEY'RE SPASTIC BLIND SEIZING AND SEVERELY DEVELOPMENTALLY DELAYED. AND IT REALLY IS A TROUBLE DISEASE. JUST TO MAKE SOME POINTS, THESE ARE BROTHERS WHOSE OLDEST BROTHER DIED AT AGE TWO AND AT AUTOPSY THEY DIAGNOSED CAR BAY. HE SET HAD JUST BEEN BORN AND HE WAS CLOSE TO A YEAR OF AGE. HE WAS ALREADY HAVING SYMPTOMS HE HAD DEVELOPED NORMALLY UNTIL HE WAS ABOUT SEVEN MONTHS OLD AND THEN STARTED LOSING MILE STONES. AND HE WAS A FEW WEEKS OLD WHEN THE DIAGNOSIS WAS MADE IN THE FAMILY. HE WAS TRANSPLANTED AT THREE WEEKS OF AGE AFTER -- HE WAS TRAGEDY PLAPTD AT 1TRANSPLANTED AT 13 MONT HS OF AGE. THEY'RE BIGGER AND THEY HAVE HAIR. BUT BASICALLY NEUROLOGICALLY THIS CHILD TRANSPLANTED THREE WEEKS OF AGE IS NORMAL AND THIS CHILD HAS SEVERE MOTOR DISABILITY, ALTHOUGH COGNITIVELY HE'S NORMAL AND KNOWS EVERYTHING THAT'S GOING ON BUT HE NEVER REGAINED ANY OF THE MOTOR FUNCTION THAT HE LOST. THE CHILD WAS DIAGNOSED AT FIVE DAYS OF AGE AFTER A FAILED PGD AND WAS TRANSPLANTED 19 DAYS OF AGE AND I'LL SHOW YOU AN OLDER PICTURE BUT SHE'S COMPLETELY NORMAL. THIS CHILD, HER SOLDIER SISTER HAD DIED AND HER OLDER BROTHER HAD DIED. PARENTS DIDN'T BELIEVE IT WOULD HAPPEN AGAIN SO SHE WASN'T TESTED UNTIL SHE WAS OVER A MONTH OF AGE AND SHE WAS TRANSPLANTED OVER TWO MONTHS OF AGE AND AGAIN SHE HAS SEVERE MOTOR DISABILITY, COGNITIVELY NORMAL BUT WITHOUT VERY EARLY INTERVENTION THE MOTOR DISEASE IS ALREADY PROGRESSING. JUST IN TERMS OF OVERALL SURVIVAL FOR THE GROUPS TRANSPLANTED 58 CHILDREN WITH CARBAY OF WHICH 25 PR NEWBORNS. THE OVERALL SURVIVAL OF THE GROUP IS ABOUT 60% BUT THE NEW CORN SURVIVAL IS 90% AT 12 YEARS. JUVENILE KIDS HAVE ABOUT 80% SURVIVAL AND THEY PROGRESS LESS RAPIDLY. AND THE CHILDREN WHO PRESENTED AS INFANTS BUT NOT NEWBORNS, SOME NEW DIAGNOSIS IN THE FAMILY CHILD ALREADY HAVE ONLY ABOUT A 25% SURVIVAL. AND THEIR QUALITY OF LIFE IS POOR. THEY DON'T REGAIN NEUROLOGIC FUNCTION THEY'VE LOST AT THE TIME OF TRANSPLANT. THEY ONLY STABILIZE. NOW, I JUST SHOWED YOU IN THAT MOTORIZED WHEELCHAIR WAS TRANSPLANTED RELATIVELY EARLY BUT OBVIOUSLY HAS GOT MOTOR DISEASE. WE STARTED TO LOOK TO SEE IF SOME OF THESE CHILDREN ALREADY HAD PROBLEMS EVEN AT BIRTH. SO THESE ARE MRI OF THE SPINAL CORD TRACK -- OF THREE DIFFERENT TWO-DAY OLD BABIES WITH KNOWN INFANTILE CAR BAY DISEASE WHO SUBSEQUENTLY WENT ON TO TRANSPLANT. I DON'T THINK YOU NEED TO BE A RADIOLOGIST TO SEE THE DIFFERENCE BUT THIS CHILD'S TRACK LOOKS RELATIVELY NORMAL. THE YELLOW IS EARLY MYELINATION BECAUSE BABIES ONLY START MILE NOTING THE END OF THE THIRD TRIMESTER OF PREGNANCY. THIS CHILD ALSO HAS A NORMAL TRACT AND WHICH CHILD HAS A SCIFTY KINASKITY KIND OF RATHERY LESS ORGANIZED TRACK. ALL THREE OF THESE CHILDREN THEY'RE ALL MERELY EIGHT YEARS OLD NOW. THESE TWO CHILDREN WALK AND THIS CHILD DOESN'T. SO BECAUSE OF THIS AND OTHER WORK, I'M NOT SHOWING YOU WE FEEL LIKE WE WANT TO KNOW THAT IN MANY CHILDREN, THERE'S DAMAGE PRENATALLY. AND ALSO THAT WE HAVE A MARKER AT BIRTH FOR PROGNOSIS WHEN WE DISCUSS WHAT OUT COMES MIGHT BE LIKE FOR A FAMILY WHO IS TRYING TO MAKE A DECISION ABOUT WHETHER THEIR CHILD SHOULD GO THROUGH A TRANSPLANT WHICH IS AN AGGRESSIVE LIVE THREATENING PROCEDURE AND THREE WE HAVE A TARGET FOR SELF THERAPY BECAUSE WE ALREADY CAN SEE THIS DAMAGE AND