Decoding genetic skin disorders: lessons and new technologies

Decoding genetic skin disorders: lessons and new technologies


>>GOOD AFTERNOON, EVERYONE. WELCOME TO THE WEDNESDAY AFTERNOON LECTURE SERIES. THOSE OF YOU HERE IN MASUR AND MANY OTHERS WHO ARE LISTENING IN THE VIDEOCAST THESE ARE OUR SPECIAL OPPORTUNITIES IN THE MIDDLE OF THE WEEK TO HEAR FROM SCIENTISTS WHO IS DOING EXCITING WORK THAT I THINK OFTEN ENLIVENS OUR EXPERIENCE AND SOMETIMES SUGGESTS NEW IDEAS TO ALL OF US THAT HAVE A CHANCE TO SOAK UP WHAT IS BEING PRESENTED. FOREFORTUNATE TODAY TO HAVE AS OUR SPEAKER DR. AMY PALLER WHO COMES US FROM NORTHWESTERN WHERE ME IS PROFESSOR AT THE WALTER J.HAMLIN CHAIR AT THE DEPARTMENT OF DERMATOLOGY AND PROFESSOR IN THE DEPARTMENT OF PEDIATRICS. RESIDENT DIRECTOR FOR DEPARTMENT OF DERMATOLOGY AND ATTENDING AT THE CHILDREN’S HOSPITAL OF CHICAGO. GOT HER UNDERGRADUATE IN BROWN, MASTER’S AT GENETICS AND M.D. AT STANFORD. FOLLOWING RESIDENCIES IN PEDIATRICS AND DERMATOLOGY AT NORTHWESTERN POST DOCTORAL FELLOWSHIP IN THE PLACE NEAR AND DEAR, UNC WHERE SHE WORKED WITH ROBERT BRIGMAN WENT BACK TO CHICAGO WHERE SHE HAS BEEN IN VARIETY OF INCREASINGLY SIGNIFICANT LEADERSHIP ROLES TO HER CURRENT POSITION THERE AT NORTHWESTERN UNIVERSITY FEINBERG SCHOOL OF MEDICINE. HER RESEARCH FOCUSED ON AREAS OF DERMATOLOGY THAT ARE EXCITING AND CUTTING EDGE BOTH UNCOVERING GENETIC CAUSES FOR CERTAIN SKIN DISEASES, BUT ALSO VERY INVESTED IN COMING UP WITH THERAPEUTIC STRATEGIES INCLUDING PRETTY EXCITING EXOTIC THINGS LIKE NANOPARCELS THAT ARE LOADED UP WITH WITH siRNA, MAYBE EVEN SAY SOMETHING ABOUT THAT. SHE’S ALSO BEEN A DEDICATED SERVANT TO THE NIH SERVING ON STUDY SECTIONS, THANK YOU, AMY. CURRENTLY SERVES AS MEMBER OF THE NIAMS COUNCIL. SHE’S A LONG TERM GRANT RECIPIENT, WE WOULD LOVE TO BE ABLE TO SAY THAT HER GRANT SUPPORTS WILL BE STABLE AS IT POSSIBLY CAN BE OF COURSE OUR CURRENT ENVIRONMENT MAKES THAT A LITTLE TOUGHER BUT SHE’S OBVIOUSLY BEEN VERY SUCCESSFUL AND I SUSPECT WILL CONTINUE TO BE. IT’S GREAT PLEASURE TO BE ABLE TO HAVE HER HERE THIS AFTERNOON, PLEASE JOIN ME IN WELCOMING DR. AMY PALLER. [ APPLAUSE ]>>I’M SO HONORED TO TALK TO YOU ABOUT GENETIC SKIN DISORDERS WHERE WE’RE GOING IN NEW THERAPY THAT CAN BE APPLIED TO THE POPULATION. I’M GOING TO START BY TELLING THAT YOU WHEN I TALK ABOUT GENODERMATOSES I’M TALKING ABOUT THE RANGE OF GENETIC SKIN DISORDERS. SOMETIMES LIFE THREAT ANYONE DISORDERS. TALK ABOUT TWO GROUPS AMONG THE MANY GROUPS OF DISORDERS THAT ARE GENETIC THAT HAVE THESE MANIFESTATIONS. I’LL BE TALKING ABOUT BLISTERING DISORDERS AND INHERITED GROUP CALLED EB, EPIDERMOLOGIST. OUR PROGRESS IN UNDERSTANDING GENETIC DISORDERS OF THE SKIN EB SIMPLEX. AUTOSOMAL DOMINANT BLISTERING DISORDER. THIS IS THROUGH THE WORK OF A LAB. WE KNEW THAT THIS WAS AUDILES ORDER THAT INVOLVED BASAL SITE BECAUSE OF THE FACT THAT ULTRA STRUCTURAL STUDIES FROM THE LATE 1960s HAD SHOWN THAT IN FACT THERE WAS CLEAVAGE THROUGH THE BASAL SITE AND INTACT BASAL MEMBRANE. A CLEAVAGE THAT WAS ABOVE THAT ABNORMALITIES IN THE APPEARANCE. THE LAB THEN WAS ABLE TO DO WHAT WE USED TO DO TO DISCOVER GENE DEFECTS. THIS IS RADIO LABELED. HERE YOU CAN SEE MUTATIONS WERE FOUND IN THE PRIMARY CAROTIN OF THE BASAL SITE AND HOT SPOT RG125 WAS DISCOVERED CONTINUES TO BE THE HOT SPOT FOUND TODAY. IN LOOKING AT ANOTHER AUTOSOMAL DOMINANT BUSINESS TORING FORM CALLED AT THAT TIME HYPERKERATOSIS NOW CALLED EPIDETERMINE LYTIC. KEEP THESE IN MIND I’LL TALK ABOUT DISORDERS I’M SHOWING YOU NOW.