Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov >> GOOD AFTERNOON, WELCOME TO GROUND ROUNDS. TODAY TWO COLLEAGUES FROM NINDS WILL PRESENT THEIR CURRENT AND RESEARCH AND PROGRESSIVE EN ENCEPHAL OPATHY OOR PML. I AM GOING TO INTRODUCE BOTH SPEAKERS AND THEN THEY WILL DO THEIR PRESENTATIONS, AND IF TIME PERMITS BETWEEN THEM, WE CAN HAVE SOME QUESTIONS AND IF NOT, WE'LL DO ALL THE QUESTIONS AT THE END. OUR FIRST SPEAKER IS DR. AVNES, CLINICAL DIRECTOR OF THE NATIONAL INSTITUTE OF NEWER LODGEIC DISEASES AND STROKE. HE'S ALSO CHIEF OF THE INFECTION INFECTIONS AND NERVOUS SYSTEM AND THE TRANSLATIONAL NEWURO SCIENCES CENTER. HE EARNED HIS MEDICAL DEGREE FROM THE CHRISTIAN MEDICAL COLLEGE IN 1981. AND IN 1988, HE COMPLETED BOTH A NUROLOGY RESIDENCY AND /AEA NEWEURO NEUROIMMUNOLOGY FRELLOWSHIP AT THE UNIVERSITY OF TEXAS HEALTH CENTER IN HOUSTON. HE THEN CAME TO NIH AS /AA CLINICAL FELLOW IN THE AN ENTIRE OF MOLECULAR VIROLOGY IN THE LABORATORY OF VIRAL AND MOLECULAR PATHOGENESIS, AND THEN COMPLETED HIS FELLOWSHIP IN NEWUROVIROLOGY IN 1990. HE THEN LEFT THE NIH AND TOOK A POSITION AT THE UNIVERSITY OF MAN /TOITOBA IN CANADA AND THE UNIVERSITY OF KEN /TUTUCKY AND FROM 2002 TO 2011, HE WAS PROFESSOR OF NEWUROLOGY AND NEWEUROSCIENCES AT JOHNS HOPKINS UNIVERSITY, WHERE HE SERVED AS DIRECTOR OF THE DIVISION OF FAILULUOROIMMUNOLOGY AND NEWER /HROPBUROLOGICAL INFECTIONS, AS WELL AS CO-DIRECTOR OF THE NEWURO NEUROAGE TRANSLATIONAL RESEARCH CENTER. HE RETURNED TO THE NIH IN 2011 AS THE CLINICAL DIRECTOR OF THE INSTITUTE. HIS RESEARCH IS FOCUSED ON STUDYING THE PATH /OFIZPHYSIOLOGY OF HIV INFECTION AND HIS CURRENT LAB RESEARCH IS FOCUSED ON UNDERSTANDING HOW THE RESERVOIR OF NIH -- HIV IS ESTABLISHED IN THE BRAIN AND THE MECHANISMS OF NEWER OLOINJURY AND DEVELOPMENT 'S THE ASSOCIATE HE HEDITOR OF THE JOURNAL -- JOURNAL OF NEWUROVIR NEUROVIROLOGY AND HE WROTE /AA BOOK ON CLINICAL NUROVIROLOGY. HE'S A PAST CHAIR OF THE AMERICAN ACADEMY OF NEWUROLOGY AND CURRENT PRESIDENT OF THE INTERNATIONAL SOCIETY OF NEWEURO NEUROVIROLOGY. HE'S RECEIVED A LOT /OF AWARDS, INCLUDING THE PIONEER AWARD IN NEWUROVIROLOGY FROM THE INTERNATIONAL SOCIETY OF NEWEURO NEUROVIROLOGY IN 2012 AND /AA LIFETIME ACHIEVEMENT AWARD BY THE ASSOCIATION OF NEWUROLOGIST OF AMERICA AT THE AMERICAN ACADEMY OF NEWUROLOGY AND THE SILVER AWARD FOR RESEARCH AND HIV INFECTIONS FROM THE CHILDREN CHILDREN'S HOSPITAL OF PHILADELPHIA. BOTH IN 2014 AND THIS YEAR, HE WAS ELECTED CHAIR OF THE NIH MEDICAL EXECUTIVE COMMITTEE. AND HE'S GOING TO TALK ON THE PROGRESS OF MULTIFOCAL ENCEPHAL ENCEPHALOPATHY, CLINICAL MAN MANIFESTATIONS AND THERAPEUTIC A APPROACHES. BEFORE HE SPEAKS, LET ME INTRODUCE DR. USAEUGENE MAJOR, WHO IS GOING TO BE THE SECOND SPEAKER OF THIS DID YOUO. DR. MAJOR RECEIVED HIS PH.D IN MICROBIOLOGY FROM THE UNIVERSITY OF I WILLINOIS MEDICAL CENTER, WHERE HE HELPED ESTABLISH A VIRAL GENETIC CENTER FOCUSING ON VIRAL ONCOLOGY. HE HELD ACADEMIC APPOINTMENTS AT THE UNIVERSITY OF I WILLINOIS AND LOI OLA UNIVERSITY IN CHICAGO AND WAS ALSO THE ASSOCIATE DEAN FOR GRADUATE PROGRAMS AT LOI OLE OLA. HE'S AN A/SKWR*UBGT PROFESSOR AT THE GEORGE WASHINGTON SCHOOL OF MEDICINE. CAME TO THE NIH IN 1993 AS CHIEF OF THE LABORATORY OF MOLECULAR MEDICINE AND NEWUROSCIENTISTS IN NIMDS AND THAT'S -- HAS BEEN COORDINATOR OF THE AIDS RESEARCH AND HAS SERVED AS /AOEBGT -- ACT ACTING DEPUTY DIRECTOR FOR THE INSTITUTE. AND IS CO-CHAIR OF THE WHITE HOUSE OFFICE THE OF SCIENCE AND TECHNOLOGY, POLICY, INTERAGENCY COMMITTEE ON SCIENCE. IN 2014, HE BECAME A SENIOR ADVISOR TO NIMDS AT THE -- AFTER MORE THAN 3 DECADES OF FEDERAL SERVICE. HIS INVESTIGATIONS FOCUSED ON THE BIOLOGY OF VIRUS INFECTIONS AND THE NERVOUS SYSTEMS. CELLS DERIVED FROM THE HUMAN BRAIN, ESTABLISHING THE UNIQUE HUMAN BRAIN STEM CELL CULTURE FOR LINEAGE DIFFERENTIATION TO NEWUROCELLS. HE HAS MORE THAN 20 PATENTS AND TECHNOLOGY OF THE HUMAN BRAIN. HE ALSO DIRECTS THE CLINICAL LABORATORY IMPROVEMENT, AMENDMENTS OF /AA LABORATORY THAT IDENTIFIES THE PRESENCE OF JC VIRUS DNA AND CLINICAL TISSUES AS PART OF PROGRESSIVE MULTIFOLK MULTIFOCAL LUEUCOENTHEM -- EN ENCEPHAL OPATHY DIAGNOSIS AND IS A FOUNDING MEMBER OF INTERNATIONAL SOCIETY OF FAILURLUORO FLUOROVIROLOGY, A FELLOW OF THE AMERICAN NEWER /HROPBUROLOGICAL ASSOCIATION AND HAS AN HONOR AARY ELECTED MEMBERSHIP OF THE ACADEMY OF NEWUROSCIENCES. TODAY HE WILL TALK ABOUT THE BIOLOGICAL AND MOLECULAR LINK BETWEEN THERAPY AND RISKS OF PROGRESSIVE MULTIFOCAL LUKEUCOEN LEUCOENCEPHAL OPATHY. SO FIRST, LET'S WELCOME THE DOCTOR TO THE PODIUM. /PHRA [APPLAUSE] >> THANK YOU VERY MUCH, FOR THAT WONDERFUL INTRODUCTION. I HAVE TO /ADMIT IF MY MOTHER WERE HERE TODAY, SHE WOULD HAVE BEEN VERY PROUD AND IF MY MOTHER MOTHER-IN-LAW WERE HERE, SHE WOULD HAVE /PW-BEEN VERY SURPRISED. LAUGHT[LAUGHTER] TODAY I'M GOING TO TALK ABOUT PML AND GIVE YOU A BRIEF CLINICAL OVERVIEW OF THE DISEASE AND SHOW YOU THE KIND OF THINGS THAT WE'VE ENGAGED IN AS FAR AS CLINICAL RESEARCH IS CONCERNED ON PML HERE AT NIH. MOST OF IT IS QUITE RECENT, SIGH LOT /OF THINGS ARE STILL ONGOING, BUT I AM QUITE PLEASED THAT WE'E MADE PROGRESS OVER THIS pLAST LITTLE WHILE. OKAY, SO PML IS AN OPPORTUNITY OPPORTUNITYISTIC INFECTION AND MOST OF US ARE INFECTED WITH THE VIRUS FROM EARLY CHILDHOOD AND ANY CIRCUMSTANCES WHERE THERE IS IMMUNE SUPPRESSION /SP-GS, FOR EXAMPLE WITH HIV INFECTION, TRANSPLANT PATIENTS, CANCER, OR OTHER KINDS /OF IMMUNE DEFICIENCE DEFICIENCIES, THE POSSIBILITY OF THE VIRUS ENTERING THE BRAIN AND CAUSING A DISEASE INCREASES. AND DR. MAJOR WILL GO INTO MORE DETAILS BUT THERE IS A WHOLE LIST -- THIS IS THE A SHORT LIST OF /AA NUMBER OF DRUGS HALF BEEN ASSOCIATED WITH P.M. L AND THIS ONE