MAYBE WE CAN BE CREATIVE WITH THE GRAFT AND COME BACK AND TREAT THIS. FOUR, AND I'M NOT GOING TO TALK ABOUT IT TODAY BUT WE DO ALSO HAVE AN APPROACH TO TRY TO TRANSPLANT THESE KIDS IF THEY CAN BE IDENTIFIED IN THE FIRST TRIMESTER OF PREGNANCY. TO SEE IF WE CAN INDUCE TOLERANCE AND GET SOME ENZYME IN. I THINK UNLESS IN ANIMAL MODELS IF YOU DO THIS IN THE FIRST TRIMESTER OF PREGNANCY WITH A AN ENGRAPHMENT. WE HAVEN'T ACTUALLY TRANSPLANTED ANYONE YET. THIS IS THE BRAIN OF A CHILD AND I'LL SHOW YOU ANOTHER SLIDE IN A MINUTE WHO DIED AT 20 MONTHS OF AGE WHICH WAS TEN MONTHS PLUS TRANSPLANT. SHE WAS ONE OF THE SYMPTOMATIC CHILDREN WE TRANSPLANTED. SHE WAS A GIRL, HER DONOR WAS A BOY. THIS JUST SHOWED THE AGAIN XY SHOWING Y CHROMOSOMES IN MANY OF THE CELLS IN THIS CHILD'S BRAIN. NOW, IT'S NOT NECESSARILY A SURPRISE THAT ME -- WOULD TRAVEL TO THE BRAIN AND GRAFT. BUT AS WE LOOKED HARDER AT THESE CELLS SOME OF THEM LOOKED LIKE AL GORE DENIED SITES. THIS IS HOW THE INGRAPHMENT IS. WE WENT BACK TO THE LABORATORY AND TOOK -- CORD BLOOD AND ARE GROWING WHAT WE THINK ARE -- THIS IS WHAT THE CELLS LOOK LIKE AFTER THREE TO FOUR WEEKS IN CULTURE, JUST MORP MORPHOLOGICALLY. THEY'RE GROWN IN MEDIA FROM STENSTEMCELL TECHNOLOGIES AND GAS EXCHANGE. BUT THEY EXPRESS MARKERS OF AL GORE DEN DENDROSITES. THESE ARE THE AM GOES, THIS IS THE MBP STAIN AND THIS IS A SHIVER NEURON THAT WE TAKE FROM A SHIVER MOUSE WHICH IS A MOUSE THAT CAN'T MAKE MYELIN PLAYED IN CULTURE. THEN WE COCULTURE THE NEURON WITH THE AL GO AND WE CAN SEE MYELINATION ON THE NEURONS. WE CAN SEE IT'S ON EM AS WELL AND THEY ARE ASSOCIATED WITH PRODUCING MYELIN COME UP. SO WE THINK THAT WE CAN USE THIS AS AN ESSAY AND A FUNCTIONALIST ATO SAY WE HAVE A GOOD BATCH OF SELLS OR NOT TO TAKE INTO THE CLINIC. AND WE'RE WORKING AT DUKE TO GET A GIFT FROM THE ROBERTSON FOUNDATION WHICH NEIGHBORHOOD US TO BUILD A GMP LAB FOR CELL MANUFACTURING WHICH WE COMPLETED LAST SUMMER AND WHERE WE'RE IN THE PROCESS OF FINALIZING MANUFACTURING TO SUBMIT AN INB FOR A PHASE ONE TRIAL. AND WE INTENDED TO TEST THIS FIRST IN A SETTING WITH CHILDREN WITH DISORDERS WHO ARE TOO SICK FOR A STANDARD TRANSPLANT JUST FOR SAFETY. AND THEN IF IT'S SAFE AT TWO DIFFERENT DOSE LEVELS INTRASEEKLY WE'RE GOING TO COMBINE IT TO SEE IF WE CAN PROLOUNGPROLONG INGRAFTMENT. THEN WE COMBINE IT WITH A STANDARD TRANSPLANT AND TAKE THAT SMALL FRACTION TO GROW OLIGO-- WHEN THE CHILD'S THREE TO FOUR WEEKS OF AGE WE'LL PROBABLY DIRECTLY INJECT THE OLIGOCELLS FROM THAT DORCH SO -- DONOR. WE ARE ALSO COLLABORATING WITH A COMPANY TO TRACK THE CELLS BECAUSE THEY HAVE DATA ANALOGUE THAT SEEMS TO BE SOIFD. THEY'VE TESTED AN ADULT SHOWS UP ON MRI AND STAYS IN THE CELL FOR ABOUT FOUR MONTHS. SO FOR THE LAST PART OF THE TALK I'M GOING TO JUST GIVE A LITTLE BIT AND TELL YOU ABOUT WORK WE'RE NOW DOING IN CHILDREN WITH ACQUIRED BRAIN INJURIES. SO WE ARE RUNNING TRIALS NOW UNDER INDs USING AWE TALL JUST CORD BLOOD WITH CHILDREN WITH CEREBRAL PALSY AND CONGENITAL -- AND OUR THOUGHTS BEHIND THIS WAS THAT CORD BLOOD MAY, SHOULD CONTAIN CELLS THAT HAVE ANTI-INFLAMMATORY PROPERTIES OR MAY INDUCE SOME SORT OF ENDOGENOUS REPAIR THROUGH TROPHIC EFFECTS AFTER INJURY. WE KNOW CORD BLOOD CONTAINS NEURO PROGENERAL TURS THAT MIGHT ENGRAPH BUT