>>YOU WILL FACTS THEY HAD ABSENCE OF STRUCTURAL ELEMENT BELOW THE LEVEL OF IS WHERE THEIR BLISTERING OCCURRED. THE LAB THAT DISCOVERED THEREAFTER THESE MUTATIONS IN COLLAGEN 7 THAT LEAD TO THEIR DEFICIENCY. FOLLOWED THEN BY WORK DONE IN GERMANY AND HERE SHOWING MUTATIONS IN THE GENE THAT CAUSE AUTOSOMAL RECESSIVE I CAN TEE YES, SIR OF IN WHICH THESE BABIES ARE BORN SURROUNDED BY THICKENED MEMBRANE. OVER TIME OVER FIRST MONTH THAT TENDS TO CLEAR AND LEAVES BEHIND VARIABLY SCALING DISORDER AS THESE EXAMPLES SHOW YOU. THIS MOVES TO BE MUTATIONS IN A GENE CALLED TRANSGLUTAMINASE. TRANSGLUTAMINASE OR HEM ME DYSPLASIA. WITH THE DEFECT BEING IN PATHWAY. THIS DISCOVERY IN 2000FULS THE VERY FIRST ONE AMONG THESE TO ACTUALLY USE SANGER SEQUENCING TO DETERMINE THE GENE ABNORMALITY. OVER THE NEXT SEVERAL YEARS SANGER SEQUENCING DRUG DOWN COST OF DOING THESE ANALYSES BUT STILL THE GENOME IS ENTIRETY WAS DISCOVER THE USING SANGER SEQUENCING AT COST OF $100 MILLION. WITH THE AVAILABILITY OF NEW TECHNOLOGY SECT IN THIRD GENERATION SEQUENCING CAME TO BE JUST ESCALATED THIS OUTPUT IN TERMS OF PRODUCTIVITY IN THESE DISCOVERIES AND DROVE DOWN TREMENDOUSLY THE COST OF DOING THIS. WE CAN BE VERY EXCITED THE ENTIRE GENOME SEQUENCE IS SHOWN HERE THE MELANOMA CELL LINE GENOME. WHAT WE NEEDED, WHAT IS FORWARD HAS BEEN WHOLE EXOME SEQUENCING. THE OCEAN AUTOMATIC INCLUDES 1% OF THE GENO. EXOME I CAN FOR ABOUT $500. THE BEAUTY OF THIS APPROACH IS THAT UNBIASED APPROACH TO DISCOVERY. ONE CAN SIMULTANEOUS ANALYZE ALL OF THE CANDIDATE CHAIN BUT ALSO OTHERS SO YOU CAN FIND LOW FREQUENCY MUTATIONS IN KNOWN GENES. MUTATIONS IN NEWLY ASSOCIATED GENES INCLUDING REF GUY — REGULATOR GENES AND LOW FREQUENCY SNPs IN THOUSANDS OF SAMPLES. HOW HAS THIS HELPED OUR PATIENTS THAT’S WHAT I’M GOING TO SPEND THE MESS OF THE TIMETABLING ABOUT. FIRST OF ALL IT IS LED TO IMPROVED DIAGNOSIS. JUST IN THE LAST FEW YEARS ALL THESE DISCOVERIES WE’VE SEEN NEW CLASSIFICATIONS FOR A WIDE VARIETY OF DIFFERENT TYPES OF GENETIC DISORDERS. INCLUDED ONES WE’RE FOCUSING ON TODAY. VERY IMPORTANTLY LED TO LESS COSTLY GENOTYPE. LET’S TAKE AS EXAMPLE EB, BABY IS BORN WITH EB HAS BLISTERING QUITE EXTENSIVE WE WANT TO LET THE FAMILY KNOW AS SOON AS POSSIBLE ABOUT PROGNOSIS FOR THIS CHILD. BECAUSE THE BABY WHO HAS EB SIMPLEX TENDS TO HAVE DISORDER THAT CAN QUITE SEVERE PARTICULARLY FIRST TWO R FEW YEARS. SUBSEQUENTLY TENDS TO IMPROVE. MANY BY THE TIME LATE ADOLESCENTS AND BEYOND BARELY HAVE ANY ISSUES WITH BLISTERING. WE CAN TAKE JUNCTIONNAL EB, A TYPE IN WHICH MOST OF THE AFFECTED INFANTS WILL DIE BY THE END OF THE FIRST YEAR OF LIFE. THEN WE CAN TAKE RECESSIVE EB. DISORDER THAT WILL BE MENTIONING AGAIN AND AGAIN IN WHICH THESE PATIENTS TEND TO SURVIVE THE NEONATAL PERIOD BUT HAVE LIFE LONG ISSUE WITH SEVERE ITCHING, SEVERE PAIN, STARRING THAT I SHOWED YOU — SCARRING THAT IS SO FUNCTIONALLY IMPAIRING FOR THEM. IN THE PAST JUST SEQUENCING THE COLLAGEN 7 GENE THAT COSTS — MUTATIONS CAUSES COSTS $15 1/2,000. NOWADAYS WE CAN CONCERTAINLY SEQUENCE ALL OF THE POSSIBLE GENE TO WHOLE EXOME SEQUENCING FOR JUST $3,000 TO THE PATIENT. ANOTHER EXAMPLE IN THE I CAN THEE YES, SIR THESE VARIOUS
TYPES AND UNDER LYING GENOTYPE HAVE ESTABLISHED HIGH THROUGHPUT SAMPLE FOR 11 OF THESE MOST PROMINENT GENES. THE COST FOR THIS NOW IS $50 PER PATIENT AT THE SAME TIME ALL OF THESE LOOKED AT. AND FIND ALL DIFFERENT GENETIC MUTATIONS AMONG THEM. WHAT I POINT OUT HERE IS THE 20%. DID NOT HAVE A MUTATION IN ANY OF THESE GENES. THAT GIVES THE OPPORTUNITY THEN TO PERFORM WHOLE EXOME SEQUENCING AND LEAD TO GENE DISCOVERY. OF COURSE, FOR TWO DECADES NOW WE’VE BEEN ABLE TO TAKE DNA INFORMATION AND TURN INTO PRENATAL DIAGNOSIS. THIS STAGE TO THE MIDDLE OF THE 1990s I SHOW YOU EXAMPLE HERE OF ONE OF OUR PATIENTS WITH RESAYSTIVE DISTROPHIC DID NOT WANT TO HAVE ANOTHER BABY UNLESS THEY COULD BE ASSURED OF HAVING BABY WHO DID NOT HAVE THIS DEVASTATING DISEASE. WE WERE ABLE TO USE TECHNIQUES LIKE AM ME KNOW SENN TEASES TO PERFORM PROCEDURE IN THE FIRST TRIMERSER THAT WAS VERY LOW RISK. AND ADVISE HER THAT THEY WOULD HAVE. — ABLE TO USE INTER-HALL BLOOD SAMPLES. THOSE FAMILIES, WOULD NOT CONSIDER TERMINATING A PREGNANCY