HAS A PRO /PEPPENSITY FOR INVOLVING P /PH-PLT L. THE VIRUS, WE THINK MOST LIKELY ENTERS THROUGH THE ORAL AND IN INFECTION THE SURROUNDING LYMPH NODES AND THEN REMAINS RESIDENT IN THE KIDNIES AND THIS CYCLE MAY CONTINUE WITHOUT CAUSING ANY SYMPTOMS. HOWEVER, IT CAN SOMETIMES MUTATE AND ALSO STAYS IN THE MARROW AND MUTATE AND CAN THEN ENTER THE BRAIN AND CAUSE THIS DISEASE. AGAIN, DR. MAJOR WILL DISCUSS THAT BUT THIS IS JUST TO BE ABLE TO SHOW YOU AS TO HOW THE VIRUS MANAGES TO ENTER INTO THE BRAIN. IF YOU LOOK AT THE PATHOLOGY OF THIS DISEASE, YOU WILL FIND THAT IT CAUSES MY HE WILLATION AND YOU CAN SEE THERE ARE LARGE AREAS WHERE THE MYELIN IS LOST. AND IT AFFECTS DENDRITES AS WELL AS ANTHROCITES. SO THEY CAN -- IN FACT, SOMETIMES THEY CAN BE MISTAKEN FOR CANCER, BUT THEY DON'T UNDER UNDERGO MIGHT /OTOSIS. SO IN LATER STAGES OF THE DISEASE, YOU CAN THE GET MIGHT OSIS DEVELOPING IN LOSS AS WELL. SO THIS IS JUST TO SHOW YOU HOW THE DISEASE MAY PROGRESS. CAN PROGRESS OVER A MATTER OF A FEW MONTHS, ANDS IF THERE IS NO INTERVENTION DONE, IT CAN BE A NEARLY FATAL IN MOST INDIVIDUALS INDIVIDUALS. SO YOU CAN SEE THIS MODEL TYPE APPEARANCE OF THE MRI SCAN AND IF -- IT APPEARS THIS WAY BECAUSE THE VIRUS GROWS IN SMALL LOCATIONI AND EXPANDS FROM THERE THERE. YOU CAN SEE IT AFFECTS THE MOTOR AREAS OF THE BRAIN. SO IN THE SINGLE INDIVIDUAL YOU CAN SEE FIRE FEW MONTHS IT HAS PROGRESSED FROM TWO, LEE LESIONS TO MORE. IT ALSO TENDS TO GO ACROSS THE CLOSESTUM. THESE PATIENTS ARE QUITE IMMUNE EXPRESSED. -- SUPPRESSED. SO A TYPICAL PRESENTATION OF P.M. L IS PROGRESSIVE NEWER LODGEICAL DEFICITS OVER DAYS TO WEEKS. THEY OFTEN DRAW SIGNS AND AFFECTS THE SER /PWCEREBELLUM AND ARE QUITE COMMON IN THESE PATIENTS. AND THE MEAN SURVIVAL WITHOUT TREATMENT IS ABOUT 6 MONTHS AND MORTALITY IN THE -- AND PROBABLY THE SAME FOR CANCER PATIENTS. IT IS NEARLY 100%. SO WE ARE VERY INTERESTED TO IN -- IN TRYING TO DEVELOP NEW WAYS OF BEING ABLE TO INTERVENE IN THESE PATIENTS. AN NOT BE IMPORTANT ASPECT OF THAT IS HAVING A SCALE BY WHICH WE CAN ASSESS THESE PATIENTS AND SEE THE EFFECTS. WE LOOKED AT A LOT /OF EXISTING SCALES AND ULTIMATELY DECIDED THAT WE REALLY NEEDED TO CREATE A SCALE THAT WAS TYPICAL FOR P.M. L. SO THIS IS A SCALE THAT HAS A TOTAL SCORE OF 100 AND CERTAIN UNIQUE ASPECTS OF THE SCALE THAT I WILL SHOW YOU AS WE GO ALONG. SO WE APPLIED IT TO ABOUT 15 PATIENTS THAT COME TO NIH THROUGH OUR NATURAL HISTORY PROT PROTOCOL AND IN THIS PROCESPECTIVE STUDY, WE DID A NEWER /HROPBUROLOGICAL EXAM AND UNDERGO MRI AND BLOOD FOR BOTH BIOLOGICAL AND IMMUNE STUDIES. AND YOU CAN SEE THAT THERE ARE VARIOUS TYPES OF IMMUNE DEFICIENCIES THAT UNDERLIE THESE PATIENTS. THE POLICE OFFICER -- POLICE OFFICER -- PRIME MINISTERIPHERY SEEMS TO B E A POPULAR ONE. WE COMPARED IT TO A LOT /OF OTHER EXISTING SCALES, EDS IS ONE THAT IS USED FOR MULTIPLE SCLER /OOSIS MOST OFTEN AND THEY SHOW YOU THERE IS A DISCORD ANANCE BETWEEN THE P.M. L SCALE AND EDS, HOWEVER, IT DOES MATCH THE NIH SCALE BECAUSE THEY TOO /TKORB DO TAKE INTO ACCOUNT. SO JUST TO COMPARE TO THE EDS THE STANDARD SCALE FOR PATIENTS WITH PMLS AND CAN DEVELOP AND DIFFERENTIATE -- DIFFERENTIATION IS IMPORTANT. AND WHAT WE FOUND WAS FOR EXAMPLE PATIENTS WITH CORTIC O BRIGHTNESS AND I-- A FEW OTHER SYMPTOMS AND THE SCALE WOULD BE 23. AND IT BECOMES HARD. SO THE GREATER THE NUMBERS, THE WORST THE CLINICAL PARAMETERS. AND THIS WOULD GO UP ALSO AT THE SAME TIME. HOWEVER, IF WE HAD A PATIENT WHO NOW HAS DIFFICULTY WALKING ANDS HAVE -- HAS ONLY MODERATE WEAKNESS, THE SCALE TEST WOULD GO UP AND THE PMLS SCALE WOULD ONLY BE 3. WE THINK THE P.M. LS SCALE CAPTURES A LOT BETTER. AND THEN WE LOOKED AT PATIENTS AND FOLLOWED THEM ALONG FOR SEVERAL MONTHS AND SAW THAT IF THERE IS A CHANGE IN THE MRI SCAN, THE QUESTION IS DID THE SCALE ALSO REFLECT THE CHANGE, SOME SO YOU CAN SEE HERE THE CHANGE HAS GOTTEN WORSE. YOU CAN SEE THE SPREADING OVER THE SPHERE AND SOME OVER TO THE OTHER SIDE. AND THE SCALE ALSO REFLECTS THE CHANGE FROM 8 TO 19. SIMILAR TO HERE, PATIENT WHO GOT WORSE. AGAIN, THIS GOES FROM 24 TO 30. AND A PATIENT WHO HAS BEEN IMPROVED GOES FROM 5 TO AND YOU CAN SEE CHANGES ON THE MRI SCAN. SO WE THINK THAT THE P.M. L SCALE IS QUITE SENSITIVE TO SUCH CHANGES AND THE CLINICAL PROGRESSION, AS WELAS CHANGES THAT WE SEE ON THE MRI SCAN. SO WE PUT IN A LOT /OF EFFORT INTO LOOKING AT THE RADIO LODGE LODGEICAL FEATURES OF P.M. L AND DEVELOPED A CAREER IN LOOKING AT MRI CHANGES OF PATIENTS WITH MULTIPLE SCLER /OOSIS, WHICH IS ANOTHER WHITE MATTER DISEASE AND ADAPTED THE SAME TECHNIQUES TO STUDY P.M. L. AND IN THE OTHER RANGE AT NIH IS WE HAVE THE ABILITY TO SCAN PATIENTS QUITE FREQUENTLY AND THAT CAN SOMETIMES BE VERY REVEALING. SO HERE IS A SINGLE INDIVIDUAL WHO WAS MONITORED OVER ALMOST 6 MONTHS. BY REPEATED MRI SCANS AND YOU CAN SEE ON THESE IMAGES THAT AS THE DISEASE PROGRESSES, THE VENN VENTRICLES ARE GETTING /SKPHRARPBLGT LESIONS HERE AND THE BRAIN APPEARS TO BE SLINK SHRINKING. SO AND THIS IS THE STANDARD SEQUENCE THAT MOST PEOPLE WOULD USE OUTSIDE OF NIH. HERE THEY USE A P 2 STAR AND THAT ALLOWS YOU TO LOOK AT IT MUCH BETTER. AND YOU CAN SEE THAT RIGHT AT THE GRAY-WHITE JUNCTION THERE IS A LITTLE DARK RIBBON HERE AND THIS ACTUALLY INCREASES AND INVOLVES MORE AND MORE AREA AND A PERIOD OF 6 MONTHS OF THE ENTIRE RIB -- RIBBON HERE. SO THERE IS A PROGRESSION OF THE DEPOSITION IN /THIS REGION THAT WAS NOT EVIDENT FROM THE PREVIOUS IMAGE. NOW, THEN HE HAS THE ABILITY TO LOOK AT SEA WATER AND THIS IS WHAT I'D LIKE TO EMPHASIZE. IT MEANS THAT THERE IS SOME ACTIVE NECROSIS TAKING PLACE AND AS YOU CAN SEE OVER A PERIOD OF TIME, WE HAVE MORE HERE. SO ALTHOUGH THIS WOULD SUGGEST THAT THE LESION