>> I'M VICKY WHITTEMORE, PROGRAM DIRECTOR AT NINDS. I WELCOME YOU TO THE CURING EPILEPSIES CONFERENCE, SETTING RESEARCH PRIORITIES. AND IT'S OUR PLEASURE TO HAVE ALL OF YOU HERE JOINING US VIA ZOOM. UNFORTUNATELY, THE CONFERENCE WE HAD PLANNED FOR APRIL WE HAD TO POSTPONE, AND WE WERE HOPING THAT WE WOULD BE FACE TO FACE ON THE NIH CAMPUS, WHICH OBVIOUSLY DID NOT HAPPEN, BUT WE'RE PLEASED TO HAVE YOU HERE EITHER ON THE ZOOM PLATFORM OR VIA THE NIH WEBCAST. WITH NO FURTHER ADO IT'S MY PLEASURE TO INTRODUCE DR. WALTER KOROSHETZ, DIRECTOR OF NINDS, WHO IS GOING TO KICK OFF THE CONFERENCE FOR US. DR. KOROSHETZ? >> THANK YOU VERY MUCH, VICKY. THANKS, EVERYBODY, FOR JOINING. WE'RE LOOKING FORWARD TO A GREAT CONFERENCE. VERY IMPORTANT CONFERENCE, NINDS, I THINK TO THE EPILEPSY COMMUNITIES AS WELL. SO JUST TO CUT TO THE CHASE, NINDS IS THE LEADING FUNDER OF EPILEPSY RESEARCH, AND YOU CAN SEE OVER THE YEARS THE FUNDING HAS BEEN STABLE, CERTAINLY NOT COMMENSURATE WITH BURDEN OF ILLNESS DUE TO EPILEPSY BUT THAT'S TRUE WITH MOST OF OUR ILLNESSES, YET HOPEFULLY TO DEMONSTRATE TO YOU ALMOST -- A GREAT DEAL OF RESEARCH WE DO SPECIFICALLY ON BASIC MECHANISM OF BRAIN FUNCTIONS ARE RELEVANT TO EPILEPSY RESEARCH AS WELL. NEXT SLIDE. SO, THE MISSION OF NINDS IS TO SEEK FUNDAMENTAL KNOWLEDGE OF THE BRAIN AND NERVOUS SYSTEM, TO USE THAT KNOWLEDGE TO REDUCE THE BURDEN OF NEUROLOGIC DISEASE, AND WE'RE BASICALLY ON POINT WITH REGARD TO APPROVING OUR ABILITY TO ACHIEVE OUR MISSION WITH REGARD TO EPILEPSY. AND SO WHAT DO WE DO AS AN INSTITUTE? WE'RE THE TAXPAYERS' INVESTMENT IN NEUROLOGIC RESEARCH A I CROSS A SPECTRUM OF AREAS IN BASIC RESEARCH WHERE MOST OF OUR FUNDING GOES. WE HAVE SUBSTANTIAL EFFORTS IN TRANSLATIONAL RESEARCH, WHICH IS BRINGING NEW THERAPIES TO THE MARKET, AND ALSO IN CLINICAL RESEARCH DOING CLINICAL TRIALS. WE ARE INVESTED IN TRAINING A TALENTED AND DIVERSE RESEARCH WORKFORCE, AND THE CONFERENCE TODAY REALLY RELATES TO THESE LAST FOUR ITEMS, WE'RE ALWAYS LOOKING TO IDENTIFY GAPS IN RESEARCH AND PUBLIC HEALTH NEEDS, AND THAT'S REALLY THE CORE FEATURE OF THIS CONFERENCE. WE'RE HERE TO SUPPORT THE DEVELOPMENT OF TOOLS AND RESOURCES TO ENABLE DISCOVERIES, AND WE'D LOVE TO KNOW WHERE THOSE IN EPILEPSIES MIGHT BE, PARTICULARLY WHAT TOOLS THE EPILEPSY COMMUNITY MIGHT TAKE FROM PARTICULARLY THE BRAIN INITIATIVE, WHICH IS A FOCUS ON UNDERSTANDING CIRCUITS AND HAS DEVELOPED AMAZING TOOLS FOR CIRCUIT DISORDERS, EPILEPSY BEING, YOU KNOW, THE MODEL CIRCUIT DISORDER. ALSO IT'S IMPORTANT FOR US TO BE COMMUNICATING COLLABORATE WITH STAKEHOLDERS INCLUDING THE PUBLIC WHICH THIS MEETING ALLOWS US TO DO. AND THE WHOLE GOAL BEHIND ALL THESE ISSUES IS TO HELP US TO EVALUATE AND CONTINUOUSLY IMPROVE AS AN INSTITUTE. NEXT SLIDE PLEASE. SO, THE BENCHMARKS HAVE BEEN REALLY IMPORTANT TO THE RESEARCH COMMUNITY. THESE ARE EPILEPSY RESEARCH BENCHMARKS THAT THE COMMUNITY HAS ADOPTED AND FOLLOWED THEIR PROGRESS OVER THE YEARS, AND I THINK HAS HAD IMPORTANT INFLUENCES ON WHAT WE FUND, AS WELL AS WHAT THE RESEARCH COMMUNITY ENGAGES IN. THIS MEETING IS TO HIGHLIGHT SCIENCE GAPS AND OPPORTUNITIES IN EPILEPSY RESEARCH. WE'RE LOOKING FOR BROAD INPUT AND WE'VE DONE THIS IN THE PAST WITH RFIS, REQUEST FOR INFORMATION. AND TOGETHER WITH THAT INFORMATION, THIS I THINK WILL INFORM THE EPILEPSY RESEARCH COMMUNITY OVER THE NEXT 5 TO 7-YEAR TIME FRAME. WE'RE ASKING PEOPLE TO CONSIDER THE REALLY IMPORTANT THINGS HELP US DEVELOP BETTER TREATMENTS FOR FOLKS WITH EPILEPSY, MAYBE PREVENTING EPILEPSY, ALSO A GREAT TIME TO THINK ABOUT THINGS THAT ARE PARADIGM-SHIFTING RESEARCH THAT, YOU KNOW, IF WE MAKE AN INVESTMENT IN AREA A OR B, COULD THAT REALLY KIND OF CHANGE THE GAME FOR A PARTICULAR TYPE OF EPILEPSY. I WANTED TO ADD THE CAVEAT WE'RE SEEKING INPUT FROM ALL, AS A GOVERNMENT AGENCY WE CANNOT TAKE CONSENSUS RECOMMENDATIONS FROM ANYTHING EXCEPT THE FEDERAL ADVISORY COUNCIL, THAT'S OUR NINDS HAS AN ADVISORY COUNCIL THAT MEETS THREE TIMES A YEAR, AND THAT'S THE ONLY GROUP THAT LEGALLY CAN GIVE CONSENSUS RECOMMENDATIONS, BUT WE TAKE INPUT FROM EVERYONE AND WE'RE REALLY LOOKING FORWARD TO THE INPUT WE RECEIVE TODAY. NEXT SLIDE. SO IN SETTING THE PRIORITIES, AN OPPORTUNITY FOR THE STAKEHOLDERS TO PROVIDE INPUT ON TRANSFORMATIVE RESEARCH PRIORITIES FOR THE FIELD, AND TO COME TOGETHER TO FIND WAYS TO MOVE TOWARDS OUR COMMON GOAL WHICH IS TO CURE EPILEPSY. THE FOCUS AREAS WE THOUGHT MIGHT BE IMPORTANT WOULD BE RESEARCH THAT ACCELERATES DEVELOPMENT OF NEW TREATMENTS, THAT CAN BE TRANSLATED TO INDIVIDUALS WITH EPILEPSY, OPPORTUNITIES FOR INCREASED DATA SHARING AND COLLABORATION, IDENTIFYING GAPS AND OPPORTUNITIES FOR ADVANCING RESEARCH IN THE EPILEPSY, AND ALSO TO LEARN ABOUT THE CHALLENGES FACED BY THE EPILEPSY COMMUNITY AND THE RESEARCH COMMUNITY AND THE PATIENTS AND HOW THEY MIGHT BE BETTER ADDRESSED. THAT'S KIND OF THE OVERALL BIG PICTURE SETTING FOR TODAY'S CONFERENCE, BUT WE'RE REALLY WITH THE BENCHMARK EPILEPSY CAN GET INTO THE WEEDS AND COME IN WITH REALLY GOOD INPUT IN PARTICULAR AREAS AS WELL. NEXT SLIDE. BESIDES THIS CONFERENCE, NINDS HAS WORKSHOPS WHERE THEY ALSO OBTAIN INPUT FROM EXPERTS AND PATIENTS, AND ADVOCACY GROUPS IN EPILEPSY. THERE WAS A RECENT ONE ON METABOLISM-BASED EPILEPSY, AND ONE ON POSTTRAUMATIC EPILEPSY IN MARCH, NEXT SLIDE, TOPICS BASED. I WANT TO LET PEOPLE KNOW NINDS CONTINUES TO SUPPORT OVER THE LAST 45 YEARS THE EPILEPSY THERAPY SCREENING PROGRAM WHICH IS BASED OUT OF UNIVERSITY OF UTAH, AND HERE THERE ARE MULTIPLE RIGOROUS EPILEPSY MODELS THAT ARE AVAILABLE FOR PEOPLE TO COME IN AND TEST THEIR DRUGS, A WIDE OPEN SYSTEM FOR PEOPLE TO COME IN AND TEST THEIR DRUGS IN THESE EPILEPSY MODELS, VERY HELPFUL IN THE PAST IN DEVELOPING NEW ANTI-CONVULSANTS AND HOPE IN THE FUTURE IT WILL FOCUS ON DEVELOPING TREATMENTS FOR DRUG RESISTANT EPILEPSY, POTENTIALLY TREATMENTS THAT WOULD PREVENT EPILEPSY FROM COMING AFTER, SAY, SOMEONE HAS THE FIRST SEIZURE OR SOMEONE HAS A TRAUMATIC BRAIN INJURY WHERE THE EPILEPSY COMES ON WEEKS, MONTHS, EVEN YEARS LATER. NEXT SLIDE. EXAMPLES OF THINGS WE'VE DONE IN TERMS OF THIS TRANSFORMATIVE SPACE, IT'S CERTAINLY BEEN CENTER WITHOUT WALLS PROGRAM STARTED IN EPILEPSY, NOW WE ALSO BROUGHT THEM TO SOME OF THE OTHER AREAS AT NINDS BECAUSE THEY HAVE BEEN SO SUCCESSFUL. CERTAINLY THE ONES SURROUNDING GENETICS HAVE LED TO DISCOVERY OF NUMEROUS DIFFERENT MUTATIONS THAT LEAD TO EPILEPSY, SOME TYPES OF EPILEPSY, AND NOW WITH THESE MUTATIONS WE HAVE ANOTHER CENTER WITHOUT WALLS PROGRAM TO EVALUATE MECHANISM BY WHICH THESE MUTATIONS DO LEAD TO EPILEPSY. THE HOPE IS THAT WE CAN DEVELOP KIND OF PRECISE TREATMENTS FOR THESE GENETIC EPILEPSIES, AND PERHAPS LEARN SOME INFORMATION THAT WILL CARRY OVER MORE GENERICALLY TO EPILEPSY AND LEAD TO TREATMENTS FOR EVEN A WIDER SPECTRUM OF PATIENTS. NEXT SLIDE. AND I JUST WANT TO END BY SAYING AS I MENTIONED OFF THE BAT THAT I THINK WE'RE ENTERING A TREMENDOUSLY NEW AND EXCITING AREA IN EPILEPSY RESEARCH, WHEN THESE NEW TOOLS THAT ARE COMING OUT OF THE BRAIN INITIATIVE ARE REALLY FOCUSED HEAVILY ON UNDERSTANDING THE CIRCUITS THAT UNDERLIE EPILEPTIFORM BEHAVIOR. FOR FOLKS WHO DON'T KNOW THESE TOOLS THAT CAME OUT OF THE BRAIN INITIATIVE ARE CALLED BRAIN INITIATIVED -- BRAIN