WE'RE NOT REALLY THINKING THE MECHANISM FOR THIS WOULD BE ENGRAPHMENT. WE WOULD CROSS THE BLOOD BRAIN BARRIER AND WE'VE WORKED WITH INVESTIGATOR NAMED SAID TAN AT THE UNIVERSITY OF CHICAGO WHO HAS A MODEL AND TO WHOM WE GAVE HUMAN CELLS AND SHOWED BENEFICIAL FUNCTIONAL OUTCOMES AND PHOTOGRAPHICKING OF THOSE CELLS TO THE BRAIN AT 24 HOURS AFTER INJECTION WHICH WAS DONE ON DAY ONE. SO THESE, EVEN THOUGH IT'S A XENO GRAPH MODEL, THESE ARE IMMUNOCOMPETENT RABBITS DO HAVE THE PURPLE LINE WITH TREATED ANIMALS, THE TURQUOISE AND YELLOW ARE JUST CONTROL WITH MEDIA OR SALINE ANIMALS BUT POSTURE, LOCOMOTION AND BALANCE FOR ALL IMPROVED IN THE TREATED ANIMAL. THERE WAS LESS SPASTICITY AND LESS DYSTONIA IN TREATED ANIMALS. NOW I WOULD BE THE FIRST TO SAY I'M NOT SURE HOW WELL THE ANIMAL MODELS REALLY TRANSLATE INTO HUMANS EFFECTS BUT AT LEAST WE HAD SOME EVIDENCE IN ANIMAL MODEL OF EFFICACY. SO OUR STUDIES RIGHT NOW THEY'RE ONGOING AS ONE CALLED BABY BACK, BABY BRAIN AWE TALL GUST CORD INCLUDED WHICH IS HIG HYPOXIC -- IN BABES WHO ARE KOOSTLED AS STANDARD OF -- IN THE FIRST COUPLE DAYS OF LIFE. WE HAVE A STUDY OPENING NOW FOR POST -- WITH CONGENITAL LEFT HEART SYNDROME NOT TO HELP THEIR HEART BUT TO HELP THEIR BRAIN RECOVER FROM IMPACT WHICH CAUSES STROKE AND OTHER HYPOXIC INJURY. AND THEN A CEREBRAL PALSY STUDY WHICH I'LL TALK ABOUT IN A MINUTE. I JUST WANT TO GIVE YOU A FEW ANECDOTES ABOUT HOW KIND OF COMPLICATED IT WAS TO SET THESE STUDIES UP I HOW MUCH THE RIGHT WAY. BUT THESE STUDIES WE HAD MOMS DELIVERING TERM BABIES WHO WERE EXPECTING TO BE HEALTHY AND HAD FIELDED THE STRESS KIND OF THE END OF LABOR DURING LABOR AND WE WERE PRECIPITOUSLY DELIVERED. WE REALLY DIDN'T HAVE TIME TO CONSENT THE MOM OR THANK YOU ABOUT -- AND ANY OF THOSE THINGS. SO WE WORKED OUT A MECHANISM TO OBTAIN DELIVERING THE BABY OBTAIN VERBAL ASSENT FROM THE MOTHER TO AT LEAST COLLECT THE CORD BLOOD AND THEN COME BACK LATER TO TALK TO THE MOM ABOUT PARTICIPATING IN THE STUDIED. IF THE MOMMA GREED TO -- AGREED TO PARTICIPATE IN THE CORD STUDY -- DEBLEAT DEPLETED ON THE SAME ISSUE WE USE FOR BANKING. WE HAD TO ADJUST VOLUMES FOR TREATING VERY SMALL BABIES BUT THE BABY IS PRETREATED WITH HYDROCORTISONE. CELLS ARE INFUSED INTRAVENE I INTRAOUSLY A ND ANY CELLS NOT USEDDOR FROZE I FOR FUTURE USE IF NEEDED. WE GIVE THE BABIES, AND SINCE THESE ARE FRESH CELLS THERE'S NO ISSUE WITH DMSO. AND WE ARE TREATING THESE BABIES AND FOLLOWING REACTIONS AS WELL AS 18-MONTH FOLLOW UP FOR FUNCTIONAL DEVELOPMENT AND SURVIVAL. THIS IS JUST A PICTURE OF THE INFUSIONS THAT WE CREATED FOR SMALL BABIES BECAUSE IF WE USE THOSE BAGS EXPFER WANTE AND EVERYBODY WANTED TO GET THE LAST CELLS IN PEOPLE GOT TOO ENTHUSIASTIC ABOUT RINSING THAT BAG AND GIVING THAT BABE TOO MUCH FLOWED. SO WE CAREFULLY METERED THE VOLUME OF THE INFUSION, THE NUMBER OF CELLS, THE NUMBER OF RED CELLS AND THE FLUSH JUST TO CLEAR THE LINE. WE ALSO WORKED WITH FI O BIO PHASE SO THAT IF THIS WERE TO WORK AND THAT'S AN IF AT THIS POINT, WE WOULD HAVE A MACHINE LIKE THAT IN A LOCAL BLOOD BANG. THE CELLS COULD BE OPERATED AND FOUR DOSES COULD BE REMOVED FROM THE BAG STERILELY IN A CLOSED SYSTEM. FOR ADMINISTRATION. WHEN WE FIRST STARTED DOING THIS WITH OUR AWK STA OBSTETRICIANS WE HAD A BIG FAILURE