IS SLIHRINKING, THESE TWO SEQUENCES SHOW YOU THAT THERE IS ACTIVITY TAKING PLACE IN /THIS REGION THAT WOULD NOT HAVE BEEN -- USUALLY STUDIED OTHER SEQUENCES. AND THIS IS A GALLOWIN IIAN SCAN AND THIS SHOWS YOU NO EVIDENCE THAT YOU CAN SEE EITHER. SO HERE IS ANOTHER INDIVIDUAL, AGAIN TO SHOW YOU HOW BY MRI WE CAN TRACK THESE LESIONS AND SHOW OVER A PERIOD OF TIME THIS REGION HAS -- LESION HAS GOTTEN BETTER. HOWEVER, THIS DARK SOMAL THAT YOU SEE HERE IS AGAIN ON A P 2 SHOWING DEPOSITIONS AND THAT HAS NOT CHANGED. OVER A PERIOD OF TIME. SO WE SUGGEST THAT THE PATH /OFIZZ PATHOPHYSIOLOGY OF THESE TWO THINGS MIGHT BE DIFFERENT. SO ONE OF THE OTHER THINGS THAT DANNY WRIGHT AND HIS TEAM HAS DONE IS THEY'VE DEVELOPED TECHNIQUES FOR MRI SCANS. SO TAKE OUT THE BRAINS AT AUTOPSY, FIX THEM AND THEN THEY COULD PUT IT IN THE MRI SCAN. NOW, THE INTERESTING THING IS THAT ALL CLINICAL STUDIES HERE Y AND THEN SCANNERS ARE HAPPEN FROM MONDAY THROUGH AVAILABLE ON WEEKENDS. SO YOU CAN TAKE A BRAIN, PUT IT IN THERE AND IMAGINE IT FOR THE ENTIRE WEEKEND. SO THAT'S INCREDIBLE WHAT THEY ARE ABLE TO DO. AND SO THEY TAKE THE EQUIVALENT OF ALMOST 250 MICRON AN ENTISECTIONS FROM ONE END /-OF THE BRAIN TO THE OTHER. AND IF YOU WANTED TO DO THAT SOME PLACE ELSE, THE AMOUNT OF M MRI WOULD NEVER BE AVAILABLE TO YOU AT ANY OTHER IN/STKPAOUGTS COST OF THAT WOULD BE INCREDIBLE INCREDIBLE. SO BUT THE AMOUNT OF INFORMATION YOU CAN GREEN FROM THIS IS ABSOLUTELY MIND-BOGGLING. YOU CAN SEE -- LOOK AT /WUPB ENTIRE HERE AND YOU CAN SEE THAT THESE LESIONS CLEARLY SHOW YOU HOW THAT APPEARS ON A MRI SCAN WOULD APPEAR OUT.^ SEE THESE SMALL, SMALL ELECTIONS HERE AND DARK AREA AND THEN YOU CAN SEE THIS DARK RIBBON RIGHT ACROSS THE JUNCTION. AND THEN HERE YOU CAN SEE IT MUCH BETTER SO IT'S VERY CLEAR. SO IN AN AUTOPSY BRAIN YOU HAVE THE OPPORTUNITY TO THEN STAIN IN ND SO YOU CAN SEE HERE ALL THIS DARK STAINING HERE SUGGESTING THERE IS IRON IN THE BRAIN ITSELF. SO WE CAN CONFIRM THAT WHAT LOOKS ON THE MRI IN, IN FACT, IRON ITSELF. YOU GO IN THE SUPER/TPEURFICIAL AREAS OF THE CORTEX, YOU DO NOT SEE THAT DEPOSITION. OKAY, SO HOW WOULD WE TREAT P.M. L? AND THERE IS REALLY NO GOOD ANTIVIRALS TREATMENT AVAILABLE FOR PML AT THE MOMENT AND THAT IS NOT FROM A LACK OF TRYING. SO YOU ONLY TREAT AS TO RESTORE THE IMMUNE FUNCTIONS. SO YOU CAN EITHER -- IN HIV INFECTED INDIVIDUALS GIVE THEM AIRPORT VIRAL DRUGS AND AS THAT IMPROVE THE IMMUNE SYSTEM, IT MAY TAKE CARE OF THE VIRUS ITSELF. AND IN CANCER PATIENTS STOP TAKING CHEMOTHERAPY, IF POSSIBLE POSSIBLE, PATIENTS WHO HAVE A DRUG THAT IS SUPPRESSING THE IMMUNE SYSTEM, YOU CAN WITHDRAW THAT DRUG AND WITH PATIENTS WITH MULTIPLE SCLER /OOSIS GETS RID OF THE ANTIBODY. IN PATIENTS WHO, IF YOU DO -- THERE IS A RISK THAT THEY MAY DEVELOP A CONSTITUTION SYNDROME AND THAT IS THE INFLAMMATION WITHIN THE BRAIN CAN BE TO THE EXTENT WHERE IT MIGHT DAMAGE THE HOST THEMSELVES. IN PATIENTS WITH HIV INFECTION, THE MORE IMMUNE-SUPPRESSED THEY ARE, THEN YOU START ANTIVIRALS THERAPY. THE GREATER OF CHANCES THERE ARE OF DEVELOPING AN IMMUNE RE/KOPB RECONSTITUTION SYNDROME. WE'VE TRIED /TO DIV /KWRAO*EIDE THEM INTO TWO DIFFERENT TYPES. ONE IS DELAYED AND SIMULTANEOUS AND THAT MEANS THAT FAY PATIENT HAS PL -- PML FIRST AND SECOND ARY TO /TTHAT AND THEN THEY DEVELOP THE VIRUS. THERE ARE INDIVIDUALS AT THE TIME OF DIAGNOSIS, THEY HAVE SOME INFLAMMATION ASSOCIATED WITH THEM AND AS YOU CAN SEE BY CONTRAST ENHANCEMENT OF THE MRI SCAN AND WE CALL THAT SIMULTANEOUS VIRUS AND THE DIFFERENTIATION IS IMPORTANT BECAUSE THE PROGRESS /TPHONOSIS OF THESE INDIVIDUALS IS FAR BETTER THAN THOSE WITH THE DELAYED ON SET OF THE VIRUS. AND IT MAKES SENSE BECAUSE YOU ARE -- YOUR ONLY CONTROL OF THE INFECTION IS / IMMUNE SYSTEM. SO YOU HAVE A BETTER CHANCE OF CONTROLLING IT. THE MRI CONSTITUTION SYNDROME CAN BE QUITE VARIABLE. SO YOU CAN SEE A CIRCUMSTANCE FERENTIALAL TYPE OF ENHANCEMENT IN SOME INDIVIDUALS CAN BE QUITE PROMINENT OR CAN BE QUITE SUBTLE SUBTLE. ANOTHER IS A MODULAR ENHANCEMENT WITHIN THE LESION ITSELF AND CAN BE PROMINENT OR SOMEWHAT SUBTLE. AND THE OTHER SINGLE INDIVIDUAL CAN HAVE BOTH TYPES OF ENHANCE ENHANCEMENTS WITHIN THE BRAIN. SO YOU CAN HAVE NON-ENHANCING LESIONS AS WELL AS ENHANCING LESIONS WITH THE SAME INDIVIDUAL INDIVIDUAL. HERE AGAIN TO SHOW YOU THAT THOSE PATIENTS WHO DO DEVELOP A /SPRAOEURS HERE INVOLVING NEARLY HALF OF THE HEMISPHERE ON THIS SIDE AND YET WAS ABLE TO SURVIVE SURVIVE, ALTHOUGH IT LEFT THE PATIENT WITH ATROPHY OF THE BRAIN ON THAT SIDE. [VIRUS AND]. THIS IS AGAIN TO DEMONSTRATE A MIXED PICTURE. I DRAW YOUR ATTENTION TO TWO LIVE LESIONS HERE. /SKWREFRLT ONE ON THE RIGHT SIDE AND THIS IS INCREASING WITH TIME TIME. WHILE ANOTHER ONE SEEMS RELAT RELATIVELY STABLE OVER A PERIOD OF TIME. IF YOU LOOK AT THE AMOUNT OF LIN LINEAR ENHANCEMENT, THERE IS A POSTEER PART OF THIS LESION AND YOU CAN SEE THE EXTENSION OCCURS IN THE ANTERIOR PART. NOT ONLY THE LESIONS CAN BE DIFFERENT IN DIFFERENT PARTS OF THE BRAIN BUT EVEN WITHIN THE LESIONS, THERE CAN BE DIFFERENT AREAS OF PROGRESSION OF THE DISEASE ITSELF. SO TREATMENT AND PROGRESS NOSEIS BECOME SOMEWHAT CHALLENGEING IN THESE PATIENTS. IF YOU WERE TO LOOK AT IT PATH LODGE ICALLY, WHAT YOU WILL FIND IS THAT DOES THE PATIENT HAVE A WHOLE-BRAIN? ONLY FEW LABS AROUND /THE WORLD ARE ABLE TO DO IT. THIS IS ONE THAT I BORROWED FROM THE LITERATURE FRAY GROUP IN FRANCE AND THEY SHOWED THAT HERE IS THE LESIONS OF PML AND HERE IS ONE THAT THEY FOCUSED ON FURTHER TO SHOW THE PRESENCE OF A SMALL BLOOD VESSEL AND THERE ARE LOTS OF CELLS ALL AROUND THEM. IN THE TYPE D CELLS WERE T CELLS HERE, WHICH IS CLOSE TO THE BLOOD VESSEL. THE AMOUNT OF VIRUS IS ACTUALLY VERY LITTLE