RESEARCH THROUGH INNOVATIVE NEUROTECHNOLOGIES, AND IT'S DEVELOPING THESE NEURO TECHNOLOGIES THAT NOW ALLOW YOU TO LOOK AT, SAY, A MILLION NEURONS SIMULTANEOUSLY IN, SAY, AN EPILEPTIFORM ANIMAL MODEL AND TRY AND UNDERSTAND HOW THE EPILEPSY GENERATES ITSELF, WHAT STOPS IT IN THE END, AND HOW YOU CAN MODULATE THE ACTIVITY TO PREVENT THE SEIZURE ACTIVITY SO THESE TECHNOLOGIES WHICH WERE JUST KIND OF A FIGMENT OF THE IMAGINATION FIVE YEARS AGO ARE NOW AVAILABLE IN MANY LABS ACROSS THE COUNTRY, AND THERE ARE MANY MORE COMING OUT OF THE BRAIN INITIATIVE, SO I THINK THAT IF THERE'S SOMETHING LOOKING TO THE FUTURE THAT COULD REALLY CHANGE THE GAME IN EPILEPSY, KEEP YOUR EYE ON THESE NEW TOOLS AND HOW THEY ARE ADAPTED BY THE EPILEPSY RESEARCH COMMUNITY. NEXT SLIDE. I WANT TO END BY THANKING THE JUNIOR INVESTIGATORS WHO WON THE JUNIOR INVESTIGATOR AWARDS FOR THE EPILEPSY CONFERENCE. THEY GET FREE TRAVEL TO THE ZOOM MEETING. BEING FACETIOUS HERE. THEY WOULD HAVE GOTTEN FREE TRAVEL TO THE MEETING BUT NOW WE'RE IN ZOOM, MANY ARE WORKING AT NOTE TAKERS AND ARE TAKING PART IN THE CONFERENCE, AND I WANT TO CONGRATULATE THEM AND THANK THEM AND NO PRESSURE BUT THE FUTURE OF EPILEPSY IS ON YOUR SHOULDERS. SO THANKS VERY MUCH. AND WITH THAT I'D LIKE TO END AND GO BACK TO VICKY WHITTEMORE WHO WILL CONTINUE THE CONFERENCE. THANKS, EVERYONE. I LOOK FORWARD VERY MUCH SO TO YOUR INPUT. >> THANK YOU, DR. KOROSHETZ. CAN I HAVE MY FIRST SLIDE? THANK YOU. GO TO THE NEXT SLIDE PLEASE. AND THE NEXT SLIDE. SO, JUST AS A REMINDER OF WHERE THE EPILEPSY RESEARCH BENCHMARKS CAME FROM, THEY WERE DEVELOPED REALLY BUILDING ON THE MOMENTUM OF THE FIRST CURING EPILEPSY CONFERENCE THAT TOOK PLACE IN 2000, WHICH WAS A WHITE HOUSE-INITIATED CONFERENCE, REALLY SEEN AS TURNING POINT FOR RESEARCH ON THE EPILEPSIES. SO THERE WAS A SHIFT IN THE FOCUS FROM TREATING SEIZURES TO IDENTIFYING CURES, TO FIND NO SEIZURES, NO SIDE EFFECTS, AS WELL AS TO IDENTIFY WAYS IN WHICH TO PREVENT EPILEPSY IN THOSE AT RISK. SO THE BENCHMARKS OVER THE YEARS HAVE BEEN USED AS A WAY TO COMMUNICATE AND ADD IMPORTANT RESEARCH PRIORITIES AND AS A FRAMEWORK REALLY FOR BENCHMARKING OR LOOKING AT THE PROGRESS THAT'S BEEN MADE OR IDENTIFYING AREAS IN WHICH THERE IS PROGRESS, MORE PROGRESS IS NEEDED. SO, THERE HAVE BEEN SUBSEQUENT CONFERENCES IN 2007, AND 2013, WHICH LED TO REVISIONS OF THE BENCHMARKS AFTER EACH OF THOSE CONFERENCES. IN THE NEXT SLIDE, SO THE ORIGINAL BENCHMARKS REALLY FOCUSED ON THREE AREAS, UNDERSTANDING HOW EPILEPSY DEVELOPS, FINDING WAYS TO PREVENT SEIZURES FROM DEVELOPING, AND AT-RISK INDIVIDUALS, FINDING GETTER WAYS TO STOP SEIZURES WITHOUT SIDE EFFECTS IN THOSE WITH EPILEPSY. AND THE NEXT SLIDE. SO, AS I SAID, THE BENCHMARKS HAVE REVISED FOLLOWING EACH OF THE CONFERENCES WHICH WILL BE THE CASE AFTER THIS CONFERENCE, AND THE BENCHMARK STEWARDS COMMITTEE HAVE ALREADY DONE A TREMENDOUS JOB OF REVISING EXISTING BENCHMARKS. THERE WAS A CAMPAIGN ON THE NINDS PUBLIC CROWDSOURCING WEBSITE WHERE PEOPLE COULD MAKE COMMENTS ON THOSE BENCHMARKS, AS WELL AS ON THE TRANSFORMATIVE RESEARCH PRIORITIES WHICH WILL BE THE FOCUS OF THIS CONFERENCE. IN 2007 AND 2013 SOME IMPORTANT ASPECTS OF EPILEPSY RESEARCH WERE ADDED TO THE BENCHMARKS, SO SUDEP WAS ADDED, SUDDEN UNEXPECTED DEATH, AND THE COMORBIDITIES, NEUROLOGIC, PSYCHIATRIC, AND SOMATIC CONDITIONS ALSO VERY IMPORTANT ASPECTS OF EPILEPSY, BESIDES SEIZURES. MOST IMPORTANTLY, IT WAS RECOGNIZED THAT THERE ARE MANY FORMS AND CAUSES OF EPILEPSY SO THE CONFERENCE WAS CHANGED FROM CURING EPILEPSY TO CURING THE EPILEPSIES. NEXT SLIDE. 2021 EPILEPSY RESEARCH BENCHMARKS ARE CURRENTLY POSTED ON THE NINDS WEBSITE AS WELL AS ON THE PUBLIC CROWDSOURCING SITE, IDEASCALE.GOV, AND REALLY FLESHING OUT THE AREAS OF EPILEPSY RESEARCH ACROSS THESE FOUR AREAS. MANY-- ALL OF THE BENCHMARK STEWARDS AND AREA LEADS WHO ARE PART OF THE BENCHMARKS COMMITTEE ARE JOINING US HERE IN THIS MEETING, EITHER SPEAKERS OR BREAKOUT MODERATORS OR PARTICIPATING IN DIFFERENT WAYS IN THE CONFERENCE SO WE LOOK FORWARD TO REALLY ACTIVE DISCUSSION AS WE GO THROUGH THE CONFERENCE AND INTO THE BREAKOUT GROUPS. AND THE NEXT SLIDE. I'VE JUST LISTED HERE IN THE REFERENCES IN THE SLIDE AND THE NEXT SLIDE, FOR ALL OF THE PUBLICATIONS THAT COME ABOUT THE EPILEPSY BENCHMARKS, AND ALL OF THESE REFERENCES AND LINKS TO PAPERS WILL BE ADDED TO THE EPILEPSY -- CURING THE EPILEPSIES WEBSITE ON THE NINDS WEBSITE. WITH THAT I WILL STOP, AND I WILL INTRODUCE MY FRIEND AND COLLEAGUE ILENE MILLER, WHERE THE EPILEPSY LEADERSHIP COUNCIL BENCHMARKS WORK GROUP, WHO IS GOING TO TALK ABOUT WHY THE BENCHMARKS MATTER. ILENE? >> GREAT. MY DEEPEST GRATITUDE TO VICKY, TO DR. KOROSHETZ AND STEWARDS FOR CONVENING A MEETING WHERE ALL OF THE PEOPLE LIVING WITH EPILEPSY, ADVOCATES, RESEARCHERS, JUNIOR INVESTIGATORS, AND CLINICIANS CAN JOIN TOGETHER. NEXT SLIDE. NEXT SLIDE. COMING OFF A DECADE OF BRAIN RESEARCH REVELATIONS, THE 2000 CURING THE EPILEPSY CONFERENCE REPRESENTED A TRULY PIVOTAL MOMENT, A LANDMARK MINDSET SHIFT FROM TREATING TO CURING EPILEPSY. TWO YEARS LATER MY SON MARK WAS BORN WITH THE PECULIAR SMIRK AND GIGGLE, BEGINNING A FIVE-YEAR DIAGNOSTIC ODYSSEY, FOLLOWING MANY MISDIAGNOSED HE WAS DIAGNOSED WITH A RARE STRUCTURAL EPILEPSY. NEXT SLIDE. FAILED MEDICATIONS, FREQUENT AND LONGER SEIZURES, CONFLICT WITH DOCTORS ADVISED US, REGRESSION BY PUBERTY WAS UNLIKELY AND UNDERWENT EXPERIMENTAL GAMMA KNIFE SURGERY AND FOR THREE YEARS WE HELD OUR BREATH TO SEE IF SEIZURES WOULD STOP OR DIMINISH. THE SAME YEAR THE CONFERENCE, BENCHMARKS WERE ADDED INSPIRED BY DR. LOWENSTEIN, STANDING ON A TABLE AND ASSERTING IT WASN'T ENOUGH TO SIMPLY COME TOGETHER, THAT THE COMMUNITY NEEDED TO IDENTIFY GAPS AND PRIORITIES AND ROUTINELY MEASURE PROGRESS AGAINST GOALS. NEXT SLIDE. FAST FORWARD TO 2013, MARK WAS STILL SEIZING, WE WERE LIVING WITH MANY NON-SEIZURE SIDE EFFECTS. WE SCHEDULED AND CANCELED LASER SURGERY THREE TIMES WEIGHING BENEFIT OF PERMANENT SEIZURE CESSATION AGAINST RISKS FOR OUR OTHERWISE TYPICALLY DEVELOPING SON. THE STRESS IN OUR HOME WAS TRULY PALPABLE. IT MARKED THE THIRD CONFERENCE AND THIS TIME A SHIFT IN SCOPE, CONFERENCE WAS RENAMED CURING THE EPILEPSIES IN RECOGNITION THAT EPILEPSY WAS A MULTIPLICITY OF DISEASES, CAUSES, AND COURSES. NEW BENCHMARKS WERE ADDED TO ADDRESS THE COGNITIVE, PSYCHIATRIC, PSYCHOSOCIAL AND OTHER COMORBIDITIES OF EPILEPSY BEYOND SEIZURES THAT FRANKLY WERE OFTEN WORSE THAN THE SEIZURES THEMSELVES. NEXT SLIDE. ULTIMATELY, A MEDICATION CHANGE IN PREPARATION FOR SURGERY THAT NEVER OCCURRED SIGNIFICANTLY REDUCED MARK'S SEIZURES. GAP YEAR ABROAD,ED HADED HEADED TO THE COLLEGE, INTERESTED IN NEUROSCIENCE I MIGHT ADD BUT I'M STRUCK WE'VE BEEN CURING EPILEPSY FOR MY SON'S LIFETIME. FIVE YEARS TO DIAGNOSE THIS, ELEVEN YEARS TO CONTROL, DESPITE MEDICATIONS AND SURGERY MARK STILL SEIZES, TAKES DAILY ANTI-SEIZURE MEDICATION, AND SCHOOL, WORK, SOCIAL AND HEALTH DECISIONS ARE INFLUENCED BY HIS EPILEPSY. AND WE ARE AMONG THE LUCKY ONES WITH CONTROL. 