RATE. THE BLUE LINE IS COOL BEEBTZ. THE GREEN LIGHT IS COLLECTIONS FROM BABIE WHOCOLLECTIONSOF BABIES TO MIGH T HAVE -- WHEN WE FIRST STARTED -- IF YOU GET THE LEFT SIDE OF THE SLIDE WE WERE MISSING BABIES WHO WERE COOLED AND THEIR CODE BLOOD WAS NOT BEING COLLECTED. WE TALKED TO THE OD'S ABOUT WHY IT WAS HAPPENING, WHY THEY JUST WEREN'T SURE WHO TO COLLECT FROM. AND WE ALSO WEREN'T MAKING THE BAGS FOR COLLECTION AS ACCESSIBLE SO WE MADE TWO INTERVENTIONS. WE TOLD THE OBESE COLLECT FROM ANYBODY YOU'RE NOT SURE ABOUT. AND WE PUT COLLECTION BAGS IN EVERY SINGLE DELIVERY ROOM SO THEY COULD GRAB IT AND USE IT AND IT HAS A CLAMP TO CLEAN THE CORD IN THE BAG. ONCE WE DID THAT IN THE GREEN LINE YOU CAN SEE THAT WE COLLECTED MORE UNITS THAN WE HAD BABIES WHO NEEDED INFUSIONS. BUT WE DIDN'T. NOW I THINK PROBABLY MOTIVATED BY THE FACT THAT THIS MIGHT HELP THE BABY ARE VERY MOTIVATED, COLLECT ALL THE TIME, COME BACK TO US WITH YTH ABOUT HOW TO IMPROVE COLLECTIONS. AND I REALLY THINK THE BABY IS THE FULCRUM FOR ALL OF THIS. BUT WE WERE SUCCESSFUL WITH THAT. NOW, I DON'T HAVE RESULTS OF THAT STUDY. THERE ARE 24 BABIES ENROLLED, OUR GOAL IS 30. SO I MIGHT HAVE SOMETHING TO TELL YOU BUT I WILL TELL YOU THAT THE OB'S SEEM TO BE ENTHUSIASTIC ABOUT THESE BABIES AND FOLLOW UP AND THEY'RE NOT LOOKING AS IMPERATIVE AS THEY WOULD HAVE EXPECTED. WE ALSO PUBLISHED IN A SAFETY STUDY IN CHILDREN WITH CEREBRAL PAM SEE WHO CAME TO US FOR INFUSION OF THERE OWN APPALL GUST CORD BLOOD APPEARANCE JUST BECAUSE THEY ELECTED TO DO PRIVATE BANKING. AND ALL THESE PATIENTS WERE SELF REFERRED AND WE THEN QUALIFIED THEM AND THEIR CORD BLOOD AND INFUSED 184. WE HAD CRITERIA AND STILL DO FOR SELECTION AND ACCEPTANCE OF THE CORD BLOOD. THIS MAKES A LOT OF FAMILIES ANGRY BECAUSE MANY ARE PRIVATELY BANKED. CORD BLOODS DON'T MEET THESE STANDARDS BUT WE HAVE ENFORCED THEM AND WE CONFIRM IDENTITY BY CHECKING ON THE CHILD AS WELL AS SOMETHING ATTACHED TO THE CORD BLOOD IN ORDER FOR THE CHILD TO COME ON STUDY. I WILL SAY WE HAVE HAD A FEW THAT TURNED OUT NOT TO BE THAT CHILD'S CORD BLOOD OR IN TWIN DELIVERIES AND IT WAS THE OTHER BABIES. AND WE DO NOT USE THOSE. AGAIN WE DID INFUSIONS IN 184 PATIENTS. THEIR AGE WAS YOUNG, 2.3 YEARS WITH EITHER CEREBRAL PALSY OR KECONGENITAL -- IN OUR CLINIC AFTER PREMEDICATION WITH BENADRYL, HIDE CORE SORT OF HYDROCORTISONE . IN TWO OF THOSE CASES WE COULD NOT COMPLETE THE INNEUTION AND WE HAD ONE -- INFUS INFUSION AND WE HAD ONE MOTHER WHO GOT A REACTION IN THE DMSO THAT CAME OUT -- SHE HAD TO BE TREATED WITH BENADRYL IN THE CLINIC BUT EVERYBODY RECOVERED AND THERE WERE NO SERIOUS REACTIONS. ONE OF THE I GUESS JUST FUNNY THING THAT HAPPENS IN PEDIATRICS. NOW, IN THIS STUDY WHICH WAS A SAFETY STUDY, EVERYBODY WAS LOOKING FOR EFFICACY, AND IT'S VERY HARD TO DETERMINE. I'M A PEDIATRIC ONCOLOGIST BY TRAINING AND DEAL WITH CHILDREN WITH CANCER AND LIFE THREATENING DISEASES ALL THE TIME BUT THIS IS A MUCH HARDER CONSTITUENCY OF PARENTS IN MY VIEW TO DEAL WITH BECAUSE THEY REALLY HAVE CHILDREN WITH CHRONIC IMPAIRMENT AND NO END POINT. AND SO THEY ARE HUGELY MOTIVATED BY BEING ABLE TO DO SOMETHING THAT MIGHT HELP. I THINK IT EMPOWERS THEM TO RELATE DIFFERENTLY TO THEIR CHILD AND THERE ARE MANY PLACEBO EFFECTS. EVERY FAMILY, I