COMPARED TO THE AMOUNT OF CELLS. SO THE IN/TPHRAFLAMMATORY CELLS. BUT WHAT IS ALSO QUITE FAS FASCINATING IS /THE CELLS ARE TRAPPED AROUND AND EVERY BROWN SPECK IS A C /TK-FPD 8 CELL AND LAYERS AND LAYERS ARE TRAPPED. AND IT APPEARS THAT THE MI MIGRATION OF THESE CELLS FROM THE BLOOD VESSEL INTERLESION MIGHT SOMEHOW BE IMPAIRED. SO AS A /SAESAID THAT THE PL -- P.M. L VIRUS CAN BE -- THESE ARE GOOD GOOD, BAD OR UGLY. IT'S GOOD BECAUSE WE NEED IT IN ORDER TO CONTROL THE INFECTION. HOWEVER, IF IT'S SEVERE, IT CAN RESULT IN HERNIATION AND DEATH OF THE PATIENT. SO OUR ABILITY TO DIFFERENTIATE GOOD FROM BAD IS CRITICAL, BECAUSE THOSE THAT WE THINK HAVE MORE THAN THEY NEED TO CONTROL THE INFECTION SHOULD BE TREATED WITH STEROIDS. WHAT ABOUT MONITORING PATIENTS IN THE VIRAL LOAD AND THAT POSES ANOTHER CHALLENGE IN PATIENTS. YOU SAY OKAY, IF THE MRI DOESN'T HELP, MAYBE IT SHOULD BE CONTROLLING THE INFECTION. UNFORTUNATELY, WHAT HAPPENS IS THAT A NUMBER OF PATIENTS WHO HAD MULTIPLE SCLER /OOSIS DEVELOPED P.M. L AND WE TOOK OUT THE DRUGS BY -- AND THEN WHEN WE -- THEY DEVELOPED THE VIRAL LOAD AGAIN AND WHAT WAS FOUND WAS THAT THE VIRAL LOAD WENT UP. AND HERE TWO PATIENTS AND YOU CAN SEE THAT THE VIRAL LOAD GOES UP /SAND GIVE THEM STEROIDS AND ULTIMATE LIP THE VIRAL LOAD COMES DOWN. SO IT'S QUITE POSSIBLE THAT AS THESE T CELLS LINES THE INFECTED CELLS, THERE IS VIRAL DNA IS SPILLING OUT /OF THOSE INFECTED CELLS. SO I THINK WHAT IS IMPORTANT FOR US TO DO NEXT IS TO BE ABLE TO -- ABLE TO LOOK AT THE DNA AND TRY TO FIGURE OUT WHICH ONE IS REPRESELICATING DNA AND WHICH IS JUST BITS AND PIECES OF VIRAL DNA FLOATING AROUND. NOW, WHERE DO WE GO FROM HERE? A LOT /OF EFFORT HAS BEEN PUT INTO DRUG ANTI-THERAPY AND. AS OF YET IT'S STILL PRE PRECLINICAL. WE ARE ALSO LOOKING TO DEVELOP SPECIFIC RESPONSES SO THAT INDIVIDUALS WHO ARE UNABLE TO BE EFFECT /KWREUIVE IN /AEA IMMUNE RESPONSE, COULD USE EITHER A SUBTYPE TO STIMULATE AND GIVE IT BACK TO PATIENTS OR T CELLS WITH A T CELL RECEPTOR THAT WOULD TARGET THE VIRUS ANTIGEN AND WE ARE CONTEMPLATING ABOUT GIVING AN ANTIBODY TO P /TK-FPLD 1 FOR INDIVIDUALS WHERE THERE MAY BE IMMUNOEX IMMUNOEXORGANIZATION AND STIMULATE A RESPONSIBILITY DIRECTED AGAINST /THE VIRUS. SO WE HAVE DEVELOPED A WHOLE BATTERY OF ANTI-SENSE MOLL CUMES AND EACH ONE /OF THEM HAS BEEN SCREENED IN DR. MAJOR'S LAB AND WE NEED -- MADE TWO MODIFICATION MODIFICATIONS TO THE MOLECULES. ADDING THERE AS WELL AS A MODIFICATION TO THE OXYGEN ON THE RIBOSE ITSELF AND THAT PROVIDES STABILITY TO THE DNA. AND THE WAY THAT THEY ACT IS THEY BIND TO THE RNA, FORM A DUPE /HR*EBGS, WHICH IS THEN DEGRADED. THE DNA VIRUS -- IT DOES NOT GET RID OF THE VIRUS ITSELF BUT CONTROLS IT. SO WE SCREENED A WHOLE LOT /OF THEM AND FINALLY IDENTIFIED ONE THAT WE CALL THE VIRUS IN THE RED BARS HERE /TO CONTROL REPRESELICATION IN VITRO REALLY WELL WELL. WHILE ONLY A VERY HIGH DOSAGE CAUSES SIGNIFICANT TOXICITY. THAT'S WHERE WE STAND AT THE MOMENT TO DEVELOP A DELIVERY SYSTEM TO BE ABLE TO DELIVER IT DIRECTLY INTO THE CELLS OF INTEREST. AND THOSE STUDIES ARE ONGOING. I'D LIKE TO STOP HERE BY ACKNOWLEDGING A NUMBER OF PEOPLE WHO HAVE DONE A LOT /OF WORK HERE HERE. LAWYURA WAS A POST DOC IN MY LAB WHO ORIGINALLY DESIGNED THE MOLL MOLECULES. LEE HAS DONE SOME EXPERIMENTS WITH THESE THAT I HAVEN'T SHOWN TO YOU TODAY. AND THESE ARE BOTH STAFF SCIENTISTS WHO WORKED ON THE DEVELOPMENT OF THE PROTOCOL, AS WELL AS HELPING WITH THE NIH P.M. L SCALE. CORT ESE RUNS THE NEWEUROLOGY CLINICAL AND IS INSTRUMENTAL IN DEVELOPING CLINICAL /TRAOEUTRIALS WITH IMMUNORAIDIATED THERAPIES THAT ARE BEING DEVELOPED IN COLLABORATION WITH DANNY HEWITT, JOHN AT NCI, AS WELL AS STEVE ROSENBERG. AND IN THE LAB WHO DID ALL THE EXPERIMENTS THAT I SHOWED YOU AND ALL THE NEWUROLOGY HAS BEEN DONE BY DANNY. AND I'LL STOP HERE AND TAKE QUESTIONS. /PHRA [APPLAUSE] >> THANK YOU FOR THE OPPORTUNITY TO BE HERE. VERY NICE INTRODUCTION. I WOULD SAY I HAD THE PRIVILEGE OF MEETING HIS MOTHER, AND I INDEPENDENTLY CONFIRMED WHAT HE HAD TALKED ABOUT BEFORE. SO WE'RE GOING TO CHANGE SOME OF THE FOCUS ON P.M. L, AND WE'RE GOING TO TALK ABOUT THE VIRUS AND THE BIOLOGY AND THE PATH PATHOGENESIS OF THIS INFECTION THAT LEADS TO /THE DESTRUCTION OF THE CYTES. IN A PARTICULAR SETTING IN WHICH WE FIND A VERY HIGH INCIDENCE OF PML RELATED NOT TO THE UNDER UNDERLYING DISEASE SO MUCH BUT TO THE THERAPY THAT'S GIVEN FOR UNDERGOING DISEASE T GIVES ME A UNIQUE OPPORTUNITY TO STUDY ISSUES OF THE BIOLOGY OF THIS IN INFECTION IN THE BRAIN AND WE'LL GO THROUGH THAT AND HOPEFULLY AT THE END WILL BE ABLE TO CONVINCE YOU THAT WHAT WE THINK IS /THE CURRENT STATE /--OF-THE-ART IN UNDERSTANDING THIS DISEASE P.M. L. SO THIS IS WHAT WE'RE GOING TO TALK ABOUT. AS -- PML O/OCCURS WITH INDIVIDUALS AND AFFECTS THE NERVOUS SYSTEM. SO WE SEE THIS UNDERLYING DISEASES AND ORGANI TRANS TRANSPLANTATION AS IMMUNE SYSTEM IS SUPPRESSED BY CHEM THERAPIES. AND ABOUT TEN YEARS AGO IN /AA PHASE THREE CLINICAL TRIAL OF THE HUMANIZED ANTIBODY, WHICH IS DIRECTED TO THE BETS, IT BLOCKS THE LUEUCKOCYTES SO IT CANNOT BIND THEM AND THE CELLS INTO THE BRAIN, IT HHAS BEEN A VERY SUCCESSFUL THERAPY. THERE WERE MANY EPISODES IN MULTIPLE SCLER /OOSIS PATIENTS. AND SURPRISINGLY ENOUGH WHAT HAD OCCURRED IN A NUMBER OF INDIVIDUALS IS THAT WITH MS AND UNDERLYING DISEASE AND OTHER THERAPY, P.M. L HAS OCCURRED IN THESE INDIVIDUALS AT AN EXTREMELY HIGH INCIDENCE FOR THIS RELATIVELY RARE DISEASE. WE'LL GO THROUGH THEM. SO FOR /AA LONG /PERPERIOD OF TIME P.M. L WAS ONLY SEEN IN MS PATIENTS REGARDLESS OF PRIOR SUPPRESS AANT TREATMENT OR EXPOSURE TO J /KR-FPC VIRUS. AND ONLY IN THOSE QUOTATION MARKS HERE BECAUSE MORE RECENTLY OVER /THE /HRAFLAST