20 YEARS AFTER THAT FIRST CONFERENCE, A THIRD OF ALL PEOPLE ARE STILL WITHOUT ANY CONTROL, AND FOR THE PEOPLE LIVING WITH EARLY LIFE RARE SEVERE OR INTRACTABLE EPILEPSIES, THE COURSE AND PROGNOSIS CAN BE DEVASTATING. MANY CHILDREN, SIBLINGS, PARENTS AND LOVED ONES ARE STILL DYING FROM EPILEPSY-RELATED CAUSES. NEXT SLIDE. WE HAVE AN INCREDIBLY ROBUST ECOSYSTEM FILLED WITH PASSIONATE, DEDICATED CHAMPIONS OF RESEARCH, YET CURRENT PACE AND EXISTING INFRASTRUCTURE IT WILL TAKE HUNDREDS OF YEARS TO CURE THOUSANDS OF EPILEPSIES, DISEASE BY DISEASE. TIME IS BRAIN, MOVEMENT, MEMORY, INDEPENDENCE, CONTROL. TIME IS LOST LIVES. TIME IS A LUXURY OUR FAMILIES DON'T HAVE. WE MUST FIND FUNDAMENTALLY NEW WAYS TO ORGANIZE OUR COMMUNITY, TO CURE THE EPILEPSIES, FASTER, MANY DISEASES AT A TIME. NEXT SLIDE. WE'VE SEEN WHAT LARGE-SCALE INITIATIVES INSPIRED BY THE BENCHMARKS HAVE KNISHED, -- ACCOMPLISHED, IMAGINE IF WE WENT FURTHER, IF THAT GENETICS CONSORTIUM WAS LINKED TO A LEARNING HEALTH SYSTEM AND BIOMARKER CONSORTIUM, ALL OF WHICH PROVIDED PUBLICLY AVAILABLE DATASETS TO FUEL BASIC RESEARCH, A COLLABORATION THAT CREATES A CONSTANT FEEDBACK LOOP TO LEARN AND APPLY THOSE LEARNINGS. WE NEED TRANSFORMATIVE CHANGE, TO OVERCOME SYSTEMIC IMPEDIMENTS. THERE'S A ROADMAP, FORTUNATELY, IN THE CHILDREN'S ONCOLOGY GROUP SUCCESS IN PEDIATRIC CANCER, NOT WITH STANDING BIOLOGICAL AND OTHER DIFFERENCES, COG DEMONSTRATES HOW WE CAN OVERCOME THE SAME SYSTEMIC BARRIERS ON NATIONAL EVEN GLOBAL BASIS TO CHANGE OUTCOMES FOR PATIENTS IN A TIME THAT MATTERS. AS WE EMBARK ON CURING THE EPILEPSIES CONFERENCE NUMBER 4, AND TO QUOTE WALTER, PARADIGM-SHIFTING RESEARCH REQUIRES SHIFTING THE PARADIGM. THIS TIME, IT IS TIME TO OVERHAUL THE EPILEPSY INFRASTRUCTURE, TO INTEGRATE BASIC CLINICAL TRANSLATIONAL AND IMPLEMENTATION SCIENCE, BECAUSE SILOS OF RESEARCH AND CARE ARE FAILING OUR LOVED ONES. THANK YOU. IT IS MY PLEASURE TO INTRODUCE DR. ANN PODURI, PROFESSOR OF NEUROLOGY AT HARVARD MEDICAL SCHOOL, AND DIRECTOR OF THE EPILEPSY GENETICS PROGRAM AT BOSTON CHILDREN'S HOSPITAL AND FORMER JUNIOR INVESTIGATOR AT CURING THE EPILEPSIES CONFERENCE. AS CO-CHAIR OF THE BENCHMARK STEWARDS COMMITTEE SHE WILL TALK ABOUT LAYING GROUND WORK FOR TRANSLATION. >> THANK YOU SO MUCH, ILENE. NEXT SLIDE PLEASE. NEXT SLIDE. WELCOME TO ALL OF YOU. I'M GRATEFUL FOR THE OPPORTUNITY TO MEET DESPITE DIFFICULT TIMES. THANK YOU FOR COMING TOGETHER TO LISTEN TO MANY VOICES, TO SHARE YOUR IDEAS AND TO LAY THE GROUND WORK FOR TRANSFORMATIVE RESEARCH AND TRANSLATION OF RESEARCH TO CURE THE EPILEPSIES. WE'RE HERE TO FOCUS ON THE VERY LOFTY BUT NECESSARY GOAL OF CURING THE EPILEPSIES. LET ME POSE THREE SETS OF CONDITIONS. FIRST, LET US REMIND OURSELVES WITH MANY BACKGROUNDS AND PERSPECTIVES WHY EPILEPSY AND WHY FOCUS ON RESEARCH IN EPILEPSY. SECOND, WITHIN EPILEPSY WHAT SHOULD BE THE FOCUS OF OUR RESEARCH EFFORTS? THIRD, WHAT ARE THE BIG UNANSWERED QUESTIONS WE NEED TO ADDRESS TO CURE THE EPILEPSIES AND HOW CAN WE ADDRESS THEM TOGETHER? SIMPLY PUT, WE'RE ASKING YOU TO KEEP IN MIND WHY FOCUS FOR THREE DAYS TOGETHER ON WHAT, AND HOW WE CAN ADDRESS UNANSWERED QUESTIONS ON EPILEPSY THROUGH RESEARCH AND TRANSLATE THEM TO PATIENTS. NEXT PLEASE. WHY EPILEPSY? EPILEPSY IS AN URGENT PROBLEM AFFECTING 1 IN 26 PEOPLE, ALL OVER THE WORLD, YOUNG AND OLD FROM EVERY RACE AND STATUS WITH IMPACT ON SURVIVAL, MORBIDITY, MORTALITY. WHY RESEARCH? CENTURIES INTO THINKING ABOUT EPILEPSIES WE HAVE MANY UNANSWERED QUESTIONS, TO EVEN THINK ABOUT CURING THIS CONDITION WE NEED TO UNDERSTAND ITS CAUSES, MANIFESTATIONS AND FUNDAMENTAL SCIENCE UNDERLYING BRAIN DYSFUNCTION IN EPILEPSY. WE ALSO NEED RESEARCH TO UNDERSTAND HOW TO MEASURE THE MANIFESTATIONS AND IMPACT OF THAT ON OUR PATIENTS, HOW TO ASSESS IMPACT OF POTENTIAL TREATMENTS AND ONE DAY HOW TO PREVENT EPILEPSY AND TOLL ON PATIENTS AND FAMILIES. NEXT PLEASE. WHAT RESEARCH NEEDS TO BE DONE? WE HEARD FROM VICKY AND ILENE AROUND EPILEPSY AND COMORBIDITIES, RESEARCH INTO CAUSES, MECHANISM, TREATMENT AND PREVENTION, DEFINED AND REDEFINED PRIORITIES TOGETHER AS A COMMUNITY AND INVITE YOU TO THINK TOGETHER ABOUT WHERE WE CAN TAKE THE NEXT LEAPS OF PROGRESS IN THE BENCHMARK AREAS AND BEYOND THE EXISTING BENCHMARK AREAS. NEXT PLEASE. NOW IT'S 2021. OUR COMMUNITY HAS MADE TREMENDOUS PROGRESS FINDING CAUSES AND ACKNOWLEDGING DIVERSITY OF CAUSES, AND THE WORLD-WIDE BURDEN OF EPILEPSY. DRILLING DOWN AND EVEN AS YOU'LL HEAR DEVELOPING SPECIFIC TREATMENTS FOR SOME SPECIFIC CAUSES. >> TWO-MINUTE WARNING. >> WE HEAR URGENCY, OUR PATIENTS, FAMILIES, FROM PHYSICIANS TREATING PATIENTS. WE NEED TRANSFORMATIVE APPROACHES. WHAT ARE THE QUESTIONS TO ADDRESS TOGETHER AND HOW CAN WE TAKE THEM ON? THESE ARE THE SAME QUESTIONS PATIENTS AND FAMILIES HAVE BEEN ASKING, WHY DID THIS HAPPEN, WHY DID IT START NOW, WHAT CAN WE DO AND HOW WILL THIS AFFECT THE REST OF OUR LIVES. WHO IS AT RISK FOR EPILEPSY? WE'VE MOVED IN THE IMAGING AND GENOMIC ERAS TO IMPROVED UNDERSTANDING FOR CAUSATION, WHETHER ACQUIRED, GENETIC, INFLAMMATORY OR STILL UNKNOWN. WE NEED TO TRANSLATE FINDINGS AND SHIFT PRACTICE TO ADDRESS THE BASIC QUESTION EACH PATIENT AND FAMILY WILL ASK REASONABLY, WHY? WE NEED TO ASK NOT ONLY WHY DOES EACH PERSON FROM EPILEPSY ON THE TRANSLATIONAL FRONT BUT ALSO AS RESEARCH COMMUNITY WHY DO SO MANY PEOPLE HAVE EPILEPSY OVER THE COURSE OF A LIFETIME, WHY ARE HUMAN BRAINS SO VULNERABLE, WHAT'S THE NATURE AND REASON FOR THIS INTRINSIC VULNERABILITY AND HOW CAN WE CONTROL IT? HOW DO SEIZURES START AND STOP FOR A PERSON WITH EPILEPSY? WHAT KEEPS THINGS IN CHECK FOR SO LONG UNTIL THE FIRST SEIZURE OCCURS? WHAT CAN WE LEARN FROM MODELS OF EPILEPSY, FOR ACQUIRED EPILEPSY, WHAT PROCESSES LEAD FROM ACUTE EXPOSURE TO CHRONIC EPILEPSY AND CAN THEY BE INTERRUPTED AND FOR GENETIC EPILEPSY WHAT IS PROCESSES. HOW CAN THEY BE MODELED AND INTERRUPTED, HOW DO WE DEFINE AND WHAT ARE BIOMARKERS THAT REFLECT THESE PROCESSES? NEXT PLEASE. FOR THE FIELD AS A WHOLE THESE QUESTIONS NEED ALL HANDS ON DECK APPROACH, WITH BENCH RESEARCH TEAMS, CLINICAL RESEARCH TEAMS, STUDENTS, PATIENTS AND FAMILIES, FOCUSING ATTENTION ON THE IMPORTANT RESEARCH QUESTIONS TO BREAK UP ON THE FIELD AND ALLOW PROGRESS TOWARD SHARED GOALS, THESE THREE DAYS ARE THE BEGINNING OF CONVERSATION WE INVITE AND CHALLENGE YOU TO CONTINUE IN THE MONTHS AND YEARS. TO CONTINUE TO LAY THE GROUNDWORK I INVITE DR. ERIC MARSH, FROM CHILDREN'S HOSPITAL OF PHILADELPHIA, VICE CHAIR OF OUR CONFERENCE, AND RISING CHAIR OF BENCHMARKS STEWARDS COMMITTEE. ERIC? >> HI, ANN. THANK YOU ALL. I'M ERIC MARSH, VICE CHAIR OF BENCHMARKS COMMITTEE STEWARDS COMMITTEE TASKED TO INTRODUCE THE TRANSFORMATIVE RESEARCH PRIORITIES, TO BRING US TOGETHER FOR THIS CONFERENCE. I'D LIKE TO THANK THE THEM FOR BRINGING US TOGETHER. NEXT SLIDE PLEASE. DISCLOSURES. NEXT SLIDE PLEASE. THANK YOU ANN, VICKY AND ILENE. THE BENCHMARKS HAVE BEEN STABLE SINCE INCEPTION, WITH NOTABLE ADDITION OF COMORBIDITIES AND SUDEP MAJOR FOCUS OF RESEARCH THERE'S BEEN REMARKABLE BUT STEADY PROGRESS OVER 20 YEARS, MANY ASPECTS REMAIN, SUBSTANTIAL QUESTIONS. THERE'S BEEN NO SIGNIFICANT CHANGES TO PROGNOSIS, TREATMENT, OR OUTCOME. OUR ABILITY TO DIAGNOSE GENETICS OF GROWING PROPORTION OF PEOPLE OCCURRED, GENETICS OF THE COMMON EPILEPSIES AND PREDISPOSITION REMAINS UNSOLVED. WITH ADVANCES IN COMPUTATIONAL POWER, MOLECULAR AND GENETIC TOOLS, PHARMACOLOGY AND IMAGING AND PHYSIOLOGIC TECHNIQUES THE FIELD IS READY FOR