YET WANT TO BE ASSURED OF A NORMAL BABY WHICH IS PREIMPLANTATION DIAGNOSIS WHICH IS NOW BEEN USED FOR SEVERAL GENETIC SKIN DISORDERS WHICH IN VITRO FERTILIZATION WILL GUARANTEE NORMAL BABY THROUGH TAKING A SINGLE CELL FROM THE BLASTOMER, ANALYZING IT ONLY IMPLANTING THOSE FERTILIZED EGGS THAT WILL BE ASSURED OF HAVING A NORMAL BABY. NOW I’M GOING TO SPEND THE REST OF THE TIME TALKING ABOUT HOW UNDERSTANDING THE UNDERLYING PATHOGENESIS AND OBTAINING GENOTYPE INFORMATION CAN ACTUALLY LEAD TO NEW PHARMACOLOGIC AND NEW GENETIC INTERVENTIONS, WE’RE GOING TO BE COVERING A LONG LIST OF EXAMPLES THAT MAY BE APPLICABLE TO GENETIC SKIN DISORDERS. I’M GOING TO START WITH THE CONCEPT OF READTHROUGH TALK ABOUT THAT FOR ONE OF THE DISORDERS RECESSIVE DISTROPHIC EB. AMINOGLYCOSIDES MADE READ THROUGH PREMATURE TERMINATION CODONS. 10-25% OF MUTATIONS THAT CAUSE EB LEAD TO THESE PREMATURE TERMINATION CODONS. IT’S BEEN SHOWN THAT EVEN THOUGH WE KNOW 50% IS FINE, EVEN AS LITTLE AS 35% OF NORMAL COLLAGEN 7 LEVELS SHOULD BE ENOUGH TO STABILIZE THE SKIN. A BEAUTIFUL WORK DONE IN A LAB, CELLS TRANSFECTED WITH CONSTRUCTS CONTAINING NULL MUTATIONS, WERE TESTED AND GENTAMICIN WAS ABLE TO INDUCE UP TO 70% WILDTYPE COLLAGEN 7 LEVELS. NOW, THERE IS ANOTHER WAY, GLYCOSIDE THAT IS ACTUALLY AVAILABLE CALLED PTC124 YOU PROBABLY HEARD OF IT, BEEN USED FOR OTHER DISORDERS BUT UNFORTUNATELY THAT DID NOT INTRODUCE. RATHER DID NOT REDUCE THE COLLAGEN 7 EXPRESSION. NOW, TOPICAL GENTAMICIN IS AVAILABLE. AND WE’VE BEEN ABLE TO USE THAT NOW IN SEVERAL OF OUR PATIENTS WITH SOME GOOD SUCCESS I SHOW YOU THIS YOUNG BOY, HIS CELLS WERE TESTED BY DR. CHEN IN THESE STUDIES AND IN FACT THESE STUDIES SHOWED THAT HE COULD GET 46% WILDTYPE COLLAGEN 7 LEVELS WHEN NEW CELLS WERE EXPRESSED TO GENTAMICIN, HE WAS ONE OF THE FIRST THAT WE TESTED. WE FOUND THAT WHEN WE TOPICALLY APPLIED GENTAMICIN REALLY EXPEDITED THE WOUND HEALING IN THIS BOY RECALCITRANT SKIN. THE PROBLEM IS THAT WHEN WE’RE APPLYING — THERE MAY BE SIGNIFICANT SYSTEMIC ABSORPTION, GIVEN THE KNOWN RENAL AND EAR TOXICITY OF GENTAMICIN WE DO NEED TO KEEP THAT IN MIND AND LIMIT THE APPLICATION FOR MORE DIFFICULT TO HEAL AREA. NOW, ANOTHER TECHNIQUE NOW USE OF COMPETENT PROTEIN. NOW AVAILABLE RECOMBINANT 7 COLLAGEN PROTEIN. INTRAVENOUS DELIVERY OF COLLAGEN 7 INCREASES THE DEPOSITION OF THE WOUND MIAMI DRAIN ZONE. AND ACCELERATE WOUND HEALING NOT JUST IN RECESSIVE, BUT ALSO IN MICE COULD BE NEW TREATMENT IN GENERAL FOR WOUNDS. I’M HAPPY TO SAY THAT FDA APPROVED FOR HUMAN TRIALS WITH COLLAGEN 7 INJECTION, THOSE WILL SHORTLY BE MOVING FORWARD. ONE OF THE QUESTIONS THAT IS RAISED BY THESE IS WHETHER THESE IMMUNOCOMPETENT INDIVIDUALS WITH RECESSIVE DB HAVE BEEN MINIMALLY EXPOSED OR NOT AT ALL TO SOMETHING TO BE AWARE OF. SOMETIMES — I SHOW YOU AN EXAMPLE OF THIS IN THESE PATIENTS WITH CHILD SYNDROME AS I MENTIONED EARLIER. THE DISORDER WITH ICHTHYOSIS AND DYSPLASIA AND LIMB DEFECTS AS YOU CAN SEE HERE. IN THIS GIRL WHO HAD THIS DISORDER HAD TO DISARTICULATE THAT LIMB AND SO AS YOU CAN SEE SHE HAS AN AMPUTATION AT THE KNEE AREA. THESE PATIENTS TOLERATE ANYTHING TOPICALLY VERY POORLY WE END UP USING BLAND EMOLLIENTS, CAN INHIBIT THAT. WE PUT TOGETHER A TOPICAL FORMULATION OF 2% STATIN AND 2% CHOLESTEROL TO BLOCK HMG-COA REDUCTIVE AND ADDED END PRODUCT. I SHOW YOU HERE IN THE DRILL THAT I SHOWED YOU BEFORE IN YET ANOTHER PATIENT THAT THERE WAS DRAMATIC CLINICAL, HISTOLOGIC AND ULTRA STRUCTURAL IMPROVEMENT OVER PERIOD OF JUST A FEW MONTHS. I’VE NOW HEARD FROM AT LEAST A DOZEN PATIENTS FROM AROUND THE WORLD IN WHOM EACH HAS EXPERIENCED IMPROVEMENT WITH THE TECHNIQUE. IN FACT IN THE GIRL THAT I SHOWED YOU SHE’S NOW ABLE TO WEAR HER PROSTHESIS AND HAVE A MUCH MORE NORMAL LIFE BECAUSE OF THIS SIMPLE INTRODUCTION OF PATHOGENESIS-BASED TOPICAL THERAPY. NOW, WE CAN MOVE OVER TO CELL THERAPY