SEVERAL MONTHS HAVE -- THERE WILL -- -- HAVE BEEN TWO CASE THAT'S OCCURRED IN MS PATIENTS /KWR-PLT NOW, THIS IS TWO CASES OUT /OF PERHAPS ALMOST SEVERAL /HUHUNDRED THOUSAND PATIENTS WHO HAVE BEEN TREATED WITH ONE OR ANOTHER DRUG. WE ONLY SAW P.M. L IN MS PATIENTS. INTERESTINGLY ENOUGH IN /THIS SITUATION HERE PATIENTS ARE TREATED WITH THAT ANTIBODY. P.M. L WAS ARE NOT -- REALLY THE ONLY SIGNIFICANT ADVERSE IN EFFECT THAT TREATMENT. AND WHAT I FIND PARTICULARLY UNIQUE ABOUT THE CIRCUMSTANCE IS THIS LAST POINT HERE THAT P.M. L AND MS ARE TWO VERY DIFFERENT DISEASES THAT IS FOUND IN THE BRAIN AS /AA SINGLE PATIENT. THIS IS UN/PRES /TKEPPRECEDENTED IN NEWER LODGEICAL DISEASES. P.M. L AND M -- MS HAVE VERY DIFFERENT PATH /OJEGENIC MECHANISMS AND AGENTS, /SOPLT WHY DOES THIS HAPPEN? JUST /AA FEW THINGS ABOUT P.M. L THAT PERHAPS WILL HELP IN UNDERSTANDING THIS. THE VIRUS IS COMMONLY SPREAD IN THE POPULATION. WHEN IT ENTERS INTO THE BRAIN OR THE WHITE MATTER, THE PRINCIPAL TARGET IS /THE DENDRITES AND IT REMAINS WITHIN THE NUCLEUS THAT HAVE CELLS AND SPREADS OUT AND GRADUALLY DIES,.^ IT'S MULTIFOLK MULTIFOCAL. IT'S ACUTE INFECTION BUT IT CAN BE PERSISTENT. P.M. L PATIENTS WHERE WE HAVE E - LONGITUDINAL C /TP-FPLFS TO LOOK FOR VIRAL LOAD,, THAT EVEN IN THE PRESENCE OF IRIS, MANY OF THESE ECTION. INDIVIDUALS NEVER CLEAR THE AND WE WANT /TO PURSUE THAT IN GREATER DEPTH TO UNDERSTAND THIS IN MORE MECHANISTIC WAYS. THE VIRUS SEEMS TO BE LATENT WITH KIDNEY AND IMMUNE SYSTEM CELLS AND OCCURS IN INDIVIDUALS WHERE YOU HAVE IMMUNE DIS R MODULATION OF THERAPIES. DYSFUNCTION, EITHER SUPPRESSION WHAT WE'RE TRYING VERY HARD, AS YOU JUST HEARD, THERE REALLY ISN'T ANYTHING EXCEPT THE IM IM/PABIMPACT OF THE VIRUS. AND NO MODEL FOR THIS DISEASE. AND THAT'S NOT FOR /AA LOOK -- LACK OF TRYING. THIS IS THE VIRUS THAT WE'RE HUMAN POPOVIRUS AND THERE IS AN IN/TRAOEGING DNA THAT'S PACKED INTO THAT STRUCTURE AND I SUGGEST THAT PROBABLY ALMOST EVERYONE IN /THIS AUDIENCE HERE HAS SEEN THIS VIRUS, NOT VISUAL VISUALLY BUT BY INFECTIONS. WE TEST /THE PROTEINS ON THE OUTSIDE SURFACE OF THE VIRUS. ACTUALLY, WHAT YOU SEE HERE IS THE ANTIGEN THAT WE USE TO COAT AT SAY TO DETERMINE THE PRESENCE OF ANTIBODY. SO JUST TO GO THROUGH THIS. FOR OUR PARTICULAR PURPOSES THE VIROLOGY AND SUBPARTICLE LESIONS LESIONS. THIS IS AN ARRAY OF THE ASSEMBLY OF THIS VIRUS OF /AA DEN TRICITE. SOME CHARACTERISTICS OF THIS, IS THAT THIS VIRUS HAS AN EXCEPTION EXCEPTIONALLY NARROW -- FOR /AA LONG /PEPERIOD OF TIME WE CAN ONLY GROW THIS VIRUS IN HUMAN CELLS. SO WE IDENTIFIED A NUMBER OF SYSTEMS AND CELLS. CONTROL OF IN INFECTIONS IS /THE TRANSSCRIPTION TRANSSCRIPTIONAL LEVEL AND ISSUES ASSOCIATED WITH THIS AND WE WON'T TALK ABOUT THAT TOO MUCH TODAY BUT WE WILL TALK ABOUT ANOTHER DNA BINDING PROTEIN THAT WE FIND IN PRO GENT GENTORS. WAIST KEY FEATURE IN THE PATH PATHOGENESIS OF THIS. WITH THESE KINDS /OF CLINICAL SYSTEMS -- SYMPTOMS, HOWEVER, IN ORDER TO MAKE A DIAGNOSIS OF P.M. L, YOU NEED SOME EVIDENCE OF THE VIRUS. SO /-MANY YEARS AGO, WHEN THE MAJORITY OF P.M. L PATIENTS WERE IDENTIFIED AS AIDS PATIENTS, HIHIV INFECTED IS AN INDIVIDUAL IS POSITIVE, WE DEVELOPED AN ASSAY USING PROBES AND WHAT YOU SEE HERE IS /THE INFECTED NUKCLEUS IN WHICH YOU HAVE VERY HIGH NUMBERS OF DNA PRESENT IN HERE. WE CAN CO-AGITATE THAT TO 10 TO THE 11TH OR 12TH IN /TPHANY ONE IN INFECTED CELL. THIS HAPPENS TO BE THE AUTOPSY TISSUE FROM ONE /OF THOSE MS PATIENTS WHO DEVELOPED P.M. L IN ONE OF THE INDEX CASES. NINE, TEN YEARS AGO. SO WE HAVE TO LOOK AT THE VIRAL GENOME. ES AREN'T USED, RARELY BIOPSY USED FOR LOOKING FOR THE PRESENCE OF VIRUS. SO CERTAINLY BUT C /TP-FPFS IS AND PART OF THE CLIA LABORATORY THAT WE HAVE, WHERE WE HAVE VALID /A*ATED CERTIFIED ASSAYS OR THE HYBRID HYBRIDIZATION OF THE ASSAYS. FOR THIS, THIS WAS A VIRAL GENOME 5.1 AND SO WE TARGET, WE CALL IT MULTIPLEX. TWO DIFFERENT REGIONS OF THE VIRAL LEM -- GENOME. ONE IN THE NON-STRUCTURAL SEQUENCE HERE, WHICH IS HIGHLY CONSIDER AANT OF THE VIRAL GENOME. THIS IS CALLED T FOR TRANSFORMATION. AND THIS IS A UNIQUE SERIES OF NUCLEOTIDES THAT TELLS US IF THE DNA IS PRESENT, IS HIGHLY CONSERVED. SO IT IS SPECIFIC FOR J /KR-FPC. IT DOESN'T CROSS REACT WITH A ASSAY RELATED TO /THE VIRUSES IN THE POPULATION. AND THE OTHER REGION IS /THE REGULATORY REGION HERE, AND IT COMES IN TWO DIFFERENT VARIETIES IN THE HUMAN POPULATION. ONE IS CALLED THE ARCHETYPE, WHICH IS THE VIRAL DNA WHICH WE SEE EXCRETEED IN THE URINE. AND IT HAS A PARTICULAR ARRANGE ARRANGEMENT OF THE NUCLEOTIDES. THIS IS THE REGION OF THE VIRUS THAT DRIVES THE INFECTION. WHAT SEEMS TO OCCUR IS THAT THERE IS A CHANGE FROM THE ARK ARCHETYPE ARRANGEMENT OF THESE SEQUENCES FROM THIS ARRANGEMENT TO WHAT IS CALLED THE PROTOTYPE, WHICH IS TAKEN FROM J /KR-FPC HIMSELF. BY A SERIES OF ARRANGEMENTS, THIS IS VIRTUALLY NON-PATH JEN JENIC. THIS IS THE PATH /SKWREOGENIC VARIANT. SO IF THE VIRAL DNA IS PRESENT, HOW MUCH IS THERE? AND WHETHER WE COULD DISTINGUISH BETWEEN A NON-PATH /SKWREOGENIC AND A PATH /SKWREOGENIC VARIANT? SO JUST TO GIVE YOU AN APPRECIATION OF THE REGULATORY REGION, WE HAVE MAPPED OVER SOME PERIOD OF TIME A NUMBER OF DNA BINDING PROTEINS TO ABOUT 50 NUCLEOTIDES FROM THE ORIGIN OF DNA REPRESELICATION. FOR EXAMPLE, ALS ONE JUXTAPOSEED IS A PATH /SKWREOGENIC VARIANCE THAT WE IDENTIFIED IN P.M. L BRAIN TISSUE. I AM GOING TO TALK ABOUT SOME OTHER BINDING SITES IN HERE THAT ARE ASSOCIATED WITH THE INFECTION. SO WHERE TO WE SEE P.M. L PRE PREDOMINANTLY NOW? CERTAINLY IN THE HIV INFECTED INDIVIDUALS SEEMS TO BE ABOUT 1% 1%, ABOUT ONE OUT /OF 100 INDIVIDUALS OF PATIENTS WHO HAS P.M. L. THOSE DATA IS NOT -- ARE NOT AS RIGOROUS BUT DIFFICULT TO DETERMINE