TRANSFORMATIVE SET OF RESEARCH QUESTIONS TO LEAD TO BENCHMARKS IN 2028 THAT WILL LOOK DIFFERENT THAN TODAY AND RAISE QUESTIONS ON THE PATH TO IDEAS. THE GOAL OF THIS CONFERENCE IS TO FURTHER SPARK THAT DEBATE. NEXT SLIDE. THE AES EPILEPSY RESEARCH BENCHMARKS COMMITTEE WAS CHARGED WITH IDENTIFY PARADIGM-SHIFTING QUESTIONS TO PUSH BENCHMARKS TO DIFFERENT PLACE, ASKED QUESTIONS WITH THE FOLLOWING PREMISE, TO IMPROVE OUR UNDERSTANDING OF THE EPILEPSIES, AND PEOPLE'S LIVES WITH EPILEPSY, STIMULATE NOVEL AND INNOVATIVE RESEARCH, ENCOURAGE MULTI-DISCIPLINARY APPROACHES, ATTRACT NEW THINKING ON THE RESEARCH IN EPILEPSIES, IDENTIFY SPECIFIC AREAS OF RESEARCH THAT IF SUCCESSFULLY UNDERTAKEN PRESENT OPPORTUNITIES FOR TRANSFORMATION AND UNDERSTANDING IN TREATMENT OF EPILEPSY. NEXT SLIDE PLEASE. MANY IDEAS WERE GENERATED, AND THESE ARE REPRESENTED IN THIS WORD STAR. FOR SPECIFIC DETAILS GO BACK TO THE IDEA SCALE CAMPAIGN WEBSITE VICKY POSTED EARLIER. WITH DIFFERENT TECHNOLOGIES AND TYPES OF EPILEPSIES, SPANNING FROM CLINICAL TO BASIC RESEARCH QUESTIONS, THE BENCHMARK COMMITTEE GENERATED INTERESTING QUESTIONS, NINDS WANTED TO BRING IN COMMUNITY INPUT ABOUT WHAT TRANSFORMATIVE QUESTIONS ARE FOR RESEARCHERS AND PATIENT COMMUNITY. TO DO THIS A TWO-PART PLAN WAS INITIATED, FIRST PART IDEA SCALE CROWDSOURCING CAMPAIGN WAS LAUNCHED. THERE WERE 25 IDEAS SUBMITTED FOR TRANSFORMATIVE RESEARCH PRIORITIES AND THESE IDEAS WERE VIEWED OVER 500 TIMES. >> TWO-MINUTE WARNING. >> MANY FOCUSED ON FOUNDATIONAL CHANGES TO THE WAY EPILEPSY RESEARCH CLINICAL AND BASIC SHOULD BE PERFORMED. THE HOPE OF THE CAMPAIGN WAS TO HAVE MORE OF A DISCUSSION ABOUT RESEARCH IDEAS BUT UNFORTUNATELY MUCH OF THE SUBSTANCE WAS ON IMPLEMENTATION, NOT AS MUCH BACK AND FORTH WITH ONLY 26 COMMENTS ABOUT THE 25 IDEAS. THE IDEA SCALE CAMPAIGN AND BENCHMARK STEWARD TEAM IDEAS LED TO RESHAPING OF THE CONFERENCE FROM APRIL TO TODAY. WITH FOCUS NOW ON DETERMINING WHAT ARE THESE TRANSFORMATIVE RESEARCH IDEAS FOR THE EPILEPSY COMMUNITY. NEXT SLIDE PLEASE. SO, WE'RE NOW TASKED TO THINK BEYOND OUR PATIENTS, LABS, OUR WORK AND CONSIDER TRANSFORMATIVE IDEAS TO MAKE A MARKED CHANGE IN EPILEPSY RESEARCH. TALKS AND PANELS OVER THE CONFERENCE ARE MEANT TO ACT AS SPRINGBOARD TO NEW CONCEPTS AND IDEAS, WE SHOULD FOCUS ON RESEARCH IDEAS THAT WILL ADDRESS THE UNKNOWNS AS ANN SAID, ADDRESS WHY AND WHAT. THE TRANSFORMATION OF THE INFRASTRUCTURE TO COLLECT, SHARE, DISSEMINATE IDEAS IS NEEDED BUT LET'S FOCUS THREE DAYS ON RESEARCH QUESTIONS AND RESEARCH PRIORITIES. PLEASE SHARE IN THE NEXT FEW DAYS YOUR IDEAS AND DISCUSSIONS IN THE BREAKOUTS AND CHATS. DON'T HOLD BACK. WE WANT TO HEAR ALL EXCITING IDEAS THAT YOU POTENTIALLY HAVE. THE AGENDA FOR THE CONFERENCE IS ONLINE. I HOPE YOU'LL PARTICIPATE IN THE ENTIRE CONFERENCE. I HAVE THE PLEASURE TO INTRODUCE THE MODERATOR OF SESSION 2, EXPEDITING TARGETED TREATMENTS FOR THE EPILEPSIES, DR. DANIEL LOWENSTEIN, PROVOST AT UCSF MEDICAL CENTER. DR. LOWENSTEIN, THANK YOU FOR MODERATING SESSION 2. >> THANK YOU, ERIC. AND WELCOME, EVERYONE. I'M VERY PLEASED TO HELP INTRODUCE THIS NEXT SESSION ON EXPEDITING TARGETED TREATMENTS FOR THE EPILEPSIES AND WE'LL KICK OFF WITH A PERSONAL STORY FROM AMBER FREED, PARENT AND ADVOCATE. >> YOU ARE MUTED, IF YOU COULD UNMUTE. >> CAN EVERYBODY HEAR ME? >> WE CAN, THANK YOU. >> WONDERFUL! WELL, THANK YOU SO MUCH FOR HAVING ME TODAY. I'M AMBER FREED. AND IT'S MY PLEASURE TO SPEAK. I'M THE FOUNDER AND CEO OF SLC6A1 CONNECT. AFTER YEARS OF OF I.V., IF WE WELCOMED TWIN BABIES IN MARCH OF 2017. LIFE WAS PERFECT. WE WERE SO CONTENT. THAT BOTTOM LEFT-HAND PICTURE IS MY HUSBAND GRABBING HIS CHEST, WHEN HE REALIZED WE WERE HAVING TWINS BUT THE MOMENT HE REALIZED HE WAS NEVER GOING TO RETIRE. NEXT SLIDE. VERY EARLY ON, I NOTICED THAT MAXWELL WASN'T PROGRESSING THE SAME WAY HIS TWIN SISTER RILEY WAS. HE MISSED EVERY MILESTONE. HE HAD TO STRAIN STEREOTIES. AFTER A THOUSAND APPOINTMENTS, MISSED DIAGNOSES, INVASIVE PROCEDURES WE BEGAN GENETIC TESTING. DOCTORS LED US TO THE BAD NEWSROOM WHEN WE RECEIVED RESULTS. I WAS SHAKING WITH ADRENALINE, WHEN MY BEAUTIFUL INNOCENT LITTLE SON WAS DIAGNOSED WITH LETTERS AND NUMBERS SLC6A1, THE ONLY THING I COULD THINK OF WAS WHY IS HE BEING DIAGNOSED WITH A FLIGHT NUMBER? DOCTORS DIDN'T KNOW ANYTHING ABOUT IT, OTHER THAN ONE PUBLICATION WRITTEN OUT OF DENMARK. I REMEMBER DOCTORS LISTING ALL OF THE THINGS HE COULD PROBABLY NEVER DO, AND THAT LIST JUST FELT ENDLESS. IT WAS PIERCING MY HEART. MY HUSBAND'S SHOULDERS BEGAN TO QUIVER, I GRABBED HIS KNEE. I SAID, MARK, DON'T CRY. THIS IS NOT GOING TO BE MAXWELL'S STORY. IT WAS IN THAT MOMENT THAT I DECIDED TO FIGHT LIKE A MOTHER. I WAS GOING TO FIGHT LIKE THE THIRD MONKEY ON THE LOADING DECK TO NOAH'S ARK AND IT STARTED TO RAIN. I LEFT MY CAREER AS AN EQUITY ANALYST THE SAME DAY AND HAVEN'T LOOKED BACK SINCE. NEXT SLIDE. IN JUST UNDER TWO YEARS, WE'VE MADE REMARKABLE PROGRESS. WE HAVE GENE REPLACEMENT THERAPY ON THE HORIZON WITH CORPORATE SPONSOR. WE'RE WORKING ON NUMEROUS ANTISENSE APPROACHES, ONE IN LARGE PART THANKS TO MR. STANLEY CROOKE. WE'RE ALSO STARTING A DRUG REPURPOSING PROGRAM BEGINNING EARLY THIS SPRING. I PERSONALLY RAISED OVER $2 MILLION, IN 18 MONTHS. AND ONE POINT I'D LIKE TO MAKE ABOUT THESE ACCOMPLISHMENTS IS THAT WHILE I'M PROUD, YOU KNOW, I CERTAINLY DIDN'T ASK FOR THIS JOB. IT WAS MY BEAUTIFUL LITTLE SON, AND I WOULD WALK TO THE END OF THE EARTH FOR HIM, AND NOW NOT ONLY MY SON BUT ALL OF THE CHILDREN AFFECTED BY THIS HORRIBLE DISEASE. >> TWO-MINUTE WARNING. >> ONCE YOU SEE THE NEED IN THIS SPACE YOU JUST CAN'T TURN YOUR HEAD. AND SO WHAT I'VE ACCOMPLISHED IS NOT TYPICAL, RATIONAL, OR REALLY EVEN HUMANE. THERE'S BEEN A LARGE OPPORTUNITY COST INCLUDING TIME WITH FAMILY AND EVEN MY PERSONAL HEALTH. NEXT SLIDE. BEING AFFECTED BY EPILEPSY IS HORRIBLE. MY GOAL IS TO WORK MYSELF OUT OF A JOB. I'VE HAD TO TEACH MYSELF MICROBIOLOGY, I'VE BECOME A PROFESSIONAL CAT HERDER OF ROUNDING SCIENTIFIC PROFESSIONALS. AND THE STRESS THIS CREATES ON A FAMILY IS UNSUSTAINABLE. THE AMOUNT OF THERAPISTS IN OUR HOME IS RIDICULOUS, I WAS THINKING OF INTERESTING STATISTICS TO INCLUDE, AND ONE I'D LOVE TO JUST KNOW IS HOW MANY TRIPS WERE NOT TAKEN TO DISNEYLAND BECAUSE OF ILLNESS OR BEHAVIOR? NEXT SLIDE. LASTLY I WOULD LIKE TO SAY THAT MY THEME IS TO FIGHT LIKE A MOTHER, FOR US ALL TO FIGHT. THERE ARE SO MANY TRANSLATIONAL GLIMMERS OF HOPE NOW AFTER EPILEPSY STATISTICS HAVE REMAINED VIRTUALLY STAGNANT FOR THE PAST 20 YEARS, DESPITE AN EXPLOSIVE GROWTH IN NEW ANTI-EPILEPTICS. I FIND PATIENT ORGANIZATION IT MAKES MOST SENSE TO FUND TRANSLATIONAL OPPORTUNITIES TO HELP CHILDREN IN OUR LIFETIME. MAXWELL SEASON 3. GOVERNMENT FUNDING IS MORE SCARCE FOR DISEASE-SPECIFIC TRANSLATIONAL PROGRAMS. TO PUT THIS IN PERSPECTIVE, A PHASE 1 GENE THERAPY TRIAL CAN RUN UPWARDS OF $10 MILLION FOR AN ORGANIZATION. >> TIME EXPIRED. >> THIS DOESN'T LEAVE A LOT OF ROOM AND I ENCOURAGE US ALL TO FIGHT WITH THE URGENCY WE HAVE DONE WITH COVID AND AIDS AND FOCUS MORE ON N OF A FEWS FOR TRANSLATIONAL THERAPIES. THANK YOU SO MUCH. >> THANK YOU, AMBER. YOUR LIVED EXPERIENCE EXPLAINS WHAT MOTIVATES ALL OF US TODAY. SO, NOW MY ASSIGNMENT IS TO CONSIDER HOW WE SHOULD BE