AND BECAUSE THE SKIN SO HIGHLY — WE CAN CONTINUE GRAFTING WITH GENE CORRECTION TO EXPRESS THE NORMAL GENE PRODUCT. WE CAN THINK ABOUT THIS FOR OUR PATIENTS WITH EB. IN FACT IN 2006 CASE WAS PUBLISHED FROM PITLY IN WHICH RETROVIRAL GENE CORRECTED GRAFT FOR FUNCTIONAL EB WERE APPLIED. IN A FOLLOW-IN PAPER MORE THAN SIX AND HALF YEARS LATER THEY WERE STILL THERE AND DOING WELL. STUDY ABOUT TO START AT STANFORD WHICH COLLAGEN 7 CORRECTIVE WILL BE GRAFTED FOR RECESSIVE DISTROPIC EB. NOW, THIS IS A FIRST STEP, CERTAINLY NOT GOING TO BE THE ANSWER FOR THESE PATIENTS, THERE ARE MANY IMITATIONS. GRAFTING CAN ONLY BE DONE TO LIMITED AREA. SECOND OF ALL JUST CAN’T GET THE MUCOSA. CAN BE TERRIBLY INCAPACITATING FOR THEM. A SURGICAL MANIPULATION IN PATIENT WHO GETS BLISTERS CONSTANNOUSLY LET ALONE WITH TRAUMA CAN BE RISKY THE ISSUE WITH ANY TYPE OF THESE VIRAL CONSTRUCTS WITH THE NORMAL GENE POSSIBILITY OF INSERTIONNAL ONCOGENESIS. ONE GOOD THING YOU CAN THINK ‘BOUT IS THAT IF THERE IS GOING TO BE A CANCER IT’S LIKELY TO INVOLVE THE SKIN, BE VISIBLE, AMENABLE TO SURGICAL EXCISION. HOWEVER, THIS IS A TECHNIQUE THAT IS GROWING, IN RECENT PAPER STRESS HAD IS IMPORTANT THAT IS CHOOSING THE USE WISELY. TEST ONE WITH THAT IS GOOD STEMNESS AND MAX MA’AMLY EXPAND AND SAFETY, INCLUDING ASSAY OF TUMOR GENESIS IN MOUSE MODELS. — IT’S BEEN SHOWN TAKING STEM CELL TRANSPLANT YOU GIVE THEM TO PATIENTS WITH RECESSIVE, CERTAINLY BEFORE WITH MUST MODELS, COLLAGEN 7 WILL HOLD TO THE WOUND. IN A STUDY THAT WAS REPORTED ABOUT FIVE YEARS AGO FIVE OUT OF SEVEN OF THESE FIRST PATIENTS WERE ALIVE AFTER 500 DAYS INCLUDING HEALING IN A WOUNDED AREA, AT 180 DAYS OUT THE DEPOSITION OF COLLAGEN 7. IN FACT VIC ON TOLLER AT UNIVERSITY OF MINNESOTA HAVE CONTINUED THESE STUDIES NOW WITH BETTER RESULTS, REDUCED CONDITIONING, DECREASING THE RISK. TO INCREASE AND STILL HIGH RISK THESE PATIENTS ARE SHOWING SLOW IMPROVEMENT ALTHOUGH OUT COME IS VARIABLE. UPCOMING CHANGE TO BE CONSIDERED IS THE RECENT DISCOVERY THAT ONE CAN REPURPOSE AMD3100, A CXCR4 INHIBITOR, RELEASE FROM THE RARE ROW, LOW DOSE WHICH DOES AND DRAW TO THE SKIN IN MOUSE MODELS BETTER TAKE. USING SOMETHING OR AS A GRAFT. THE BEAUTY OF THIS TECHNIQUE IS USE PATIENTS OWN CELLS AVOIDING. THERE IS SOME WONDERFUL WORK BEING DONE. ALSO WANT TO MENTION THE POSSIBILITY OF USING TALEN AND CRISPR, THIS IS TECHNOLOGY THAT CAN CLEAR THE MUTANT SEQUENCE AND THROW DUES THE NORMAL GENE SUCH WAY THAT RANDOM INSERTION, OF COURSE AVOIDS VIRUSES. BUT ONE OF THE BIG PROBLEMS WITH THIS IS THAT IT’S STILL VERY LOW CORRECTION, OR UNTIL WE CAN ADEQUATELY — NEED TO BE CAREFUL OF THAT TECHNIQUE. I ALSO WANT TO MOVE ON TO TALK ABOUT DOMINANT NEGATIVE DISORDERS. BECAUSE HERE WE HAVE DIFFERENT SITUATION FROM WHAT WE’VE BEEN

OF HIGHLY TALKING ABOUT LARGELY WHERE ORIENTED HOLLY GROW NUCLEOTIDES. THERE CAN BE A GOAL PARCEL STARTED OUT WITH SOME OF THOSE. MORE RECENTLY WE SWITCHED INTO SELF ASSEMBLING STRUCTURES. WHAT IS BEAUTIFUL ABOUT THESE THAT THEY CAN BE DELIVERED TOPICALLY IN COMMON MOISTURIZERS, AGENTS THAT REQUIRE NO EXTRA CHEMICAL OR PHYSICAL MEANS IN ORDER TO GET THROUGH THAT EPIDERMAL BARRIER. TO DAY NO EVIDENCE OF ANY TOXICITY OR AFFECTS. WE’VE SHOWN EXCELLENT KNOCK DOWN IN CELL AND MOUSE MODELS AND PUBLISHED ON THE KNACK DOWN EPIDERMAL GROWTH FACTOR. FOR COMING OUT THIS WEEK. TARGETED siRNA. THAT COMPLETES LIPID RAFT-BASED REGULATOR OF INSULIN SIGNALLING AND NORMALIZE IT DIABETIC WOUND HEALING IN THESE MODELS. WE CAN ALSO ACHIEVE KNOCK DOWN. I SHOW YOU HERE siRNA SNA WHICH I SHOWED YOU PREVIOUSLY IN CAROTIN 14 AT THE RG125 SITE. YOU CAN SEE THAT WITH THIS SCRAMBLE WE DON’T KNOCK DOWN THE GREEN LABELED ABNORMAL MRNA BUT DO KNOCK DOWN SPECIFIC siRNA THE ABNORMAL LEAVING BEHIND THE NORMAL CAROTIN STRUCTURE. OF CAROTIN 14. NOW, I WANT TO SHOW YOU ONE MORE AREA THAT WE’RE WORKING ON