TALK TO EVERY FAMILY AND I SAY YOU'RE NOT GOING TO SEE ANYTHING IN A FEW DAYS OR A FEW WEEKS. AND EVERY ONE OF THEM CALLS ME UP OR WRITES ME AND SAYS I KNOW YOU SAID I WON'T SAY THINKING BUT. I THINK IT'S REALLY THE HOPE OF WANTING TO SEE SOMETHING. SO WE FELT AT THE END OF THE DAY, WE COULD NOT TELL IF FLFSZ AN EFFECT. THE OTHER THING TO JUST MENTION IS CHILDREN WITH CEREBRUM PALSY HAS IMPROVED TO SOME DEGREE. SO IF THEY IMPROVE, YOU CAN'T NECESSARILY SAY IT'S BECAUSE OF THE INTERVENTION ITSELF. AND SO WE KNEW WE NEEDED A RANDOMIZED TRIAL. I'LL COME BACK TO THAT IN A SECOND. I WANT TO ALSO SHOW YOU THE DIFFERENCE IN THESE IN BLUE AND THIS INCLUDES EVERYTHING WE ACCEPT AND REJECT IN THE PUBLIC BANK. SO THE VOLUME IN THE PRIVATELY COLLECTED UNITS WITH 60 MILLS WITH A COUNT OF ABOUT 500 MILLION CELLS CLOSE TO AS OPPOSED TO NINE MILLS WITH A BILLION OR 1.1 BILLION CELLS. AND ONLY 14% OF THESE COLLECTED AWE TALL GUST COR TALL GUST -- FOR THE NATIONAL CORD BLOOD ANYONE. I THINK THAT'S IMPORTANT BECAUSE THESE CELLS ARE VALUABLE AND I THINK THE SAME STANDARDS NEEDS TO BE APPLIED TO BOTH PUBLIC AND PRIVATELY COLLECTED UNITS. SO NOW AGAIN BECAUSE OF THE SUPPORT WE HAVE THROUGH THE ROBERTSON FOUNDATION, WE ARE IN THE MIDDLE OF A RANDOMIZED PLACEBO CONTROLLED TRIAL OF AWE TALL GUST CORD BLOOD IN CHILDREN WITH IS A PARTICULAR CP AND WE COLLECTED THAT BECAUSE THERE ARE GOOD MEASURES TO SCORE RESPONSES IN THAT PARTICULAR FORM OF CT. CHILDREN HAVE TO BE AGE 1 TO 6. THEY HAVE TO HAVE AN ELIGIBLE CORD BLOOD AND ONE OF THE MAIN SCALES WE'RE USING IS CALLED THE GROSS MOTOR FUNCTION MEASURE AND THEY HAVE TO BE MODERATE TO SEVERE BUT THEY CAN'T BE VERY MILD OR MORIBUND TO BE ON THE STUDY. SO THAT WOULD BE A LEVEL ONE OR A LEVEL FIVE. SO BLINDED CROSS OVER DESIGN I'LL SHOW YOU AND THE EVALUATIONS ARE DONE BY TEENS OF NEUROPSYCHOLOGISTS AND NEUROFUNCTIONAL TESTING MRI'S AND FUNCTIONAL MRI MANY -- AND QUALITY OF LIFE. OUR PRIMARY END POINT IS GOING TO BE A POSITIVE RESULT WILL BE MORE THAN A 30% INCREASE IN THE PREDICTED GMS SCORE AT ONE YEAR. SO THIS IS THE MOTOR FUNCTION SCORE VALIDATED FOR CHILDREN WITH CP THAT SAYS IF YOU'RE AGE ONE AND YOU HAVE THIS LEVEL OF FUNCTION AT AGE TWO YOU WILL HAVE THAT LEVEL OF FUNCTION. AND THEY HAVE TO BE ABOVE 30% OF WHERE THEY WOULD HAVE PREDICTED TO BE FOR AGE IN ORDER TO BE SUPPORTIVE OF A RESPONSE. WE'RE CURRENTLY IN LOWERING, WE'RE MORE THAN HALFWAY THROUGH ACCRUAL. THIS JUST SHOWS YOU THE STUDY DESIGN SO FAMILIES CONTACT US BY PHONE AND WE GET THEIR PERMISSION VERBALLY THROUGH A PHONE CONSENT TO SCREEN THE CORD BLOOD TO SEE IF IT'S ELIGIBLE PIE CRITERIA PROVIDED BY THE BANK. IF IT IS ELIGIBLE IT'S SHIPPED TO DUKE. THE FAMILY GOES FOR A QUALIFYING VISIT. THEY HAVE A WHOLE SERIES OF TESTS BY A NEUROLOGIST AND ENVIRONMENTAL NEW -- NOT BY ME. IF HE THIS NEED ELIGIBILITY REQUIREMENTS AND THE PARENTS SIGNS CONSENTS, THEY ARE RANDOMIZED. IT'S HEALING ALL THE RANDOMIZATION PROTOCOLS. IF THEY RANDOMIZE ON ONE WHEN THEY GET THEIR OWN CORD BLOOD THE NEXT DAY AND IF THEY HAVE A RANDOMIZED PLACEBO. THE FDA LET US USE A PLACEBO THAT REALLY MIMICKED WHAT A CORD BLOOD INFUSION COULD LOOK LIKE AND SO IT'S PC199 WHICH IS A CULTURE MEDIA SMIZIKED WIT SPIKED WITH THE CELLS SO THEY CAN SMELL AND -- AS