THINKING ABOUT MOVING TOWARDS TARGETED THERAPIES FOR THE EPILEPSIES. NEXT. HERE ARE MY DISCLAIMERS AND DISCLOSURES. NEXT. LET ME TELL YOU FROM THE OUTSAID MY MAIN POINTS. FIRST, CONCEPT OF IDENTIFYING EFFECTIVE TARGETED TREATMENTS FOR EPILEPSIES IS HARDLY NEW. SECONDLY, FROM A RELATIVE PERSPECTIVE, WE HAVEN'T MADE A GREAT DEAL OF PROGRESS IN EPILEPSY TREATMENT OVER THE PAST 50 YEARS, ALTHOUGH THERE ARE DEFINITELY DIFFERENT OPINIONS ON THIS. THIRD, THE LIMITS IN PROGRESS ARE AT LEAST PARTLY EXPLAINED BY THE VALIDITY OF OUR MODELS, ENORMOUS CHALLENGE TO UNDERSTANDING, COMPLEX NATURE OF THE HUMAN BRAIN, AND LACKING TOOLS NEEDED TO DECIPHER BIOLOGICAL BASIS OF EPILEPSY. FINALLY, THE DIGITAL REVOLUTION OR AS HAS BEEN CALLED VERSION 4.0 OF THE INDUSTRIAL AGE, COMBINED WITH EMERGING TOOLS, MAY BRING US TO NEW ERA IN EPILEPSY THERAPY, ONE THAT WILL ENABLE A MULTI-DIMENSIONAL HOLISTIC APPROACH TO CARE OF THE PATIENTS. NEXT. SO, WHAT DO WE MEAN BY TARGETED THERAPY? THIS IS A DEFINITION I CAME UP WITH, INTERVENTIONS WITH A WELL UNDERSTOOD MECHANISM OF ACTION THAT FULLY AND PERMANENTLY AMELIORATES SYMPTOMS OF A DISEASE WITHOUT ANY CLINICAL OR BIOLOGICAL SIDE EFFECTS, OR PREVENTS DISEASE FROM OCCURRING IN THE FIRST PLACE, THAT'S TO BE DISTINGUISHED FROM PRECISION MEDICINE, HERE IS A DICTIONARY DEFINITION DESCRIBED AS MEDICAL CARE DESIGNED TO OPTIMIZE EFFICIENCY OR THERAPEUTIC BENEFIT FOR PARTICULAR GROUPS OF PATIENTS, ESPECIALLY BY USING GENETIC OR MOLECULAR PROFILING, TARGETING THERAPY IS MORE SPECIFIC AND MORE BROAD THAN THAT. TREATMENT OF EPILEPSY OVER THE AGES HAS BEEN ORIENTED TOWARDS FINDING THERAPIES THAT WORK. HERE IS A DESCRIPTION FOR SERAPION IN THE 4th CENTURY, ANOINT THE NECK WITH VINEGAR AND ROSE OIL, BY 18th CENTURY, TREPHINATION AND CAUTERY WAS USED, THAT EPILEPSY WAS CAUSED BY "CULT POWERS" BEGAN TO SUBSIDE AMONG HEALERS AND SCIENTISTS, THERE WAS ATTENDANT QUESTIONS OF NON-SPECIFIC TREATMENTS THAT ACCUMULATED OVER TIME. NEXT. AND THEN COMES ALONG A SWISS PHYSICIAN OF THAT TIME WHO ADVANCED CONCEPT THERE SHOULD BE MORE SPECIFIC REMEDIES FOR EPILEPSY AND WROTE, THOSE KNOWN REMEDIES THE MOST PROPER TO CHANGE THE EPILEPTIC PREDISPOSITION OF THE BRAIN. NEXT. THE MAINSTAYS FOR TREATMENT OF EPILEPSY IN 21ST CENTURY AS EVERYONE KNOWS INCLUDES PHARMACOLOGICAL, SHOWN ON THE LEFT, WHICH WE GIVE VARIOUS CHEMICAL PREPARATIONS, MOST COMMONLY ORALLY, THAT THEN GET ABSORBED INTO THE BODY, CIRCULATE, FIND THEIR WAY TO THE BRAIN, AND IDEALLY HAVE PRIMARY EFFECT ON THE UNDERLYING NETWORK ABNORMALITIES CAUSING SEIZURES. SURGERY OF VARIOUS TYPES IN THE MORE RECENT INTRODUCTION OF IMPLANTABLE STIMULATORS, WHICH ARE UNDERUTILIZED AND PROVEN TO BE EFFECTIVE IN SELECT CASES, BUT FOR THE EXAMPLE IN THE CASE OF TEMPORAL LOBE EPILEPSY IT'S NOT CLEAR THE OUTCOMES HAVE CHANGED IN ANY SIGNIFICANT WAY OVER THE YEARS. ON THE RIGHT I INCLUDE THIS ARTWORK BY JACKIE STREETEN, AN INDIVIDUAL WITH EPILEPSY FEATURED IN THE WONDERFUL BOOK" VISIONS" TO EMPHASIZE HOW LITTLE OUR CURRENT THERAPIES PAY SUFFICIENT ATTENTION TO COMORBIDITIES. AND NONE OF THESE MEET THE FULL DEFINITION OF TARGETED THERAPIES. NEXT SLIDE. THIS IS PROBABLY FAMILIAR TO EVERYONE, THESE ARE ANTI-SEIZURES DRUGS FOR TREATMENT OF EPILEPSY OVER THE YEARS. 15 IN THE FIRST GENERATION STARTING WITH BROMIDE IN THE 1800s, SEVEN IN THE SECOND GENERATION, AND 22 IN THE THIRD GENERATION, AND NOTABLY CARBAMAZAPEM INTRODUCED IN 1965. THE QUESTION IS, HOW MUCH PROGRESS HAVE WE MADE IN THE PAST 50+ YEARS, AT LEAST IN LIGHT OF OUR DEFINITION OF ADVANCEMENTS TOWARDS TARGETED THERAPIES? UNFORTUNATELY, THE EVIDENCE FOR ANY SIGNIFICANT PROGRESS IS NOT VERY COMPELLING. AND AS YOU HEARD FROM IRENE MILLER, YES, IT'S TRUE WE HAVE MORE OPTIONS, ESPECIALLY WHEN IT COMES TO DRUG-DRUG INTERACTIONS, BUT IT REMAINS THE CASE THAT ROUGHLY 1/3 OF PATIENTS DO NOT BECOME SEIZURE FREE, AND FOR THOSE WHO DO THE SIDE EFFECTS OF MEDICATIONS ARE SUBSTANTIAL FOR MANY. WHAT'S THE EVIDENCE FOR THIS PROGRESSION OR LACK THEREOF? NEXT SLIDE. HERE ARE TWO PRACTICE GUIDELINES PUT OUT IN 2018 BY GUIDELINE DEVELOPMENT SUBCOMMITTEE, AAN AND AES, REVIEWED LITERATURE OVER A 12-YEAR PERIOD THROUGH 2015 INCLUDING SIX ANTI-SEIZURES DRUGS. HERE IS TEXT FROM THE FIRST OF THE TWO PUBLICATIONS, NEW ONSET EPILEPSY ANALYSIS, NONE OF THE THIRD LINE DRUGS WERE CLEARLY SUPERIOR TO SECOND LINE MEDS. IF YOU READ WHAT'S HIGHLIGHTED, SEIZURE-FREE RATES WERE ALMOST IDENTICAL FOR THE TWO THE A SIX MONTHS AND A YEAR, DIFFERENCE IN SIDE EFFECTS, GABAPENTIN VERSUS CARBAMAZAPENE, BETTER TOLERABILITY, BUT THE THIRD COMPARISON VERSUS CONTROLLED RELEASE CARBAMAZAPENE DIFFERENCES WERE NOT REPRODUCED. ALSO, MANY NEWER DRUGS EFFECTIVE, SHOWN TO NOT BE CLEARLY BETTER THAN OLDEST DRUGS AND OVERALL SUCCESS IN ACHIEVING REMISSION HAS NOT APPEARED TO CHANGE. NEXT SLIDE. THERE WAS AN EARLIER REVIEW PAPERER BACK IN 2007 IN WHICH AMONG OTHER THINGS THEY HIGHLIGHTED RESULTS OF THE STANDARD AND NEW ANTI-EPILEPTIC DRUG TRIAL REPORTED IN 2007, AND THESE ARE DATA FROM THAT TRIAL. ON THE RIGHT IS COMPARATIVE EFFICACY OF NEW ANTI-SEIZURES MEASURES MEASURED BY TIME TO 12-MONTH REMISSION, TO GABAPENTIN AND NONE OF THE NEWER DRUGS WERE SUPERIOR IN EFFICACY, IN THE TRIAL, AND IN FACT GABAPENTIN WAS FOUND TO BE LESS EFFECTIVE AND LIMOTRAGENE WAS LESS EFFECTIVE IN THE STUDY. ON THE LEFT IS COMPARATIVE TOLERABILITY OF NEWER DRUGS, SHOWING PROPORTION OF PATIENTS WITH MOSTLY NUANCE AT EPILEPSY REPORTING ONE CLINICALLY IMPORTANT ADVERSE EVENT, NONE OF THE DRUGS SUPERIOR SUPERIOR. NEXT SLIDE PLEASE. AND THESE MORE RECENT DATA ARE TAKEN FROM A VERY IMPORTANT STUDY BY PATRICK KWAN AND COLLEAGUES, SUMMARIZED IN A RECENT ARTICLE, PAINTS A SIMILAR PICTURE. THIS IS A LONGITUDINAL OBSERVATIONAL COHORT STUDY THAT WAS CONDUCTED FOR THE EPILEPSY UNIT OF WESTERN INFIRMITY IN GLASGOW, SCOTLAND, FOLLOWED 1795 INDIVIDUALS WHO WERE NEWLY TREATED FOR EPILEPSY WITH ANTI-SEIZURE DRUGS BETWEEN 1982 AND 2012, ALL FOLLOWED FOR A MINIMUM OF TWO YEARS, UNTIL 2014 OR UNTIL DEATH WHICH EVER CAME SOONER. AND AT THE END OF THE STUDY PERIOD, 1,144 PATIENTS OR 63.7% HAD BEEN SEIZURE FREE FOR THE PREVIOUS YEAR OR LONGER. THAT 2/3 NUMBER. THE GRAPH SHOWS THREE COHORTS IN THE OVERALL GROUP DIVIDED BETWEEN THOSE WITH ANTI-SEIZURES DRUG REGIMENTS OVER THREE SUCCESSIVE DECADES, AVAILABILITY OF THIRD LINE DRUGS WOULD LEAD TO IMPROVEMENT IN ATTAINING SEIZURE FREEDOM, AND AS THE AUTHORS CONCLUDE IN THEIR PAPER IT DID NOT. SO, HOW MUCH PROGRESS HAS THERE REALLY BEEN? THIS ULTIMATELY COMES DOWN TO A MATTER OF OPINION AND NO ONE HAS A CORNER ON THE MARKET OF TRUTH. BUT, NEXT SLIDE, PERHAPS YOUR OPINION IS DRIVEN IN LARGE PART BY WHETHER YOU SEE THIS GLASS AS HALF FULL OR HALF EMPTY. NOW, I'M A GENETICALLY PROGRAMMED OPTIMIST, I SEE IT AS HALF FULL BUT DON'T FIND IT REASONABLE TO SAY EFFORT THUS FAR YIELDED A SIGNIFICANT IMPROVEMENT IN EFFICACY OF TREATMENTS, CERTAINLY IF WE'RE FOCUSED ON THE GOAL OF TARGETED THERAPIES. SO, WHAT THEN ARE THE OBSTACLES TO ACHIEVING PREDICTABLY TARGETED THERAPIES? I'D LIKE TO SUGGEST FOUR OBSERVATIONS WHICH MANY WILL PROBABLY SEE AS TRUISMS. NEXT SLIDE PLEASE. THE FIRST IS OUR LIMITED VALIDITY OF ANIMAL MODELS, AND HERE IS A QUOTE FROM WEINER THAT SAYS THE BEST MATERIAL