BECAUSE I THINK IT’S PARTICULARLY EXCITING AGAIN SHOWS THE POTENTIAL VALUE OF THESE SNAs THIS IS TARGETING TNF FOR PSORIASIS. PLAYS KEY ROLE IN THE PATHOGENESIS WE’VE NOW HAD MORE THAN A DECADE ANTI-TNF MOB TOE CLONAL ANTIBODIES THAT WE USE FOR MORE SEVERELY AFFECTED PATIENTS WITH PSORIASIS, AFFECTS ANTIBIOTIC BOUT 3% OF THE U.S. POPULATION. BUT THESE ANTIBODIES ARE COSTLY, COST ABOUT $20,000 A YEAR FOR PATIENTS. FOR THE ALMOST 90% OF INDIVIDUALS WITH MILDER THERE IS NO TARGETED TOPICAL. HOW COULD WE CONSIDER USING THESE SNAs NOW HYPE SO MALL AND SELF ASSEMBLING SNAs WE’VE SHOWED ALL OF THESE CAN PASS BEAUTIFULLY THROUGH HUMAN SKIN AS SHOWN HERE BY THIS LABELED SNA WE’VE GONE ON TO SHOW PASSES BEAUTIFULLY THROUGH PSORIASIS HUMAN SKIN WELL. WE FOUND THAT BOTH THE LSNA AND THE SELF ASSEMBLY TNF SNA SUPPRESSED TNT ALPHA BY 80% IN THESE HUMAN SOCRATIC SKIN EX PLANTS. SOME OF THE RECENT RESULTS WE’VE HAD IN THE TREATED MODEL OF THE DEVELOPMENT OF THE PSORIASIS LIKELY PRESUMPTION. WE’VE SEEN THIS BLOCKADE OF THE PSORIASIS IN THE MODEL BY TOPICALLY APPLIED TNF SNA I HOPE YOU CAN SEE HERE ON YOUR RIGHT AREA WITHIN THE BOX THAT HAS BEEN TREATED SURROUNDING IT YOU CAN SEE SOME SCALING YOU CAN CERTAINLY SEE THAT THROUGHOUT IN THESE SCRAMBLED CONTROLLED TREATED EXACTLY THE SAME OTHERWISE. I THINK IT’S EVEN EASIER TO SEE WHEN YOU LOOK HISTOLOGICALLY. HERE IS THE TNF SNA TREATED SKIN YOU CAN SEE THAT IT LOOKS NO DIFFERENT FROM THE MOUSE WHO WAS NOT TREATED AT ALL. IN CONTRAST AND VEHICLE TREATED THE SCRAMBLED CONTROL. WE CAN ALSO LOOK AT SOME OF THE MARKERS OF PSORIASIS WE CAN SEE AFFECTED INCREASE IN TNF ALPHA. AND THE SUPPRESSION OF — WHICH REPRESENTS ABNORMAL EPIDERMAL DIFFERENTIATION WE CAN SEE NO DIFFERENCE BETWEEN THAT TREATED WITH THE TNF LSNA AND UNTREATED BY ANYTHING. GOING WILLING TO ON SPEND REST OF THE TIME TALKING ABOUT MOSAIC SKIN DISORDERS. GENE MOSAICISM OCCURS WHEN AN ORGANISM IS COMPOSED OF TWO OR MORE GENETICALLY DIFFERENT POPULATIONS OF CELLS THAT ORIGINATE FROM A GENETICALLY HOME GENUS ZYGOTE. TO A NORMAL PHENOTYPE BUT SPONTANEOUS CORRECTED MUTATION. THIS IS REVERT WENT MOSAICISM. TO BE ON THE LOOK OUT BECAUSE IT CAN REALLY — WE CAN EXPAND ON PATIENT’S OWN CELLS WHETHER FOR GRAFTING MAYBE IN THE FUTURE POTENT STEM CELLS AND USE THAT. INDEED I SHOW YOU THIS PATIENT HERE THIS IS ONE OF MY PATIENTS, YOU CAN SEE SEVERE SCAR KNOWLEDGE, YOU CAN SEE TERRIBLE DEFORMITY THAT SHE HAS ON HER FOOT. SO BAD OVER LAST FEW YEARS SHE STOPPED BEING ABLE TO WALK. ALL SHE WANTS IS TO BE ABLE TO WALK AGAIN. WE’VE BEEN TORMENTED ABOUT FACT WE CAN’T DO SERIAL GRAFTING HOW CAN WE DO A SURGICAL PROCEDURE WHEN SHE WON’T HEAL. BUT THIS GIRL AND I FOUND AREAS THAT NEVER BLISTERED ON HER YOU CAN SEE AREA ON HER BACK AND LEG. WE WERE ABLE TO BIOPSY THE AREA ON THE LEG SHOW IN FACT THAT THIS AREA PRODUCED COLLAGEN 7. WORKING WITH A DOCTOR AT THE UNIVERSITY OF MINNESOTA WHO HAS FACILITY WE’VE BEEN — WE’RE GOING TO BE ABLE TO USE THESE PHENOTYPICALLY NORMAL CELL TO PROVIDE A GRAFT AND MOVE FORWARD WITH THE SURGICAL PROCEDURE SHE SO MUCH WANTS. MOSAICISM CAN ALSO LEAD TO LOCALIZED SKIN DISORDERS. AND IN FACT THESE DISORDERS HAVE SHOWN HERE BY — WHAT LED TO DESCRIBE LINES NAMED AFTER HIM IN 1901. THESE LINES SEEM TO BE LINES BY WHICH MOSAICISM OCCURS WHEN THERE IS A CHANGE IN THE EPIDERMAL CELL. AND LINES OF EMBRYO LOGIC DEVELOPMENT. WE HAVE ANOTHER CELL WITH THE CHANGE ALL OF THE CELLS THAT COME OUT OF THAT IN THAT LINE AND EXPRESS THAT SAME MUTATION. BUT THERE REALLY WASN’T ANY PROOF OF IT. THE MOSAIC CHANGE JUST STAYS IN THE SKIN, BUT MAY ALSO INVOLVE GERMLINE CELLS, NOW, WHEN CELLS CAN BE LETHAL PROBLEM BUT IT CAN ALSO SOMETIMES MAN TEST GENERALIZED DISORDER. WE KNEW THIS IN THE EARLY 1990s BECAUSE OF PARENTS WITH EPIDERMAL NEVI AS SHOWN HERE WHO HAD OFFSPRING WITH EPIDERMA LYTIC ICHTHYOSIS. THE BIOPSY