OPPOSED TO THE PRODUCT. THEN THE CHILDREN FINISH A FULL WEEK OF EVALUATIONS TO COME BACK A YEAR LATER, CROSS OVER TO WHATEVER THEY DIDN'T GET THE FIRST TIME, GET A SECOND INFUSION OF WHATEVER THAT IS TO GET ANOTHER AND THEN THEY COME BACK AT TWO YEARS FOR THE FINAL SERIES OF EVALUATIONS. THE EVEN POINT THOUGH IS THIS ONE YEAR EVALUATION WHERE WE'RE COMPARING THE KIDS THAT GOT PLACEBO TO CORD BLOOD. WE'RE DOING A LOT OF IMAGING WITH THIS AND THIS IS FIBER TRACKING AGAIN THE CORED CO-SPINAL TRACKS. THIS SHOWS YOU A CHILD WITH QUAD PLEAJ WHERE THE TRACKS ARE MINIMAL. DIE PLEAJ YEAH WHERE THEY'RE SKINNIER BUT NOT TOTALLY GONE. HEMI PLEAJ YEAH WHERE ONE SIDE IS NORMAL AND THE OTHER SIDE ISN'T AND THIS IS A VERY REVEALING POPULATION BECAUSE WE CAN LOOK COPY BY IMAGING WHETHER THERE WILL BE SOME CHANGE IN THE DIMENSIONS OR DIAMETER OF THIS INJURY AND THEN THIS IS WHAT A NORMAL CHILD LOOKS LIKE. AND WE'VE GOTTEN THE RESOLUTION OF THIS KIND OF IMAGING, VERY TIGHT SO THAT WE CAN ACTUALLY SEE NERVES GOING TO THE HANDS OR FALLS OR THE FOOT SEPARATELY. AND THAT'S IMPORTANT AND WILL YOU BE CORRELATED WITH WHEREVER THE CHILD'S DEFICIT IS. I'LL JUST MENTION THIS KIND OF IMAGING, YOU WON'T SEE THESE DEFECTS ON A NORMAL MRI SO YOU HAVE TO DO THIS TRACKING IN ORDER TO SEE THEM. SO THAT STUDY IS AGAIN MORE THAN HALFWAY THROUGH ACCRUAL. WE SHOULD HAVE ANSWERS IN A YEAR AND-A-HALF. I JUST WANT TO MENTION WE'RE ALSO DOING WORK LOOKING AT WHETHER THE ALDH PRETTY CELLS FROM -- DONORS CAN CHANGE PATTERNS OR REACTIONS TO AN INJURY IN MICE UNDER GOING HIGH DOSE RADIATION FOR TREATMENT OF BLASTOMA -- AND WE HAVE SHOWN IN THIS MODEL THAT ALDH BRIGHT CELLS WHICH IS THE PINK MINIMIZED INFLATION THAT WOULD OTHERWISE BE SEEN IN THE UNTREATED MICE. THAT WOULD BE THE BLUE BAR, AND THIS IS PNF. IF1, IO10, IO5 AND IO ONE BETA. THE PURPLE ARE MICE THAT GOT ALDH AND EXERCISE. AND WE DID NOT SEE THE EFFECT WHEN WE ADDED THE EXERCISE. I'M ONLY TRYING JUST A SMORGASBORD OF DIFFERENT THINGS WE'RE LOOKING AT. AND THE REASON IS GOING TO BECOME APPARENT IN A MINUTE. SO FIRST OF ALL I WANT TO SAY THAT WE LEARNED LESSONS FROM KIDS WITH METABOLIC DISEASES UNDER GOING AL ALOGENEIC TRANSPANT FOR GENERIC DISEASES OF THE BRAIN AND WE APPLIED THOSE TO, WE ARE APPLYING THEM NOW TO ACQUIRE BRAIN INJURY. WE KNOW WE CAN SAFELY REFUSE ALL POSITIVE CORD BLOOD. WE KNOW THE QUALITY OF FAMILY BANK CORD BLOOD NEEDS TO BE IMPROVED AND WE HAVE A RANDOMIZED TRIAL TO SORT THESE OUT. THE STUDIES SHOW POSITIVE RESULTS. WE REALLY THINK THAT WE'RE NEVER GOING TO HAVE EVERYBODY'S CORD BLOOD AND THAT IT DOESN'T MAKE SENSE TO START TRYING TO SAVE EVERYBODY'S CORD BLOOD AND PERHAPS THE KIDS WHO NEED IT THE MOTION LOOK PREMATURE INFANTS AT HIGHER RISK FOR BRAIN INJURY WON'T BE ABLE TO HAVE THEIR BLOOD SAVE SAVED. WE THINK AN ALOGENEIC CORD BLOOD IS GOING TO BE NECESSARY. I WANT TO LEAVE THESE QUESTIONS TO BE DISCUSSED MAYBE RIGHT AFTER I FINISH. BUT ONE QUESTION WE HAVE IS CAN WE USE THE VALING VAST RESO IS OF CORD BLOOD BANKED FOR THERAPIES AND CAN WE CREATE AN OFTEN THE SHELF PRODUCT THAT'S ALSO GENERALLATED FROM CORD BLOOD MAYBE LIKE IPF. THE BIG FUNDMENTAL QUESTION AROUND THIS IS, ISN'T GRAPHMENT REALLY NECESSARY AND DURABLE GRAPHMENT NECESSARY FOR BENEFICIAL EFFECTS OF CELLS. SO