MODEL OF A CAT IS ANOTHER, OR PREFERABLY THE SAME CAT. LOOK, THIS IS NOT MEANT TO DISPARAGE IN ANY WAY THE ENORMOUS ADVANCES THAT HAVE BEEN AND CONTINUE TO BE MADE IN THE USE OF ANIMAL MODELS TO ADVANCE OUR UNDERSTANDING OF MANY FACETS OF EPILEPSY. AND THE SESSION THIS AFTERNOON IS FOCUSED ON THIS ISSUE. BUT THERE'S NO QUESTION THAT ANIMAL MODELS HAVE BEEN A KEY LIMITATION IN OUR ABILITY TO DEVELOP EFFECTIVE THERAPIES OVER THE PAST CENTURY. NEXT. SO, THE GREATER OUR CAPACITY TO DIRECTLY PROBE THE HUMAN BRAIN, THE FASTER OUR PROGRESS IN ACHIEVING TARGETED THERAPIES. NEXT SLIDE. SECOND, TO RECOGNIZE FUNCTIONAL COMPLEXITY OF THE HUMAN BRAIN, SELF-EVIDENT, WE'RE ATTEMPTING TO UNDERSTAND THE MOST COMPLEX ENTITY IN THE KNOWN UNIVERSE, AND THEREFORE, NEXT, SUFFICIENT INVESTMENT IN FUNDAMENTAL NEUROSCIENCE IS ESSENTIAL TO OUR LONG-TERM SUCCESS. THIRD, NEXT SLIDE PLEASE, OUR NASCENT UNDERSTANDING OF THE BRAIN ECOSYSTEM. WE ALL SUFFER TO SOME DEGREE FROM THE STREET LIGHT EFFECT, WHICH IS THE FOCUSING OF OUR ATTENTION ON WHERE THE LIGHT IS, RATHER THAN FIGURING OUT HOW TO TAKE A LOOK AT WHAT ELSE IS OUT THERE. AND THERE ARE SO MANY ALLIED FIELDS WE NEED TO PURSUE, EVEN FURTHER WITH OUR COLLEAGUES, FROM THE MICROBIOME TO ENDOCRINOLOGY TO IMMUNOLOGY, TO ENVIRONMENTAL TOXINS. NEXT. AND FOR THAT REASON, WE NEED TO BE EXTREMELY OPEN MINDED ABOUT THE FACTORS INFLUENCING BRAIN FUNCTION. NEXT. AND FINALLY, THE NEED FOR NEXT GENERATION TOOLS TO RESOLVE THIS COMPLEXITY AND YOU HEARD THIS FOR SURE FROM DR. KOROSHETZ. IF WE LOOK AT THE HISTORY OF SCIENTIFIC ADVANCEMENT, IT'S VIRTUALLY ALWAYS THE CASE THAT THE DEVELOPMENT OF NEW TOOLS ARE THE BASIS OF BREAKTHROUGHS IN UNDERSTANDING FROMS SUNDIAL IN ANCIENT TIMES TO THE MICROSCOPE IN 1600s, TO CRISPR TECHNOLOGY, THE TOOLS ARE GOING TO COME, THE ARTICLE ON THE RIGHT PUBLISHED A YEAR AGO, LIKELY FAMILIAR TO THE BASIC SCIENTISTS IN THE ROOM DESCRIBES AN ABSOLUTELY REMARKABLE TOUR DE FORCE WHERE A TEAM OF SCIENTISTS USED TWO CUTTING EDGE IMAGING TECHNOLOGIES, EXPANSION MICROSCOPY AND LATTICE LIGHT SHEET MICROSCOPY TO IMAGE THE ENTIRE DROSOPHILA BRAIN AT NANOMETRIC SCALE. NEXT. THIS FIGURE FROM THE PAPER CONTAINS EXAMPLES OF THE SPECTACULAR IMAGES THEY OBTAINED, IN THIS CASE IT SHOWS ANATOMY OF A BUNDLE OF OLFACTORY PROJECTION NEURONS, AND IF YOU LOOK CLOSELY THE SCALE BAR, LOOK REALLY CLOSELY, IN THE CENTRAL PANEL WHICH HAS THE IMAGES OF THE BOUTONS IS ONE MICRON. THE POINT IS THAT THE DEVELOPMENT OF NEW TOOLS, WHETHER ADVANCED MOLECULAR IMAGING ON IN SILICO MODELING OR NON-INVASIVE BRAIN MAPPING OF HUMANS, YET DISCOVERED TOOLS ARE CRITICAL. TO DO THIS, NEXT, WE NEED TO INTENSIFY EFFORTS TO ENGAGE BIOENGINEERS, PHYSICISTS, COMPUTATIONAL SCIENTISTS AND THE LIKE. NEXT. FINALLY I WANT TO RETURN TO THE GLASS OF WATER. AND EXPLAIN WHY I'M VERY, VERY OPTIMISTIC ABOUT THE MISSION THAT WE'RE ALL PURSUING. >> TWO-MINUTE WARNING. >> THAT RELATES TO THE OPPORTUNITY TO BE WITHIN WHAT HISTORIANS ARE CALLING THE FOURTH REVOLUTION OF THE INDUSTRIAL ERA, ERA 4.0, WHICH IS COMBINING SUPER COMPUTING WITH INTERNET OF THINGS WITH BRAIN MACHINE INTERFACES AND MORE. NEXT. AND WHICH IS ALREADY ENABLING US TO SCALE UP TEAM SCIENCE LIKE NEVER BEFORE AND USE CUTTING EDGE TOOLS TO ANALYZE LARGE COMPLEX DATASETS. NEXT. AND ONE CONCEPTUAL FRAMEWORK THE FOURTH EVOLUTION IS ALLOWING IS KNOWLEDGE NETWORK, COMBINING BIOLOGICAL ANALYSIS FROM GENOME FOCUSING ON FOR THE REMAINDER OF THIS SESSION TO THE SO-CALLED EXPOSOME. NEXT. AND THIS IS ENTIRELY ANALOGOUS TO WHAT GOOGLE EARTH OFFERS WITH VIEWS FROM OUTER SPACE DOWN TO STANDING ON A STREET CORNER. THE IDEA THEN IS TO BRING TOGETHER THESE MULTIPLE LEVELS OF COMPLEX DATASETS. NEXT. AND THEN MINE THE DATA AND USE ARTIFICIAL INTELLIGENCE AND DEEP LEARNING TO UNDERSTAND THE TARGET AND PROVIDE AS T CELL EXPRESSED THE SPECIFIC REMEDY FOR EACH PATIENT OF TARGETED THERAPY. NEXT. AND WITH THOSE THOUGHTS, I'LL CLOSE AND SAY THANK YOU. IT'S NOW MY PLEASURE TO TURN THINGS OVER TO DR. HEATHER MEFFORD, ASSOCIATE PROFESSOR AT UNIVERSITY OF WASHINGTON, SOON MOVING TO ST. JUDE'S CHILDREN'S RESEARCH HOSPITAL, TO DISCUSS GENETIC DIAGNOSIS IN THE EPILEPSIES, CHALLENGES AND OPPORTUNITIES. HEATHER? >> THANK YOU, DAN. IT'S A PLEASURE TO BE HERE. I'D LIKE TO THANK THE ORGANIZERS FOR DEVOTING A SESSION TO THINKING ABOUT THE IMPORTANCE OF GENETICS IN BOTH DIAGNOSIS AND THINKING ABOUT HOW WE CAN BETTER TARGET THERAPIES. I'D LIKE TO SAY I'M GOING TO SET THE STAGE FOR HOW FAR WE HAVE COME, SINCE THE LAST CURING THE EPILEPSIES CONFERENCE, A LOT OF WORK WAS IN PROGRESS. BUT GREATLY ACCELERATED BY DISCUSSIONS AND COLLABORATIONS THAT WERE SET IN PLACE BY THESE PREVIOUS CONFERENCES. AND THEN I'M GOING TO LEAVE IT TO ERIN HEINZ MAN TO TALK ABOUT SIGNIFICANT GAPS. I LIKE TO THINK WHY IS GENETICS IMPORTANT AND GENETIC DIAGNOSIS IMPORTANT. WE'VE HEARD FROM THAT FROM FAMILY GROUPS WHO HAVE SPOKEN TODAY. IMPORTANTLY OBTAINING GENETIC DIAGNOSIS GIVES US A CHANCE TO TALK ABOUT PROGNOSIS AND RISK WITH FAMILIES AND PATIENTS, INCREASINGLY GENETIC DIAGNOSES CAN AFFECT CHOICE OF MEDICATIONS USED TO TREAT INDIVIDUALS AFFECTED, AND ALLOWS FAMILIES TO CONNECT, WE HAVE MANY FAMILY GROUPS REPRESENTED HERE TODAY, SOME WE HAVE AND WE'LL HEAR FROM. AND THIS ALSO ALLOWS THEM TO HELP GATHER RESEARCHERS TOGETHER AND THINK ABOUT WHAT ARE THE IMPORTANT QUESTIONS AND HOW CAN WE ACCELERATE BETTER TREATMENT. AND FINALLY I THINK WE ALL THINK ABOUT THIS AS IDENTIFYING THE DIAGNOSIS, IDENTIFY POTENTIAL THERAPEUTIC TARGETS, SO TYPES OF TARGETED THERAPIES DAN ALLUDED TO. WE'RE BEGINNING TO SEE THIS REALIZED TODAY WITH CLINICAL TRIALS IN PLACE, ASO THERAPY FOR EXAMPLE. I THINK ONE OF THE THINGS THAT'S IMPORTANT TO REMEMBER IS THAT WE'RE TALKING ABOUT GENETIC DIAGNOSIS OF THE EPILEPSY, NOT EPILEPSIES, NOT A SINGLE DISEASE, SO I THINK IT'S IMPORTANT TO REMEMBER THROUGHOUT THIS MEETING THAT IDENTIFYING WHAT IS A GENETIC DIAGNOSIS MAY DIFFER IF YOU HAVE GENETIC GENERALIZED EPILEPSY, FOCAL EPILEPSY, OR DEVELOPMENTAL EPILEPTIC ENCEPHALOPATHY. GENETIC ARCHITECTURE OF MAJOR CLASSES DIFFER, BUT IMPORTANTLY THEY ALSO OVERLAP, TO SOME DEGREE, I'LL TALK ABOUT THAT. IT'S POSSIBLE THAT IDENTIFYING A TARGETED TREATMENT FOR ONE SPECIFIC FORM OF EPILEPSY, FOR EXAMPLE A DEVELOPMENTAL ENCEPHALOPATHY, IS IMPORTANT FOR THAT DISORDER ITSELF BUT MORE BROADLY ACROSS OTHER CLASSES OF EPILEPSY WHO SHARE GENETIC RISK FACTORS WITH THAT GGE. NEXT. SO WHAT HAVE WE LEARNED SO FAR ABOUT GENETICS OF EPILEPSY? IN THE EARLY AND MID-1990s MANY STUDIES WERE INFORMED BY LARGE FAMILIES WITH MULTIPLE AFFECTED FAMILY MEMBERS USING LINKAGE ANALYSIS TO IDENTIFY SPECIFIC GENES IN FAMILIES BUT IT BECAME EVIDENT QUICKLY THAT THESE TYPES OF FAMILIES ARE RARE, AND THAT THOSE DISCOVERIES DID NOT TRANSLATE BROADLY ACROSS MANY AFFECTED INDIVIDUALS. WE USED INFORMATION FROM DISCOVERIES IN THOSE FAMILIES TO THINK ABOUT CANDIDATE GENES AND MANY OF THE EARLY STUDIES FOCUSED ON ION CHANNELS, SODIUM CHANNELS, CAPACITY CHANNELS, FOR EXAMPLE. AND THIS LED TO CHANNELOPATHY HYPOTHESIS AND GENE DISCOVERIES IMPORTANT FOR RARE EPILEPSIES. EARLY TO MID-2000s GENOME-WIDE TECHNOLOGIES HIT THE SCENE, AND ALLOWED US TO MAKE SIGNIFICANT PROGRESS. THIS INCLUDED CHROMOSOME MICROARRAY