SHOW THE SAME CHANGES THAT WE FIND IN THESE INDIVIDUALS WITH GENERALIZED EPIDERMA LYTIC ICHTHYOSIS. THAT LED US TO USE THAT OLD TECHNOLOGY TO DETERMINE THAT INDEED THERE WERE CAROTIN TEN MUTATIONS. WITH PERFECT CORRELATION BETWEEN DNA SEQUENCE FROM THE LEAKSNAL VERSUS NON-LESIONNAL. LESIONS ALONG THE LINE OF BLASHKO. NOW WE HAVE WHOLE AXIOM SEQUENCING WE CAN USE THIS SO MUCH MORE EASILY TO DECODE MOSAICISM. INDEED THAT’S JUST WHAT HAPPENED. YOU CAN NOW COMPARE EXPRESS DNA FROM A LEASHNAL BIOPSY USING JUST TO NICE LATE THE TISSUE. TREMENDOUS PROGRESS IN UNDERSTANDING THESE MOSAIC BIRTH NATION OR NEVI THAT CHILDREN ARE BORN WITH. WHETHER TALKING VASCULAR BIRTHMARK. TALKING ABOUT EPIDERMAL NEVI. IT’S BEEN FOUND THAT IN EACH OF THESE SITUATIONS THESE ARE LOCALIZED SITES OF SIGNALLING PATHWAY ACTIVATION. NOW, HERE WE HAVE PORT WINE STAIN, NOT ASSOCIATED WITH ANY SYNDROME THEN PORT WINE STAINS IN ASSOCIATION WITH THE STURGE-WEBER SYNDROME. IN THE LAST TO YOU YEARS ABOUT 90% OF NON-SYNDROMIC PORT WINE STAINS AND STUGE-WEBER IS GENE IN A HOT SPOT IN GENE. IT TURNS OUT THAT THESE MU SITUATIONS IN NGAQ ACTIVATE RAS-ERK SIGNALLING. LIKE THOSE INVOLVING THE VEIN. SHOW ACTIVATING MUTATION NOT IN THAT PATHWAY BUT INSTEAD IN THE — THESE ARE ACTIVATED IN THE RECEPTOR OR TIE 2 THEY TEND TO OCCUR MOST COMMONLY AT A PARTICULAR HOT SPOT. MOST RECENTLY WE CAN LOOK AT THE OVER GROWTH SYNDROME. AND FIND HERE THAT THE MUTATION TENDS TO OCCUR IN THE CATALYTIC ALPHA SUBUNIT OF PI3 KINASE. AGAIN IN THIS SAME PATHWAY. WE SWITCH OVER TO MEL MELANOSIT PARTICULAR ACTIVATING HOT SPOT RAS MU SITUATIONS PARTICULARLY AT THE HOT SPOT OF GLYCINE 1. THEN WE CAN SWITCH OVER TO THESE LINEAR EPIDERMAL NEVI THAT DON’T SHOW THE EPIDERMA LYTIC CHANGES THAT WE SEE. IN THE ONE I SHOWED YOU EARLIER IN THAT PARENT. THIS IS A BENIGN EPIDERMAL HYPO PLASTIC DISORDER ONE CAN SEE EITHER ACTIVATE CAN MUTATIONS IN ONE OF THE RAS GENES OR SOMETHING ALONG THAT FGFR3, GI3 KINASE. COULD TELL WHICH PATHWAY BY LOOKING CLINICALLY OR HISTOLOGICALLY AT THESE EPIDERMAL NEVI ONCE AGAIN, HOT SPOT MUTATIONS. YOU’LL SEE SOME OF THE HOT SPOTS LISTED HERE PICK THE RAS HOT SPOT ARE ONES THAT WE’VE SEEN BEFORE IN THE MOSAIC DISORDERS I JUST TALKED ABOUT. WE CAN MOVE ON TO SOME SEBACEOUS, WITH WOOLY HAIRED WITH BONE ABNORMALITIES SEE THAT THESE ARE ALL AMONG THE DIFFERENT RAS MUTATIONS AND AGAIN WITH THE SAME HOT SPOTS. IT STARTS TO EXPLAIN DISORDERS, A LONG WORD THAT BASICALLY MEANS THE COMBINATION OF THE SAME AREA SOME DIFFERENT AREAS IN THE SAME INDIVIDUAL OF EPIDERMAL NEVI AND LEARN CONTINUING GUS NEVI. ANOTHER ONE PORT WINE STAINS WITH BLUE LESIONS AND MONGOLIAN SPOT. I BET THAT THESE ALL BE BE SHOWN TO SHARE ALTERATIONS. IN FACT MUTATIONS HAVE ALREADY BEEN SHOWN TO CAUSE MOST BLUE NEVI IN ADDITION TO — ABS WE DISCUSSED CAUSING PORT WINE STAINS. FINALLY CAN WE USE THIS INFORMATION THERAPEUTICALLY. TOPICAL OR FOR MORE SYSTEMIC, OR INHIBITION IMPROVE THESE LESIONS. ALTHOUGH WE STILL HAVE MORE WORK TO DO, I WOULD POSIT THAT WE SHOULD BE TRYING TO GO IN THIS DIRECTION. IN FACT — IS NOW USED TOPICALLY TO TREAT THE FACIAL ANGIE FIBROMA HAVING BETTER UNDERSTANDING ABOUT THESE THIS WAY I TRIED IT IN A 4-YEAR-OLD WHO HAD A ANGIOMA THAT WAS VERY PROBLEMATIC ON HER NECK. TREATED FOR TWO MONTHS WITH 1% TOPICAL RAPAMYCIN THIS CAUSED DRAMATIC FLAT IN THIS CASE OF THE LESION IN THIS YOUNG GIRL. THERE MIGHT BE WAYS AS WELL TO BLOCK A RAS PATHWAY BECAUSE WE NOW HAVE AVAILABLE NECK INHIBITOR. A GLIMMER OF POSSIBILITY THAT THIS MIGHT WORK FROM A FEW STUDIES. THIS STUDY JUST CAME OUT IN WHICH A KINASE INHIBITOR WAS INHIBITED THREE TIMES A WEEK FOR TWO WEEKS FOR TRANSGENIC MOUSE MODEL THAT DEVELOPS EXTENSIVE MALIAN SID I CAN NEVI OF THE SKIN PARTICULARLY IN THE FIRST WEEKS OF LIFE. AS YOU CAN SEE IN THIS MODEL THERE WAS MARKED DECREASE IN THE PIGMENTATION OF THE