EXACTLY WHAT THE STENCE OF P.M. L IS. HOWEVER, INTERESTINGLY ENOUGH NOW, IN MS PATIENTS TREATED, THE OVERALL INCIDENCE IS NOT ABOUT ONE IN 300. THERE ARE ABOUT 140,000 MS PATIENTS TREATED AND MOST -- MOSTLY IN THE UNITED STATES. HOWEVER, OF INDIVIDUALS WHO HAVE BEEN DOSED WITH THIS MONTHLY IN INFUSION, APPROXIMATELY 18 TO MORE THAN 24 DOSES, THE INCIDENCE OF P.M. L IN THOSE MS PATIENTS IS ONE IN 80. SO THERE IS A TEMPORAL RELATIONSHIP TO THE OCCURRENCE OF P.M. L. NOW WE THINK WE HAVE OR THE DATA SUGGESTS THERE ARE ABOUT 540 P.M. L PATIENTS IN THE POPULATION. AND WE STILL CONTINUALLY SEE THIS AT ABOUT 8 TO 10 CASES PER MONTH. SO THERE HAS TO BE SOMETHING SPECIFIC ABOUT THIS TREATMENT. BECAUSE MANY OF THE MS PATIENTS TREATED WITH IMMUNOSUPPRESS ANANT DRUGS HAVE NEVER BEEN EXPOSED TO THE VIRUS. A UNIQUE SITUATION AND WE SPENT SOME TIME OVER /THE /HRAFLAST DECADE WORKING THAT OUT JUST TO GET AN IDEA THEN OF WHAT THEY HAVE DONE DONE. IF WE THEN PREVENTS THAT OF IN IN/TPHRAFLAMMATORY CELLS INTO THE BRAIN, VERY SUCCESSFUL THERAPY FOR RE/HRABLAXING MS PATIENTS. WHILE WE ARE INTERESTED IN /THIS, ONE OF THE UNDERRECOGNIZED EFFECTS ISN'T SO MUCH EX/TRAP EXTRAPOLATION BUT IT'S THE EFFECT IT HAS IN MI/TKPWRAEGRATING OUT PRO /SKWREPGENITORS OUT /-FOF THE NERVE, HYPOTHESIZED THIS AND QUITE ALATION. FEW YEARS AGO THAT PERHAPS THIS IS A MECHANISM BY WHICH WE CAN UNDERSTAND THE PATHOGENESIS FROM J /KR-FPC INFECTION THAT LEADS TO SUCH A HIGH INCIDENCE OF P.M. L. BECAUSE WHAT HAPPENS HERE, BECAUSE OF THAT BLOCKAGE, THAT ACTUALLY CELLS WITHIN THE BONE MARROW MIGHT REACT BECAUSE THEY NO LONGER CAN HONE IN BECAUSE THEY ARE BLOCKED AND AT /TTHAT LEVEL AND BLOCKED AT THE ALPHA 4 BETA 1, BETA 7 AND CELLS MI/TKPWRAEMIGRATE OUT. AND WE'LL GO THROUGH THIS A LITTLE BIT LATER. WHY ARE WE INTERESTED? BECAUSE SOMETIME AGO WE WERE USING A HYBRIDIZATION QUITE FRANKLY AND CAME ACROSS A NUMBER OF PATIENTS. THIS WAS A VERY INTERESTING INDIVIDUAL WHO HAS THE SYNDROME AND DEVELOPED P.M. L AND HYBRID HYBRIDIZATION HERE. VERY HIGH NUMBER PRESENT IN THE BIOPSY OF TISSUE AND THE AUTOPSY TISSUE HERE. AND THEN WE WERE ABLE TO FIND ADDITIONAL SAMPLES OF THIS INDIVIDUAL WITH THE SYNDROME AND THERE WAS A BONE MARROW BIOPSY TAKEN AND IN WHICH WE IDENTIFIED HYBRIDIZATION POSITIVE CELLS. AND WE LOOKED AT THOSE SEQUENCES I TOLL YOU ABOUT BETWEEN THE ARK ARCHETYPE AND PROTOTYPE AND FOUND THAT THERE WERE SIMILAR SIMILARITIES AND WEREN'T IDENTICAL BUT THEY WERE ALMOST IDENTICAL. WHAT WE FOUND IN THE BRAIN AND A WHAT WE FOUND IN THE MARROW. THE INTERESTING FEATURE ABOUT THIS IS THIS BONE MARROW BIOPSY WAS TAKEN FOUR YEARS BEFORE THE DEVELOPMENT OF P.M. L IN /THIS PATIENT. PATHOGENESIS OF THIS /SR*EUPBLG -- INDIVIDUAL FROM THE BONE NAR -- MARROW AND CIRCULATION, AGAIN WITH VERY SIMILAR SEQUENCES AND THEN INTO THE BRAIN. SO WE KNEW THAT IN FACT THE TISSUE, PARTICULARLY THE MARROW, WAS IMPORTANT AND SO WHEN WE IDENTIFIED INDIVIDUALS ON THE TREATMENT HAS C /TK-FPD 34 MI/TKPWRAEUGRAT ING BY PROLIFERATION, WE BEGAN TO LOOK AT THAT. SO SEVERAL OF OUR COLLEAGUES AT UNIVERSITY OF TEXAS, SOUTHWESTERN IN DALLAS, A LARGE IN OUR LABORATORY HERE HAD ESTABLISHED A COHORT OF PATIENTS TO ASK THE QUESTION CAN WE FIND VIRUS IN /TPHANY OF THESE SUB SUBCOMPARTMENTS IN THE PERIPHERAL CIRCUMSTANCE POPULATION AND WHAT IS THE MECH MECHANISM HERE? THESE ARE JUST THREE PUBLICATION THAT'S WE HAD. I WANT TO TALK ABOUT THE T CELL RESPONSES THAT WAS MAINLY THE WORK THAT WAS DONE. PEPTIDES AROUND /THE VIROGENE -- GENOME AND A LOT -- ANOTHER PAPER THAT WE HAD IN THE NEW ENGLAND JOURNAL AND MORE RECENTLY IN CELL COMPARTMENTS IN THESE OTHER INDIVIDUALS. THESE WERE MS PATIENTS AND START STARTED TREATMENT. NONE OF THESE WERE P.M. L PATIENTS. HIS COHORT OF INDIVIDUALS SO IN / INDIVIDUALS, WE HAD HEALTHY CONTROLS. WE HAD MS PATIENTS THAT BASELINE AND STARTED FOR THE FIRST TEN MONTHS AND WE HAVE ANOTHER CO COHORT OF MORE THAN 24 MONTHS. AND IN FACT, THIS COHORT OF PATIENTS WAS VERY SIMILAR TO THE ONES THAT HAVE BEEN PUBLISHED BEFORE. AS A MATTER OF FACT, AS LONG AS YOU'RE ON THAT TREATMENT, THE LEVEL OF CD 34 PRO /SKWREPGENITORS IN YOUR PERIPHERAL CIRCUMSTANCE LAYING IS ANYWHERE BETWEEN 3 TO 10-FOLD LATER THAN MANY LEVELS AND THAT CONTINUES FOR YEARS. SOME OF THESE PATIENTS HAVE BEEN TRACKED FIRE LONG, LONG /TERD --OD OF TIME . IT'S AN INTERESTING FEN /OPHENOMENON AND PERHAPS IT'S GOING TO TAKE -- BECAUSE NOBODY REALLY UNDERSTANDS WHAT THE CONSEQUENCE CONSEQUENCES OF THAT IS. IT HAS A HIGH LEVEL OF THESE PRO GENTORS. MOST OF THESE CELLS WOULD DIFFERENTIATE TOWARDS A LINEAGE AND MOST OF THAT IN THE B CELL IMAGE. SO IN SUBCOMPARTMENTS IN THESE INDIVIDUALS IN THE ONES THAT ARE INITIATEING AND ALSO THOSE WHERE LONGER DOSES. AND WE FOUND EACH -- THESE INDIVIDUALS IN THE CD THE 19S AND CD 34S IN BOTH CIRCUMSTANCES HERE ARE HEALTHY VOLUNTEERS AS WELL. SO WE DON'T BELIEVE THAT HAS ANYTHING TO DO WITH THE ESTABLISHMENT OF LATENCY HERE BUT IT DOES MOVE THE MIGRATION OUT OF THESE CELLS INTO THE PERIPHERAL CIRCULATION. ANOTHER INTERESTING FEATURE HERE IS THAT HE WE FOUND A ANOTHER -- NUMBER OF THESE OTHER INDIVIDUALS TESTING NEGATIVE. IN FACT -- IN OTHER WORDS, THEY WERE NOT DETECTED FOR ANTIBODIES AND SOME WHO WERE NEGATIVE AND HAD PRETTY GOOD CD 4 AND CD 8 RESPONSES. SO WE COULD FIND THE VIRUS PRESENT IN INDIVIDUALS. IN THE NEW ENGLAND JOURNAL WE IDENTIFIED A NUMBER OF INDIVIDUALS WHO ALSO -- IN THE PLASMA. AS A MATTER OF FACT, WE FOUND A NUMBER OF INDIVIDUALS THAT WERE 17 AND THAT'S A PRETTY HIGH PERCENT AND A NUMBER OF THESE INDIVIDUALS WERE NEGATIVE. AND SOME OF THESE INDIVIDUALS AGAIN WHO WERE NEGATIVE WOULD HAVE T CELL RESPONSES AND I THINK WE HAVE TO BE VERY CAREFUL ABOUT HOW WE