REPRESENTED ON THE LEFT, NEXT GENERATION SEQUENCING ACCELERATING GENE DISCOVERY, AND GENOME WIDE ASSOCIATION STUDIES BY THE MANHATTAN PLAT ON THE RIGHT STUDYING LARGE GROUPS OF AFFECTED INDIVIDUALS COMPARED TO UNAFFECT THE -- UNAFFECTED GENE APPROACHES, ALLOWING MORE HYPOTHESES-FREE DISCOVERY TO FOLLOW. I THINK THE FIRST MAJOR ADVANCE WAS PROBABLY CHROMOSOME MICROAWAYS BUT WHAT ACCELERATED WAS GENOME WIDE SEQUENCING, MOST EARLY STUDIES FOCUSED ON EXOME, SEQUENCING PROTEIN CODING SEQUENCE OF DNA, ALL GENES IN THE GENOME, IMPORTANTLY DOING THIS IN A FAMILY OR PARENT-CHILD TRIO ALLOWED DISCOVERY OF DE NOVO MUTATIONS IN AFFECTED CHILDREN, THE KEY TO GENE DISCOVERY IN SEVERE DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES. IN ADDITION TO APPLYING TECHNOLOGY, THESE DISCOVERIES REQUIRED COLLABORATION AND LARGE NUMBERS OF PATIENT COHORTS, AND LARGE NUMBERS OF RESEARCH. DISCOVERIES IN DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY AND DE NOVO PARADIGMS OF THIS TYPE OF DISEASE WAS ACCELERATED BY COLLABORATIONS LIKE EPI4K. NEXT. DE NOVO MUTATIONS THAT ARE IMPORTANT FOR SEVERE EPILEPSIES ARE NOT FOUND NECESSARILY IN GENETIC GENERALIZED AND FOCAL EPILEPSIES, NOT TO THE SAME DEGREE. THINKING ABOUT THIS OVERLAPPING ARCHITECTURE WE'VE FOUND THROUGH COLLABORATIONS AGAIN LIKE EPI4K AND EPI25, WHICH FOLLOWED, SEQUENCING IN GGE AND FOCAL COULD IDENTIFY RARE VARIANTS, MAY NOT BE DE NOVO, MAY NOT SEGREGATE IN FAMILIES BUT ARE IMPORTANT FOR OTHER CLASSES OF EPILEPSY. FINALLY, APPROACHES APPROACHES THAT MIGHT ACT AS RISK FACTORS BY APPLYING GENOME WIDE ASSOCIATION STUDIES AS ALSO HIGHLIGHTED TO OVERLAPPING GENETIC ARCHITECTURE, FOR EXAMPLE, AGAIN, LARGE COLLABORATIVE APPROACHES AND THIS TIME FUNDED AND SUPPORTED BY INTERNATIONAL LEAGUE AGAINST EPILEPSY, COMMON VARIANTS INCLUDING SLC6A1 AND OTHERS. IT'S IMPORTANT TO THINK MAYBE SOME OF THE APPROACHES TO TREATMENT THAT WE IDENTIFY IN THESE MORE SEVERE EPILEPSIES MAY BE APPLICABLE TO THE MORE GENERAL AND COMMON EPILEPSIES. IMPORTANTLY, GENOME WIDE ASSOCIATION STUDY APPROACH HIGHLIGHTS POTENTIAL NEW CANDIDATES, SHOWN IN OTHER CLASSES OF DISEASE, THAT THESE CANDIDATES CAN LEAD TO VERY IMPORTANT AND EFFECTIVE THERAPIES. NEXT. SO, THIS IS SOMEWHAT UPDATED SLIDE HIGHLIGHTING GENES THAT HAVE BEEN DISCOVERED AS IMPORTANT CAUSES, NOT JUST RISK BUT CAUSES OF EPILEPSY OVER THE PAST TWO DECADES, AND WHAT'S IMPORTANT TO NOTICE IS NEXT GENERATION SEQUENCING ERA IN PURPLE HAS REALLY, REALLY ACCELERATED GENE DISCOVERY, YOU CAN SEE GENES REPRESENTED HERE PROBABLY NOT ALL INCLUDED, BUT THERE ARE NOW 100 OR MORE GENES THAT ARE IMPORTANT. >> TWO-MINUTE WARNING. >> THANK YOU. IMPORTANTLY, MOST OF THE DISCOVERIES IN PURPLE APPLY TO DEVELOPMENTAL AND ENCEPHALOPATHY. UP TO 40 TO 50% OF INDIVIDUALS WHO PRESENT WITH THE DEE AND GENETICS CLINIC, WE WANT THIS TO TRANSLATE TO TARGETED THERAPY. 40 TO 50% IS NOT TRUE FOR FOCALIZED EPILEPSIES BUT WE'RE MAKING PROGRESS THERE AS WELL. MUCH OF WHAT WE'VE DISCOVERED ABOUT GENETIC CAUSES OF EPILEPSY FROM SEQUENCING HAVE BEEN SINGLE NUCLEOTIDE CHANGES, A TO T, OR G TO C, BUT THERE ARE MANY THINGS WE'RE MISSING WHEN WE APPLY EXOME SEQUENCING TO COHORTS, AND IT'S OUR BELIEF THAT WE CAN IDENTIFY GENETIC CAUSES BY APPLYING SOME OF THE NEWER TECHNOLOGIES WHICH YOU'LL HEAR ABOUT FROM ERIN HEINZEN SHORTLY, IMPORTANT TO THINK ABOUT WHAT ARE WE MISSING FROM STUDIES DONE TO DATE. BY LOOKING, WE'RE MISSING VARIANTS, APPROACHES FOR SHORT READ NEXT GENERATION MAY MISS STRUCTURAL. WE'VE NOT IDENTIFYING EPIGENETIC VARIANTS, REPEAT CHANCE, LOW LEVEL MUTATIONS ARE MISSED. WE'RE LOOKING FOR HIGHLY PENETRANT SINGLE GENE CAUSES IN MANY STUDIES DONE BUT IT'S POSSIBLE THAT THERE ARE (INDISCERNIBLE) CONTRIBUTIONS, A MAJOR AREA OF RESEARCH FOR THE MORE COMMON EPILEPSIES TODAY. FINALLY WE NEED TO THINK ABOUT THINGS OTHER THAN DE NOVO MUTATION BUT ARE THERE INHERITED VARIANTS WITH DECREASED PENETRANTS, RISK FACTORS, WE'RE MISSING IN THESE APPROACHES. >> TIME EXPIRED. >> YOU'LL HEAR FROM ERIN ABOUT FINDING WHAT WE'RE MISSING, APPLYING NOVEL TECHNOLOGY, ANALYTICAL APPROACHES, THINKING CREATIVELY, AND THINKING ABOUT THE IMPORTANCE OF LARGE COLLABORATIVE EFFORTS TO FIND MISSING MUTATIONS. I'LL TURN IT OVER TO ERIN HEINZEN NEXT, FROM UNIVERSITY OF NORTH CAROLINA. >> THANKS, HEATHER. IF YOU COULD GO TO THE NEXT SLIDE PLEASE. THANKS FOR THE NICE LEAD-IN. I'M GOING TO PICK UP WHERE HEATHER LEFT OFF. CONTINUING THE DISCUSSION ON HOW WE CAN FIND WHAT WE'RE MISSING, SO WHAT I'VE SHOWN HERE IS OUR CURRENT KNOWLEDGE, SO IN THE SLIDE, EACH HEXAGON REPRESENTS A TYPE OF VARIANT TO CONTRIBUTE TO EPILEPSY RISK ON SOME LEVEL. SO SHADING HERE INDICATES EXTENT OF OUR KNOWLEDGE. HEATHER AND OTHERS TOUCHED ON, WE KNOW ABOUT HIGHLY PENETRANT DE NOVO VARIANTS AND LARGE COPY VARIANTS THAT CONTRIBUTE TO EPILEPSY BUT KNOW FAR LESS ABOUT NON-CODING VARIATION, EXPANSION, POLYGENIC FACTORS, WE HAVE A LOT TO LEARN ON GENETICS SIDE. SO HOW CAN WE GET SOME OF THE SHADING ACROSS ALL THESE HEXAGONS TO BE DARKER, CONTINUE GENE DISCOVERY IN EPILEPSY? MICROARRAY TECHNOLOGY HAS GOTTEN US TO THE POINT WE ARE, ONE OF THE THINGS WE NEED TO LOOK FOR IS WHAT NEW TECHNOLOGIES CAN WE IMPLEMENT, AS A START. NEXT SLIDE PLEASE. ONE BACK PLEASE. YEP, THANKS. YEAH, SO ONE OF THE CERTAINLY ADVANCEMENTS IN WHOLE GENOME SEQUENCES HAS COME A LONG WAY IN RECENT YEARS, THIS IS ONE AREA WE NEED TO BE TRANSITIONING TO. SO EXOME SEQUENCING HAS BEEN THE MAINSTAY IN GENE DISCOVERY IN EPILEPSY, LIKE HEATHER TOUCHED ON TECHNOLOGY IS GREAT FOR DETECHING SMALL VARIANTS BUT MOST IS OUTSIDE THE CODING, TO CAPTURE THE NON-REGULATORY VARIATION. TECHNOLOGY IMPROVED. WE'RE ABLE TO DETECT A LOT OF NEW VARIATION WITH STANDARD SHORT READ WHOLE GENOME SEQUENCING INCLUDING STRUCTURAL VARIATION AND SOME LOOKS AT COPY NUMBER VARIANTS, REPEAT EXPANSION, BUT WE'RE ALWAYS LIMITED BY SHORT READ FRAGMENTS. SO, YOU KNOW, TYPICALLY FRAGMENTS ARE AROUND 150 TO 200 BASE PAIRS LONG, THERE'S ALWAYS GOING TO BE CHALLENGES SORT OF REASSEMBLING THE GENOME FROM SMALL FRAGMENTS. BUT WHAT'S EVEN MORE EXCITING IS THIS EVEN NEWER TECHNOLOGY, LONG READ WHOLE GENOME SEQUENCING, SO FOR LONG READ WHOLE GENOME SEQUENCING RATHER THAN 200 BASE PAIR FRAGMENTS WE'RE ABLE TO SEQUENCE CLOSE TO 20 KB OR EVEN LARGER, AND IN SEQUENCING THESE LARGE FRAGMENTS WE'RE ABLE TO CAPTURE A LOT MORE DIFFERENT TYPES OF VARIATION, IN PARTICULAR MUCH MORE COMPREHENSIVE LOOKS ON STRUCTURAL AND COPY NUMBER VARIANTS MISSED WITH OTHER TECHNOLOGIES, REPEAT EXPANSIONS, SO ALSO HAPLOTYPES, TYPICALLY WE DO ASSOCIATE STUDIES WITH ASSOCIATION OF A SINGLE VARIANT BUT IF WE CAN LOOK AT THE VARIANT IN CONTEXT OF VARIANTS AROUND IT MIGHT HELP US MORE CLEARLY INFORM THE SPECIFIC PHENOTYPE A PATIENT MIGHT HAVE. THERE'S ALSO ADVANTAGES IN TERMS OF SEQUENCING IS HIGHER WITH GENOME, USING THIS TECHNOLOGY HAS THE ABILITY TO DISTINGUISH A BASE WITH AN EPIGENETIC MARK, WE HAVE TECHNOLOGY -- THIS HAS POTENTIAL TO HELP US WITH STUDY BE EPIGENETIC PROCESSES. NEXT SLIDE PLEASE. SO AS WE START TO PERFORM WHOLE GENOME SEQUENCING WE'LL BE ABLE TO IDENTIFY NON-CODING VARIATION, BUT THERE'S STILL GOING TO BE CHALLENGES IN TERMS OF INTERPRETING THE SIGNIFICANCE OF THESE VARIANTS, YOU KNOW, DO THESE AFFECT PROTEIN