SKIN. THROUGH THE USE OF THIS INHIBITOR. HERE IS ANOTHER ANECDOTAL EXAMPLE THAT WAS RECENTLY PUBLISHED. PATIENT WHO HAD CLEARANCE MUCH BOTH NEWLY ERUPTIVE FROM TREATMENT AND PREEXISTING MEK WITHIN MONTHS OF THE ADDITION OF A MEK INHIBITOR. PERHAPS WE CAN MAKE A TOPICAL MEK INHIBITOR AND USE THAT FOR LOCALIZED TREATMENT. REMIND THAT YOU WE HAVE THESE SMALL MOLECULE INHIBITORS THEY MAY BE USEFUL BUT ALSO HAVE POSSIBILITY OF GENE SUPPRESSION. I WOULD JUST MEMBERS THAT OUR LAB NOW DEVELOPED SNA THAT CAN SUPPRESS SGFR3 AND SUPPRESS HRAS AND WE HOPE TO MOVE THESE FORWARD AS EXAMPLES OF OTHER WAYS TO TREAT THESE CONDITIONS. THAT MOLE ON YOUR ARM. OR AS SHOWN HERE THE KERATOSIS THAT SO COMMONLY DEVELOP IN OLDER INDIVIDUALS TURNS OUT WORK THAT HAS DONE ONE CAN FIND THESE PRETTY MUCH ALL IN THE FGFR3 SIGNALLING PATHWAYS PRETTY MUCH ALL ALONG THE WAY. SO I WOULD SAY EVEN THESE ACQUIRED MOSAIC LESIONS MIGHT BE AMENABLE TO THIS NEW TYPE OF THERAPEUTIC INTERVENTION RATHER THAN A PROCEDURAL TECHNIQUE. IN SUMMARY, THIS NEW TECHNOLOGY HAS FACILITATED ADVANCEMENT ABOUT GENE FUNCTION AND EFFECTS OF GENE ALTERATION IN BOTH GENOMIC AND SKIN DISORDERS. GUIDE INK KNOW STRAIGHTTIVE TREATMENT NOW BUT EVEN MORE SO IN THE FUTURE TO REVERSE THE PHENOTYPIC CHANGES. THE DECREASE IN COSTS AND INCREASING EASE OF DECODING AN INDIVIDUAL’S CHANGE CAN LEAD TO PERSONALIZED PHARMACOLOGIC OR GENE-BASED THERAPY. AND I HAVE A LONG LIST OF INDIVIDUALS WITH WHOM I HAVE COLLABORATED AND WORKED OVER THE PAST FEW DECADES BUT I WANT TO THANK AS SHOWN HERE. I WANT TO THANK YOU FOR YOUR ATTENTION. THANKS VERY MUCH. [ APPLAUSE ]>>AMY, THANKS SOAP MUCH FOR A LOVELY TALK. WE HAVE SOME TIME FOR QUESTIONS. PLEASE GO TO THE MICROPHONES IF YOU HAVE A QUESTION.>>PERHAPS OFF TOPIC I WAS WONDERING IF YOU HAVE ANY THOUGHTS ABOUT TIC? PERHAPS OUT OF LEFT FIELD.>>WELL, YOU KNOW, I THINK ONE OF THE ISSUES WITH THAT IS THAT WE THINK THAT THE SKIN LESIONS HAVE TO DO MORE WITH METABOLIC DEFECT AS YOU KNOW THERE ARE STUDIES GOING ON RIGHT NOW LOOKING AT WHETHER YOU CAN ALTER MAGNESIUM INTAKE AND TRY TO WORK ON THAT. OBVIOUSLY IF YOU HAVE SITUATIONS WHERE YOU NEED TO REPLACE SOMETHING IN THE SKIN OR KNOCK SOMETHING DOWN WE CAN USE THAT AS ANOTHER EXAMPLE THERE MIGHT BE WAYS TO MOVE FORWARD. THAT’S A LITTLE BIT OF DIFFERENT DISORDER. BECAUSE WE THINK WHAT IS GOING ON IN THE SKIN MAY BE SOMEWHAT OF SECONDARY PHENOMENON. VERY GOOD QUESTION.>>THANKS FOR EXCELLENT TALK. YOU MENTIONED ON ONE SLIDE SEVERAL OF THE CAROTINS ARE DIFFERENTIALLY EXPRESSED IN ORAL CANCER. SO I WAS WONDERING WHAT APPLICABILITY OF YOUR S siRNA TECHNIQUE FOR THAT DISEASE.>>WHAT WE HAVE DEVELOPED THE BEAUTY IS POTENTIAL FOR TOPICAL APPLICATIONS THROUGH EPIDERMAL BARRIER. WHEN WE TREAT ORAL CANCER WE HAVE TWO PROBLEMS. ONE IS — IT’S NOT — QUITE DIFFICULT TO TREAT THE TECHNOLOGY YOU DON’T HAVE THE BARRIER, BUT VERY IMPORTANTLY NUMBER TWO TOPICAL TREATMENT AS YOU MAY WELL KNOW IS VERY DIFFICULT BECAUSE IT’S HARD WITH ORAL AND HAVE TYPE OF CANCER. THAT WOULD BE THE TYPE OF THING THAT ONE WOULD WANT TO USE A SYSTEMIC APPROACH. THERE ARE SYSTEMIC APPROACHES BEING DEVELOPED FOR RNA AND TECHNOLOGIES THAT WOULD DO BETTER IN TERMS MUCH STAYING AROUND. HOPEFULLY WITH TARGETING SEQUENCES THAT ALLOW ONE TO RIGHT TO CARCINOMA IN THAT PARTICULAR AREA. TOPICAL APPROACH CAN BE VERY DIFFICULT.>>HOW WOULD THIS RELATE TO ABUT LESIONS SUCH AS BASAL CELLS CARCINOMA, ET CETERA, IN TERMS OF WE ALWAYS THINK OF THESE IN TERMS OF SUN DAMAGE OR 134 TYPE OF DAMAGE. BUT HOW MUCH COULD THIS ACTUALLY BE IN TERMS OF HOW YOU’RE DESCRIBING THINGS?