DEFINE EXACTLY WHAT A EXPOSURE TO VIRUS IS. AND /AA NUMBER OF INDIVIDUALS WERE IN ALL COMPARTMENTS. IN THE SERUM, AS WELL AS IN THE THE -- CD 19 AND CD 34S. SO HOW DOES THIS TIE IN THEN? THE UNIVERSITY HOSPITAL THERE IN THE LABORATORY BEGAN LOOKING AT GENE EXPRESSION PATTERNS IN PATIENTS. AND IT TURNS OUT THAT MICRO MICRO/R-FP(MICRO)RNA (MICRO)RNAS ARE DISREGULATED IN MS PATIENTS. AND THAT HAS AN ADDITIONAL EFFECT. AND THEY IDENTIFIED THE MICROOR MICROORNA 126 HERE AS BEING RELATED BY THOSE INDIVIDUALS. ONCE -- WHY DOES THAT BECOME IMPORTANT? BECAUSE OF THE GENES THAT ARE UP UPREGULATED OR DOWNREGULATED, THERE IS A FAMILY OF BINDING PROTEINS, ONE /OF THINK -- ONE OF WHICH IS SPY B, WHICH IS VERY IMPORTANT FOR B CELL DIFFERENT DIFFERENTIATION. AND THIS IS FROM THEIR PARTICULAR PAPER. THERE IS NO EFFECT ON THE ID UP TO ABOUT 24 MONTHS BUT WHAT HAPPENS IS THAT YOU HAVE AN UP UPREGULATION OF THESE PARTICULAR DATA DNA BINDING PROTEINS. WE WERE CRE-- VERY SEEN -- KEEN TO LOOK AT /THIS BECAUSE WE ARE VERY FAMILIAR WITH THE PROTEIN SEQUENCES REGULATORY REGION AND SEVERAL PAPERS THAT WE PUBLISHED IN THE JOURNAL OF NEWUROLOGY. WE IDENTIFIED THERE WERE A VARIETY OF BINDING SITES ON THE REGULATORY REGION. WE CAN MOVE THESE AROUND AND ACTUALLY SOMEWHAT CHANGE THE HOST RANGE OF THE VIRUS BY MOVING THE COMPONENTS AND BINDING SITES FROM ONE PLACE TO THE NEXT. CLASSIC HERE /TIN MICROBIOLOGY. SO WE LOOKED AT A NUMBER OF ISOLATES FOR P.M. L PATIENTS AND A VARIETY OF AIDS PATIENTS, A CROHN'S PATIENT AND LUPUS PATIENT, A RHEUMATOID ARTHRITIS PATIENT, AND WE FOUND THAT THERE WAS A LARGE NUMBER OF BINDING SITES IN THAT REGION AND WE IDENTIFIED WHERE THEY WERE AND IF THEY WERE FUNCTION /AAL OR NOT? SO WE WENT BACK TO LOOK ANOTHER OUR COHORT AND WHAT WE CALL A NEGATIVE FRACTION OF THE CELL AND T COMPONENTS HERE IS NO EFFECT. , HOWEVER, IN THE CD 19S AND 34S 34S, WE SEE AN /EUINCREASE IN BIND BINDING IN S S HE -- BOTH OF THESE COMPARTMENTS AND WE CAN TRACK THAT BACK TO A FUNCTION /AAL CON CONSEQUENCE OF THE INFECTION IN THE CELLS. SO OUR HYPOTHESIS SOME YEARS AGO IS WHAT HAPPENS IS WE CAN HAVE LATENCY OWCCURRING IN THE MARROW. IN OTHER WORDS, MIGRATES THESE CELLS OUT AND AS THESE CELLS DIFFERENTIATE, THEN YOU HAVE THIS UPREGULATION OF THESE DNA BINDING SITES AND S /P-FPPIB. AND THAT'S A VERY GOOD ENVIRONMENT FOR THIS VIRUS. THE VIRUS LIKES THAT. THIS DOESN'T OCCUR IN T CELLS WHICH WE CANNOT INFECT. THIS OCCURS IN CD 24 AND 20S. SO WHERE DO WE GO FROM HERE? I HAPPEN TO REALLY LIKE THIS SLIDE. IT'S A GRAPHICALLY INTERESTING ONE. YOU WILL NOTICE HERE THERE ARE FAR MORE RED LIGHTS THAT ARE -- THAN ANYTHING ELSE. THERE ARE A NUMBER OF CAUTION ARY YELLOW LIGHTS. THERE IS ONLY ONE GREEN LIGHT. SO THIS TO ME IS SOMETHING OF A WAY IN WHICH WE'VE LOOKED THAT THE PARTICULAR ISSUE ASSOCIATED WITH THESE THERAPIES AND HOW YOU MAKE -- I TALKED ABOUT THIS -- HOW DO YOU MAKE A RISK ASSESS ASSESSMENT MARKERS FOR P.M. L THAT YOU CAN MEASURE IN THE BLOOD? SO THIS IS OUR CURRENT THINKING HERE. IF YOU ARE WITH US IN THE LABORATORY, LET'S SAY 100 MLS OF BLOOD, THIS IS WHAT WE CAN TELL YOU ABOUT YOUR PATIENT. REGARDLESS OF UNDERLYING DISEASE DISEASE. LET'S SAY IT'S AN MS PATIENT, WE COULD TELL YOU WHAT IT IS AND WE CAN TELL YOU IF THERE IS A ANTI- ANTIBIOTIC OVER TIME. SOME ACTIVE INFECTIONS. WE CAN ALSO TELL YOU WHETHER OR NOT THERE IS A PATH /SKWREOGENIC GENE GENOTYPE AND IF OVER TIME THERE IS A CHANGE BETWEEN THEM. NON-PATHOGENIC AND THE PATH JEN JENIC GENOTYPE. THAT'S ALL MART -- PART OF OUR A ASSAY. BECAUSE OF THE WORK WE DID, WE IDENTIFIED SEVERAL REGIONS OF THE GENOME WHOSE PEPTIDES THEN CD 4 AND CD 8 RESPONSES AND IN IT -- IT TURNS OUT THAT THEY HAVE VERY POOR CD 4 RESPONSES. WE NOW HAVE THE ADDITIONAL IN INSIGHTS INTO LOOKING AT MOLECULAR HOST FACTORS TO SEE IF THEY ARE INCREASED AND THAT'S NOT AN EASILY THING DONE YET, BUT WE ARE GETTING TOWARDS AN IDEA WHERE WE CAN GO AHEAD AND ALSO MAKE THAT ASSESSMENT AND THAT BETWEEN IS A PART OF THE PATH /OGENESIS. SO LET ME SUMMARIZE ALL OF THIS IN THE LAST SLIDE. WHAT /I CALL PUTTING THE PIECES OF THE /PPUZZLE TOGETHER. IN ORDER TO DEVELOP P.M. L, YOU HAVE TO BE INFECTED WITH THIS VIRUS AND IT HAS TO GET TO THE BRAIN. OTHER VIRUSES ASSOCIATED WITH THIS SO A LOT /OF OTHER CONSIDERATIONS FOR IT WE DON'T KNOW WHAT THE INITIAL SITE OF INFECTION IS BUT PROBABLY SOMETHING THAT'S QUITE COMMON AND GLOBALLY THIS VIRUS IS SPREAD. SO EPIDEMIOLOGICAL STUDIES SUGGEST THAT THE MAJORITY OF THE POPULATION WORLDWIDE IS INFECTED WITH THIS AND CLEARLY THE INITIAL SITE OF INFECTION IS NOT GOING TO BE IN THE BRAIN. WASN'T LIKELY IN THE KIDNEY. AND WE SEE ABOUT 30% OF THE POPULATION WITH LARGE AMOUNTS OF VIRUS IN THE URINE AND IT'S THAT UPTYPE SEQUENCE AND NON-PATH JEN JENIC AND REGULATORY REGION. 30% IS A HIGH NUMBER. HOWEVER, WHAT CAN HAPPEN IS THAT VIRUS CAN BE RELEASED INTO THE PERIPHERAL CIRCULATION HERE AND LARGER THAN BONE MARROW ORGANIS AND MAKE THAT TRANSFORMATION FROM THIS NON-PATH /SKWREOGENIC TO THE PATH /SKWREOGENIC FORM. WE CAN IDENTIFY THAT. THIS HAS BEEN A DIFFICULT HYPOTHESIS TO PROVE IN THE LABORATORY, BUT AT LEAST THE CHANGES IN THE DNA SEQUENCE CERTAINLY MAKES THIS A VERY LIKE LIKELY THING. LET ME INTRODUCE -- WHICH FORCES THE CD 34 CELLS OUT /-OF THE MAR MARROW. AT HIGH CONCENTRATIONS. THESE CELLS HAVE A TENDENCY TO DIFFERENTIATE TOWARDS CD 19 AND 20 CELLS OVER AND ABOVE ANY OTHER LINEAGE DIFFERENTIATION PATTERN. IF IN FACT THERE IS AFFECTED CELLS HERE, UPREGULATE THIS TO 24 RNA AND YOU HAVE AN /EUINCREASE IN SPY B. WE KNOW THAT J /KR-FPC HAS THESE DNA BINDING SITES AND WE KNOW THAT IT'S FUNCTION /AAL IN HOW THIS VIRUS CAN GROW AND MAYBE IT'S FUNCTION /AAL IN CELLS AND MAYBE NOT SO