THEY WILL BE IN PATIENTS WITH BRAIN INJURY. WE'RE HOPING THE ANSWER TO THAT QUESTION IS NO, THAT YOU CAN SEE PARAFFIN TROPHIC AND OTHER EFFECTS ON ENDOGENOUS CELLS FROM INFUSED CELLS THAT WILL HELP THE BODY KNOW WHAT THE RIGHT THING TO DO IS TO REPAIR THE INJURY WITHOUT DURABLE ENGRAPHMENT OF THE CELLS AND WE CAN SAFELY GIVE THESE THERAPIES WITHOUT CHEMOTHERAPY OR SOME OF THE OTHER HIGHER RISK PARTS OF AN ALOGENEIC PROCEDURE. WE DON'T KNOW THE BEST CELLS TO USE THE BEST TIMING OR DOSE, ALL OF THOSE THINGS HAVE TO BE SORTED OUT WE HAVE. DON'T KNOW IF REPEATED DOSING WILL HAVE REVERSE EFFECTS BECAUSE OF INDUCTION OF TOLERANCE TO THE CELL AND SENSITIZATION. WE ALSO SEE IF WE ASK THE QUESTION ABOUT WHETHER THERE ARE APPROPRIATE ANIMAL MODELS IN WHICH WE CAN REALLY STUDY THE EFFICACY. NOT THE SAFETY BUT THE EFFICACY OF THE CELL THERAPIES AS PRECLINICAL STUDIES TO TREATMENTS IN MAN. I PERSONALLY THINK THAT WE SHOULD BE DOING SIMULTANEOUS ANIMAL AND HUMAN STUDIES TO TRY TO SORT OUT THE QUESTIONS FROM BOTH SIDES OF THE COIN. THIS IS JUST, IT'S PROBABLY NOT PROJECTING VERY WELL BUT OUR PLAN FOR THE NEXT FIVE YEARS FOR HUMAN AND ANIMAL CLINICAL TRIALS TO TRY TO MEET IN THE MIDDLE THE GREEN WHICH IS REGULATORY AFFAIRS TO GET ENOUGH SAFETY AND EFFICACY DATA TO TAKE AL JOE OH GENIC CELLS. I'LL END WITH A COUPLE THINGS. THESE ARE ALL THREE THAT HAVE RELATED -- FOR METABOLIC DISEASES WHO WE TOOK WITH US TO THE FDA WHEN THE NEW YORK BLOOD CENTER HAD THEIR HEARING FOR A LICENSE. WE HOPE TO CONVINCE THE FDA IT SHOULD NOT BE TIGHTENED USING CORD BLUE BUT THE METABOLIC AND SICKLE CELL CASES NEEDED TO REMAIN PART OF THE REPERTOIRE FOR TRANSPLANTATIONS. THIS LITTLE GIRL IN THE SWIMMING POOL NOW AGE SEVEN AND-A-HALF WITH CAR BAY. THIS IS A 13-YEAR OLD EIGHTH GRADER WITH FULLER AND THIS IS AN 11-YEAR-OLD WITH ADRENAL DISTROPHY. I COULD SAY THAT HE JUST GOT UP AND BY HIMSELF SAID I THINK I HEAR YOU PEOPLE SAYING YOU'RE NOT SURE CORD BLOOD WORKS FOR CHILDREN WITH METABOLIC DISEASES. I RESPRKFULLY BEG TO DIS AGREE. AND HE HAD HIS I PAD AND HE RED A WHOLE THING BUT IT WAS VERY POWERFUL AND NOBODY PUT HIM UP TO IT. BUT I THINK THAT WE'RE MAKING HUGE PROGRESS IN THESE CHILDREN PARTICULARLY IF WE GET THEM EARLY AND THAT WE HAVE TO KEEP WORKING ON IT. I WANTED TO END BY JUST SAYING THAT I COULDN'T BE HERE STANDING HERE TALKING TO YOU IF I DIDN'T HAVE A HUGE TEAM OF VERY DEDICATED PEOPLE. SEVERAL HUNDRED NOW WORKING WITH ME AT DUKE FOR MANY YEARS MANY OF THEM INCLUDING OUR TRANSPLANT TOO MANY, OUR RESEARCH FELLOWS, OUR STEM CELL LAB WHICH PREMIUMS FOR CLINICAL PROJECTS. THE PRODUCT IS CORD BLOOD BANK, THE TRANSLATIONAL MEDICINE INSTITUTE IN OUR NEW CELL THERAPY PROGRAM AND I'LL ESPECIALLY MENTION JESSICA'S SON AT A YOU'RE FACULTY MEMBER WORKING WITH ME ON THE CPT TRIAL WORKING ON NEUROLOGY AND NEURO RADIOLOGY COLLEAGUE. AND THEN HE'S DONE A LOT OF THE NEURODEVELOPMENT WORK FROM NHLBI, THE MS CORPORATION SO THE NATIONAL PROGRAM AND THE ROBERTSON FOUNDATION. AND PRIMARILY OUR PATIENTS, THEIR PARENTS AND THEIR FAMILIES WHO ARE FOR ME AT LEAST THE REAL MOTIVATORS AND THE REAL HEROES SO THE WHOLE PICTURE. THIS IS WHAT THEY PICK AND MOM HONORING THE UNIT THERE 80 POUND IV POLE UNDER GOING TRANSPLANT. THE COMMENDMENT TO THESE CHILDREN ARE