>>THOSE SIMILARLY MOSAIC DISORDERS. WITH THE BASAL CELL, FOR EXAMPLE. THE SIGNALLING PATHWAY ABNORMALITIES THERE ARE SMALL MOLECULE INHIBITORS AS YOU PROBABLY KNOW RIGHT NOW THAT BLOCK HEDGOLOGY SIGNALING PATHWAY. SMALL MOLECULE ARE COMING OUT AS WE UNDERSTAND THE PATHWAY THAT ARE INVOLVED IN THESE VARIOUS TYPES OF BENIGN MALIGNANT TUMORS WE CAN START TO IN IN IT IT. WE KNOW THAT THE PROBLEM WITH THESE SMALL MOLECULE INHIBITORS IS SOME CASES WE COULD STAY APPROACH THAT WOULD AVOWED ALL OF THE SIDE EFFECTS TALKING ABOUT THE HAIR LOSS, THE DIFFERENCES, VARIOUS OTHER SYSTEMIC PROBLEMS THAT THEY HAVE EXPERIENCED BY PUTTING SOMETHING ON TOPICALLY. BUT I THINK IN SOME CASES WITH MALIGNANCIES CONTROL WITH THAT IF YOU USE SOMETHING THAT WOULD BLOCK THAT PATHWAY. SOMETHING LEAD TO A SITUATION THAT WOULD TOTALLY CLEAR THE CANCER RATHER THAN JUST SUPPRESS. WE KNOW WHEN WE STOP ORAL INHIBITORS IT’S STILL THERE, COMES BACK. NEED TO BE WORK DONE TO COUPLE THAT WITH AN AGENT THAT WOULD NOT ONLY SUPPRESS BUT ACTUALLY KILL IT SO TO SPEAK. ONE OF THE THINGS WE’VE BEEN WORKING ON IN COLLABORATION IS ALSO ATTACHING CHEMO THERAPEUTIC AGENTS THAT COULD BE TARGETED IN CANCERS YOU CAN COME IN, SUPPRESS GENES BUT ALSO AT THE SAME TIME SELECTIVELY IN THOSE CANCER CELLS KILL THEM. I THINK THAT IS WE HAVE TO DO THAT.>>THANK YOU.>>QUITE A FEW DIFFERENT ALLELE. IN TERMS OF THE ANTISENSE OR siRNA, THERE IS NO TARGETING BUT SINCE YOU HAVE THE — YOU COULD SEE — SOME OF THIS SATURATION PROCESS IT NEEDS SOME TIME TO BUILD UP TO PREVENT THE INFORMATION THAT MADE BE CODING SOME OF THE — FOR PROLIFERATION. WHAT IS THE DELAY THAT YOU FIND BY TOPICAL APPLICATION OF SOME OF THE siRNA OR ANTISENSE.>>I MISSED THE — WHAT IS THE WHAT?>>WHAT IS THE TIME DELAY. HOW LONG TO WAIT.>>WE’VE ONLY USED IN MOUSE MODELS, THERE IS A LITTLE BIT OF DELAY OF A FEW DAYS OR WHICH IS PRESUMABLY WHILE WE’RE SUPPRESSING THE MESSAGE TURNING IT INTO PROTEIN BEFORE WE START TO SEE THINGS ACTING WITH IMPROVEMENT OVER TIME THAT GETS BETTER. I CAN’T SAY WE’VE TREATED ANY MICE FOR MORE THAN A MONTH. WE DO SEE SUSTAINED IMPROVEMENT IN STUDIES THAT WE’VE DONE SO FAR. WE STILL DON’T KNOW EXACTLY WHAT IS THE FATE AS WE KEEP TURNING OUT THESE DIFFERENT SNAs AS EXAMPLE THAT’S WHAT I HAVE THE MOST IMPORTANCE WITH. CERTAINLY GET STUCK IN ENDSOMES AND SOME OF THEM ARE IN CYTOPLASM BUT WE’VE BEEN ABLE TO SHOW THAT THEY ARE CLEARED IF WE STOP USING THEM SO THAT AFTER ABOUT TEN DAYS AFTER WE STOP PUTTING AROUND 98% OF WHAT WE MEASURE IN THE BEGINNING ARE CLEARED. WE’RE STILL TRYING TO LEARN ABOUT THIS. BUT IT TAKES JUST A FEW DAYS FOR THEM TO START WORKING AND THEN IT DOES TEND TO TURN AROUND WHEN THEY’RE ALSO IF WE JUST STOP TREATING OVER TIME. WE HAVEN’T DONE STUDIES TO SEE HOW LONG SOME OF THIS LAST.>>THANK YOU. GOOD LUCK.>>YOU’VE SHOWED STRIKING SEQUENCE RESULTS. SOME OF THESE SNAs YOU THOUGHT STRUCTURE WAS CRITICAL. YOU THINK THAT THESE ARE MORE TABLE OR PENETRATE BETTER OR SOME OF ALL OF THESE THINGS? ANY ADDITIONAL COMMENTS?>>SURE. A LOT OF THESE STUDIES HAVE BEEN DONE BY CHAD’S GROUP IN TERMS OF SOME OF THE IN VITRO WORK BUT SPHERICAL CONFIGURATION HAS BEEN SHOWN TO BE MUCH MORE STABLE TO, HAVE EXCELLENT CELL UPTAKE. COME TO LOOK AT THE MOUSE GAME SHOW THE PENETRATION SO WE WERE JUST USING PARCELS THAT DON’T PENETRATE. THAT WONDERFUL UPTAKE IN THE GREATER STABILITY AND MODIFICATIONS AS WELL, FOR EXAMPLE, IN THE STRUCTURE CAN ALSO HELP WITH THAT. BEEN GRADUALLY IMPROVING ON THE STRUCTURE.>>ARE THEY CHARGED? DO THEY PENETRATE WELL WITHOUT ADDITIONAL MANIPULATION?>>SO THEY WILL GET RIGHT INTO THE DERMIS WHEN WE LOOK AT THEM. 48-72 HOURS LATER WHEN WE LOOKED IN ORGANS TO SEE TO GET TO THE DERMIS AND THE BLOODSTREAM WE’VE SEEN A TINY BIT, LIKE ABOUT 5% OF WHAT WE SEE IN THE SKIN AT MOST IN THE LIVER REALLY NOTHING ELSE. IN ANYTHING ELSE. THEY ARE EX TREATED THROUGH THE GUT.>>ARE THERE ANY OTHER QUESTIONS FOR DR. PALER? THANK YOU SO MUCH. PLEASE JOIN — [APPLAUSE] SMALL RECEPTION IN THE LIBRARY FOLLOWING THE TALK PLEASE JOIN US FOR SOME COFFEE MAYBE A COOKIE OR TWO. THANK YOU.

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