MUCH IN THE BRAIN. J /KR-FPC CAN GROW IN THESE CELLS. AND THE PERIPHERAL CIRCUMSTANLATION THE VIRUS ITSELF REMAINS IN/TRA INTRACELLULAR IN B CELLS AND WILL BE IDENTIFIED IN AUTOPSY TISSUES IN THE BRAIN OF P.M. L PATIENTS. WE DON'T KNOW EXACTLY HOW THIS VIRUS GETS INTO THE BRAIN. AGAIN, LACKING AN ANIMAL MODEL, IT IS DIFFICULT TO SEE THAT. IN SOME CULTURES IT'S GOOD BUT IT'S DIFFICULT TO HANDLE THE VIRUS. WHAT WE THINK HAPPENS IS /THE VIRUS GETS IN /SAND IN/TRTRACELLULAR B CELLS AND THERE IS ANOTHER FAMILY OF DNA BINDING PROTEINS IN CELLS IN THE HUMAN BRAIN WHICH AUGMENTS THIS INFECTION. AND WE CAN ACTUALLY TEST -- PASS INFECTIONS TO GLIAL CELLS SO WE KNOW THAT THAT CAN OCCUR. ALL OF THAT HAS HAPPENED AND INITIATED AND THAT'S WHERE WE SEE THE LABORATORY CONFIRMATION OF THE DIAGNOSIS OF P.M. L. AND THAT'S /PUGTS THE PIECES OF THE /PPUZZLE TOGETHER. THIS IS WHAT WE THINK HAPPENS AND THERE ARE DIFFERENT UNDER UNDERLYING DISEASES AND DIFFERENT THERAPIES WHERE IT'S POSSIBLE ALSO TO IDENTIFY FACTORS LIKE THIS. SO I DON'T THINK IT'S UNIQUE TO MS PATIENTS BUT IT CERTAINLY EXPLAINS ALL THE AVAILABLE DATA IN /THIS UNIQUE SITUATION IN WHICH YOU HAVE TWO DISEASES IN THE BRAIN OF /AA SINGLE PATIENT. THE MOST IMPORTANT SLIDE IS /THE GRATITUDE FOR THE FOLKS IN THE LABORATORY WHO HAVE HELPED TO PUT ALL THE PIECES OF THE /PPUZZLE TOGETHER. SO THANK YOU. /PHRA [APPLAUSE] >> WE CAN TAKE SOME QUESTIONS. I'D LIKE TO START BY ASKING DO YOU HAVE ANY IDEA OF WHAT AGE THIS INFECTION STARTS TO APPEAR? AND WHETHER YOU HAVE ANY REASON TO BELIEVE YOU COULD DEVELOP A VACCINE? >> SO YEAH. SO IN TERMS OF AGE, WE IDENTIFY THIS AS PROBABLY SOMEWHERE AROUND JUVENILE AGE PERIODS, FIVE OR SIX AND BECAUSE OF THE EVIDENCE INDIVIDUALS BEGINNING TO DEVELOP ANTIBODIES AND YOU CAN COULD GO BY DECADE SO THAT THE INDIVIDUALS IN THEIR 20'S AND 30'S, PROBABLY 35% AND STILL 40% OF THE POPULATION HAS BEEN BY THE TIME YOU GET TO BE MY AGE AGE, IT'S 90 TO /THE 5% OF THE INDIVIDUALS ARE INFECTED. THAT MEANS IN VERY DIFFERENT A AWAYS THERE IS GOING TO BE /AA KEY FEATURE AND PROBABLY GIVE US THE BEST OPPORTUNITY TO INTERVENE IN THIS DISEASE. SO OUR EFFORTS ARE GOING IN THAT DIRECTION FOR SURE, JOHN. >> GREAT TALK. SO THE QUESTION IS DO YOU SEE DIV /KWRAO*EIDERS IN THE RECEIPTINA? OF COURSE, I SAW THE FACTORS AND IT'S PROBABLY THE CELLS ARE AFFECTED THE REGIONAL CORTEX AND THAT CAUSES BLINDNESS. BUT DOES IT APPROPRIATE -- >> INAUDIB[INAUDIBLE]. {}AND THE SECOND QUESTION RELATES TO THE EFFECT OF THE ANT -- CELLS. I COULD IMAGE THE CATEGORYING OF THE CELLS. AFTER SPENDING 12 YEARS I GAVE UP BECAUSE IT DOES NOT HAVE A TARGETED EFFECT. THEY JUST DON'T LOOK FOR THINGS INSIDE. THEY WORK BEAUTIFULLY IN /AA SING SINGLE CELL. I PUT THE CELLS, THEY KILL THE CANCER CELLS AND OTHER CELLS PRETTY WELL. BUT WHEN I INJECT IT IN THE BODY BODY, THEY JUST DON'T TARGET ANYTHING AND THERE IS NO EFFECT. SO THE QUESTION IS WHAT ANTI- ANTI-CELLS ARE YOU USING? IS IT FOR KILLING THE VIRUS OR IS IT KILLING THE INFECTED CELLS CELLS? >> SO NUMBER ONE, AIN'TGENS HAVE BEEN SHOWN TO WORK /SAND WORKS REALLY WELL INJECTED RIGHT AT THE SITE AND IT DOES ITS JOB. IN CASES OF PATIENTS WITH PML, YOU CAN INJECT DIRECTLY INTO VENT TRICKLE. AND LIKELY CANCER PATIENTS WEREN'T ABLE TO MOUNT AN IMMUNE RESPONSE AND THAT WOULD BE THE IDEAL PATIENT POPULATION THAT WE WOULD PROBABLY TARGET. AND ANOTHER THING IS OUR INTENTION IS NOT TO KILL THE VIRUS. I DON'T THINK IT WILL KILL THE VIRUS. IT IS A DNA VIRUS SO ALL YOU WOULD DO IS GET RID OF THE RNA. YOU STILL NEED THE IMMUNE SYSTEM TO GET RID OF THE VIRUS. BUT IF YOU ARE ABLE TO CONTROL IT, EVEN THOUGH IT TAKES A WHILE TO BUILD UP IN THE IMMUNE SYSTEM SYSTEM, I THINK THAT WOULD BE BEST. >> ALL RIGHT, SO THANK YOU. GOOD LUCK. >> I WONDER WHEN /AA DRUG TRIED ON THE ANIMAL MODEL. SO THE ANIMAL MODEL SHOWS THE FLARES PATTERN LIKE MS PATIENTS OR DOES IT SHOW THE PROGRESS? MS MAN -- ANIMAL MODEL? THE REASON I ASK THAT IS BECAUSE I USED THE LUPUS MODEL AND THEY DON'T HAVE THE PATTERN. THEY JUST SHOW THE CONTENT PROGRESSION. BUT WHEN I USE THE CD 11 TO TREAT THESE, I THINK THAT PROGRESSION CAN BE INDUCED TO THE -- >> I CAN ANSWER THAT VERY SIMPLY. THE ANIMALS DO NOT GET INFECTED WITH THE VIRUS, OKAY? SO THE VIRUS IS A HUMAN VIRUS THAT WILL ONLY INFECT HUMAN CELLS. IT'S NOT GOING TO DOING ANYTHING. THE ANIMAL MODELS ARE VERY DIFFERENT. THEY ARE AUTOIMMUNE DISEASE AND NOT PERFECT BUT AT LEAST YOU CAN DUCE THE T CELLS TO CAUSE DAMAGE TO THE BRAIN. BUT IF YOU PUT J /KR-FPC ONE IN THAT MODEL, IT WILL DO ABSOLUTELY NOTHING. >> HOW ABOUT MS MODEL? >> THE MS MODEL IS EXPERIMENTAL EXPERIMENTAL. >> OKAY. >> THANK YOU FOR /AA VERY INTERESTING PRESENTATION. YOU COMMENTED, OF COURSE, ON THE LACK OF SUCCESSION -- SUCCESS IN TERMS OF THERAPY TO CONTROL VIRAL REPRESELICATION AS WE HOPE TO OBTAIN IN THE CONSTITUTION. ESPECIALLY I WONDER ABOUT BRAIN, BECAUSE I KNOW THERE IS DATA FROM THE LABORATORIES, INCLUDING DR. MAJOR'S LABORATORY IN IN I VITRO MODELS. HAS IT BEEN TESTED IN HUMANS? >> SO THERE WAS A TRIAL IN HIV PATIENTS, AND BUT A NUMBER OF CIRCUMSTANCES IN WHICH P.M. L PATIENTS HAVE BEEN TREATED AND THERE HASN'T BEEN ANY SUCCESS WITH THAT PARTICULAR THERAPY. AND THE REASON I THINK IS THAT CERTAINLY IN THE PRE-CLINICAL MODELS THAT WE HAVE, YOU REALLY HAVE TO HAVE A HIGH ENOUGH CONS CONCENTRATION BECAUSE IT REALLY BECOMES PROCESPECT. AND ALTHOUGH -- THE OTHER MODIFICATION OF THAT CMX 100 REALLY LOOKED PRETTY GOOD BUT THERE WERE TOXIC EFFECT ON PATIENTS FOR THAT AS WELL. SO THERE WAS INITIAL HOPE FOR THAT. TRIALS HAD BEEN DONE, AND IT'S NOT CLEAR. IT MIGHT STILL BE CLINICALLY USED IN SOME CASES. >> THANKS TO BOTH SPEAKERS FOR A GREAT SESSION. /PHRA [APPLAUSE]