HUGE AND WE'RE BLESSED TO BE DOING THE WORK WE'RE DOING. I'LL STOP THERE AND SEE IF YOU HAVE ANY QUESTIONS. >> [INDISCERNIBLE] >> IN THE GENETIC DISEASES -- NO IN THE HIE, NO. >> THAT'S WHAT I MEANT. >> NO. >> THAT SECTION. AND [INDISCERNIBLE] DO YOU THINK IT'S I WISH I KNEW. WE'RE LOOKING AT SUBSETS NOW IN THE WAY THAT WHEN WE HAD TO DO THAT BUT IN OUR CULTURES WE CANNOT PICK OUT IN ADVANTAGES THE SUBSET OF CELLS THAT GROW IN THE A AL GOES. WE HAVE TO GO FROM THERE SO WE REALLY DON'T. WE'VE LOOKED AT 1:33, C34 AS THE MANS POPULATIONS BUT WE CANNOT DISTINGUISH THE INTEREST IN THOSE POPULATIONS. >> [INDISCERNIBLE] >> I THINK WE NEED TO GO THERE BUT THE EASY STUFF DOESN'T WORK SO I AGREE WITH YOU BUT I DON'T KNOW HOW TO DO IT. YES. >> [INDISCERNIBLE] >> YES, WE DO EXTENSIVE FLOW. 99% OF THE CELLS ARE MATURE MYELOID AND LYMPHOID AND THE NUCLEATED RED CELLS AND LESS THAN 1% ARE WHAT MIGHT BE CELLS OF INTEREST. >> [INDISCERNIBLE] >> IN THE MPS CHIM CHILDREN DEFINITELY -- WE CAN'T REALLY GO BY AND SEE THEIR HEARTS. THE BRAINS I SHOWED WERE FROM CHILD WHO DIED POST TRANSPLANT AND WHEN THAT HAPPENS WE DO ASK THE FAMILY FOR ISSUE. WE HAVE TO HANDLE THE OPPOSITE AUTOPSIES VERY CAREFULLY. IT'S GOOD NEWS WE HAVEN'T HAD THAT CIRCUMSTANCE COME UP THAT OFTEN. [INDISCERNIBLE] >> EVEN AFTER BONE MARROW TRANSPLANTATION, GLIAOR MACROPHAGES LIKE CELLS FROM THE -- HAVE BEEN KNOWN AND SHOWN TO CAUSE THE BLOOD BAIN BARRIER. CELL JUST KNOW HOW TO NEGOTIATE, IT'S NOT BECAUSE OF SIZE, THESE ARE BIG CELLS. YES. >> [INDISCERNIBLE] >> THANK YOU. >> [INDISCERNIBLE] >> I DON'T KNOW THE ANSWER. IF WE KNOW THE CANDIDATE CELL WE MIGHT BE ABLE TO USE IT PS. THAT PROBABLY IS VERY LIKELY TO BE IN THE FUTURE OF CELL THERAPY. BUT EXPANDING THESE CELLS TENDS TO BE A SUICIDE MISSION. ONCE THEY COMMIT TO DIVIDING, THEY ARE NOT ANYMORE AND THEY'RE NOT GOING TO HAVE A LONG LIFE. AGAIN WE NEED THEM TO REPAIR FOR A SHORT PERIOD OF TIME. MAYBE THAT'S ALL WE NEED IN A SHOULDER TERM PRODUCT THAT GOES THROUGH SO MANY LEVELS OF DIVISION WILL BE ENOUGH FOR PROLIFERATION. BUT IF WE NEED SOMETHING FOR LIFE LONG CORRECTION, THEN I DON'T THINK IT'S GOING TO BE POSSIBLE AT LEAST NOW WITH A SINGLE TYPE OF CELL. BUT I DON'T KNOW. YES. >> [INDISCERNIBLE] >> WE DO NOT DO ANY -- BECAUSE OF THE TREATMENT OF CHOICE BUT IT HA DONE SUCCESSFULLY, YES BUT IT HAS TO BE VERY EARLY IN THE FIRST FEW MONTHS SO FAR. >> WE'VE TESTED FETUSES AT TEN WEEKS BUT THEY'VE NOT BEEN EFFECTIVE. THE PROTOCOL IS TO GIVE IT THROUGH THE MOM'S ABDOMEN AND JUST GIVER ENRICHED POPULATION OF HEMOPOIETIC. >> [INDISCERNIBLE] >> NO, NO. JUST IN THE PAIR NEA PERITONEAL CAVITY. >> [INDISCERNIBLE] >> WE EXPECT THEM TO GRAPH IN THAT STAGE OF GESTATION THEY PROBABLY WILL ENGRAPH IN FETAL LIFER FIRST AND THEN DISSEMINATE TO MARROW. >> [INDISCERNIBLE] >> I HAD TEN FAMILIES COME TO US BUT GOOD LOOK FOR THEM. THEY WERE CARRIERS BUT NOT AN AFFECTED FETUS. AND WORE TRYING THIS FIRST AND OTHERWISE LITTLE DISEASES WHERE THE RISK -- LETHAL DISEASES WHERE THE RISK CAN BE JUSTIFIED. >> [INDISCERNIBLE] >> WE HAVE DATA ON A MOUSE MODEL THAT MARK SANDS DEVELOPED WHERE WE COMPARED IV INTRAFECAL AND INTRAPARENCHYMAL AND GOT BEST DISSEMINATION WITH THE INTRAFECAL, YES. >> [INDISCERNIBLE] >> YOU'RE WELCOME. THANK YOU.