EXPRESSION. SO JUST TO REMIND EVERYBODY PROTEINS ARE ENCODED IN OUR DNA BUT EXACTLY WHEN AND IN WHAT CELL TYPES THEY ARE SUPPRESSED IS A TIGHTLY REGULATED PROCESS DICTATED BY REGULATORY SEQUENCES IN OUR GENOMES. SO AS WE START TO GATHER THIS INFORMATION WE REALLY NEED TO BE ABLE TO IDENTIFY WHICH GENETIC VARIANTS ALTER PROTEIN EXPRESSION. SO THERE'S A LOT OF EXCITING NEW TECHNOLOGY ON THIS FRONT AS WELL, SO ATAC-SEQ, HI-C, CHIP-seq, AND THIS ALLOWS US TO NOT ONLY DEFINE WHERE REGULATORY SEQUENCES ARE IN OUR NON-CODING GENOME BUT ALSO TO STUDY EFFECTS OF GENETIC VARIANTS IN THOSE REGIONS. SO, EVEN MORE EXCITINGLY, RECENTLY THESE TECHNOLOGIES HAVE BEEN -- YOU COULD DO THESE -- APPLY THESE APPROACHES IN SINGLE CELLS, SO WE CAN ACTUALLY LOOK AT INDIVIDUAL CELLS OF INTEREST, WE CAN LOOK AT THESE PROCESSES, WHICH IS SIGNIFICANT ADVANCEMENT, I THINK IT'S GOING TO MAKE A REAL DIFFERENCE IN TERMS OF OUR ABILITY TO INTERPRET WHOLE GENOME SEQUENCE DATA. SO I WANT TO TOUCH ON IT'S NOT JUST THE TECHNOLOGICAL ADVANCES WE NEED TO BE CONSIDERING HERE. YOU KNOW, WITH THESE DATA, STAN TOUCHED ON THIS IS -- WE'RE GOING TO START TO GENERATE THESE HIGHLY MULTI-DIMENSIONAL DATASETS, WE NEED TO INVEST IN PROCESSES TO BE ABLE TO ANALYZE AND INTERPRET THESE DATA TOGETHER AS OPPOSED TO SEPARATELY TO REALIZE FULL POTENTIAL OF THE TECHNOLOGY. NEXT SLIDE PLEASE. SO, NEXT THING IS MOSAICISM. SO, AS HEATHER MENTIONED, WE KNOW THERE'S A VERY IMPORTANT ROLE FOR DE NOVO GERMLINE VARIANTS AND SEVERE SPORADIC SUBTYPES OF EPILEPSY, PLEASED TO -- BELIEVE TO ARISE IN GAMETES. CELLS CONTINUE TO DIVIDE, YOU CAN ACQUIRE MUTATIONS AT THOSE STAGES AS WELL. EXACTLY WHEN THOSE MUTATIONS HAPPEN WILL DICTATE HOW MANY CELLS, TO WHAT EXTENT MUTATION IS FOUND IN THE BODY. WE KNOW IN SOME CASES WHEN YOU TAKE A BLOOD SAMPLING, GENETIC ANALYSIS, YOU CAN SEE LOW LEVEL MOSAICISM, INDICATIVE OF EARLY POST ZYGOTIC MUTATIONS. YOU CAN HAVE MUTATIONS LATER, IN THESE CASES MUTATIONS MAY BE BRAIN TISSUE SPECIFIC. SO THERE'S BEEN LOTS OF EXAMPLES WHERE THESE HAVE BEEN FOUND PARTICULARLY IN BRAIN MALFORMATIONS, THERE'S NEW AND EMERGING INFORMATION THAT MAY PLAY A ROLE IN NON-REGIONAL FOCAL EPILEPSY, WHICH DOES AFFECT A NUMBER OF PATIENTS. SO, THERE'S ALSO QUITE A FEW TECHNOLOGICAL ADVANCEMENTS HERE, I'M GOING TO TOUCH ON THE APPROACHES WE CAN IDENTIFY VARIANTS, THESE VARIANTS ARE ESSENTIALLY HIDDEN TO US WHEN WE GO INTO A STANDARD GENETIC STUDY SO IF THERE ARE BRAIN TISSUE SPECIFIC AND WE GET A BLOOD SAMPLE AND WE ANALYZE THE BLOOD SAMPLE WE'LL MISS THE VARIANT SO THIS IS A SOURCE WHERE WE CAN REALLY IDENTIFY QUITE A FEW GENETIC CAUSES OF EPILEPSY BY STUDYING THESE MOSAIC MUTATIONS, TAKING BRAIN TISSUE FROM RESECTED CASES, PRIMARY APPROACH TO IDENTIFYING VARIANTS ALLOWS US TO LOOK AT LOTS OF DIFFERENT PATIENT SAMPLES, RELATIVELY INEXPENSIVELY, BUT NOT VERY SENSITIVE. THINGS LIKE SINGLE CELL DNA SEQUENCING, THAT OFFERS MUCH HIGHER SENSITIVITY BUT COMES WITH MUCH GREATER COST, ALSO SIGNIFICANT TECHNOLOGICAL CHALLENGES. >> TWO-MINUTE WARNING. >> THANK YOU. SO, THERE'S CELL FREE DNA SEQUENCING, TYPICALLY DNA IS LOCATED WITHIN THE CELLS IN THE NUCLEUS BUT WHEN CELLS RUPTURE AND DIE SOME DNA SPILLS OUT INTO THE BLOOD AND ALSO CSF, SO IT GIVES US AN OPPORTUNITY TO POTENTIALLY SEQUENCE THOSE AND IDENTIFY SOME OF THESE MOSAIC VARIANTS THAT MIGHT BE LOCALIZED TO THE BRAIN TISSUE. SEVERAL PEOPLE, GROUPS ARE WORKING ON THIS. IT'S REALLY EXCITING TECHNOLOGY THAT WOULD ALLOW TO US SCREEN MUCH LARGER POPULATIONS, EVEN THOSE NOT UNDERGOING SURGERY FOR MOSAIC MUTATIONS. THE LAST THING IS SOMETHING THAT HEATHER MENTIONED, THAT, YOU KNOW, THIS IS SOMETHING THE EPILEPSY COMMUNITY HAS DONE A FANTASTIC JOB ON BUT IN ADDITION TO APPLYING NEW TECHNOLOGIES AND DATA ANALYSIS APPROACHES WE NEED TO BE CONTINUING OUR WORK TO DO LARGE-SCALE COLLABORATIVE INITIATIVES FOR SOME TYPES OF VARIANTS IT'S GOING TO BE CRITICAL LIKE OLIGOGENIC AND POLYGENIC, WE NEED TO CONTINUE OUR COLLABORATIVE EFFORTS AND COMMAND THEM. NEXT SLIDE PLEASE. SO JUST BRIEFLY CONCLUDING, THIS IS GOING BACK TO MY ORIGINAL THEME, WHAT IS IT GOING TO TAKE TO GET HEXAGONS TO BE MORE DARKLY SHADED, NOT AS ABSOLUTE HERE BUT LOOKING FOR PROGRESS IN THE NEXT FEW YEARS. AND I THINK I TOUCHED ON THESE IN VARIOUS WAYS THROUGHOUT THE TALK BUT JUST TO SUMMARIZE THE THREE MAIN POINTS, CERTAINLY WE NEED TO DEPLOY SOME NOVEL TECHNOLOGIES LIKE LONG READ SEQUENCING, SELF-READ DNA SEQUENCING, CERTAINLY INVEST IN NOVEL AND CONVERGENT APPROACHES TO INTERPRET DATA WE GENERATE AND THEN AGAIN CONTINUING THESE LARGE-SCALE COLLABORATIONS. >> TIME HAS EXPIRED. >> OKAY. I'M FINISHED AND HOPE TO CONTINUE THE DISCUSSIONS IN THE BREAKOUT SESSIONS. THANK YOU. >> ALL RIGHT. THANK YOU VERY MUCH. I'M DENNIS DLUGOS, AND THANK YOU FOR THE OPPORTUNITY TO TALK ABOUT MEANINGFUL OUTCOME MEASURES IN PRECISION MEDICINE TRIALS. AS INTERVENTIONAL PRECISION MEDICINE TRIALS REALLY BEGIN IN EPILEPSY, THESE QUESTIONS HAVE BECOME SHARPER AND MORE FOCUSED, AND THE ANSWERS HAVE BECOME MORE CHALLENGING. I THINK WE CAN TAKE INSPIRATION FROM THE SUCCESSES WITHIN ONCOLOGY AND HIV AND COVID BUT HAVE TO RECOGNIZE EPILEPSY DOES NOT NECESSARILY HAVE QUICKLY MEASURABLE OUTCOME MEASURES LIKE VIRAL LOAD OR TUMOR BURDEN, AND WE JUST HAVE TO ACCEPT THAT AS WE SEARCH FOR MEANINGFUL PRACTICAL OUTCOME MEASURES IN CLINICAL TRIALS. NEXT SLIDE. NEXT SLIDE. SO, I WILL MAKE SOME BRIEF MENTIONS OF THREE DIFFERENT EPILEPSIES DURING THIS TALK, SCN 1A DEE, KCNQ2 AND KCNT 1. THIS IS IN NO WAY TO HIGHLIGHT THESE THREE AS MORE IMPORTANT THAN OTHER EPILEPSIES BUT EVERY PRECISION TRIAL WILL HAVE TO UNDERSTAND THE TRAJECTORY OF THE DISEASE, BOTH CLINICALLY AND BIOLOGICALLY. HERE IS WHAT I THINK IS BASIC FRAMEWORK FOR DECIDING ON MEANINGFUL OUTCOME MEASURES. FIRST, THE CLINICAL ONSET VERSUS BIOLOGICAL ONSET. FOR MOST GENETIC EPILEPSIES, SEIZURES TYPICALLY START AT A PARTICULAR AGE. IT MAY BE 3 DAYS, 1 MONTH, OR BETWEEN 6 AND 12 MONTHS. SO THAT IS ONE TIME THAT'S IMPORTANT, WHEN DO SEIZURES TYPICALLY AGAIN. THEN DEVELOPMENTAL CONSEQUENCES COULD PRECEDE ONSET OF SEIZURES OR FOLLOW ONSET OF SEIZURES BUT WHEN DOES THE BIOLOGICAL DISEASE REALLY BEGIN? BECAUSE IF WE WANT TO IMPACT DEVELOPMENT AND NON-SEIZURE OUTCOME IT'S NOT REALLY ABOUT WHEN SEIZURES START; IT'S WHEN DOES THE DISEASE START. AND IF WE HAVE A SENSE OF THAT, THEN WE CAN THINK ABOUT THE AGE OF THE EARLIEST POSSIBLE ENROLLMENT IN A RANDOMIZED CONTROLLED TRIAL. I'M FOCUSING ON IN THE FUTURE INTERVENTIONAL TRIALS. SO LET'S ASSUME SOME SAFETY STUDIES HAVE BEEN DONE, AND WE'RE READY TO BEGIN THE RANDOMIZED CONTROLLED TRIAL. 18 YEARS OLD, 12 YEARS OLD, 2 YEARS OLD, 1 MONTH OLD? HOW EARLY DOES THE TRIAL NEED TO BEGIN TO REALLY MAXIMIZE MEANINGFUL OUTCOMES? AND THEN THE TRIAL DESIGN. FOR NOW, I THINK WE HAVE TO EXPECT THAT FOR A PRECISION THERAPY TO BE BROUGHT TO MARKET, SUPERIORITY VERSUS SOMETHING WILL HAVE TO BE SHOWN VERSUS A CONCURRENT PARALLEL CONTROL GROUP. AND TYPICALLY, THE RANDOMIZED PHASE OF SUCH A TRIAL LASTS ABOUT THREE MONTHS, AND THERE'S EFFORTS TO EVEN SHORTEN THAT. NATURAL HISTORY STUDIES, OPEN LABEL STUDIES ARE IMPORTANT TO UNDERSTAND OUTCOME MEASURES, AND NATURAL HISTORY AND HETEROGENEITY BUT ULTIMATELY WE'LL HAVE TO FACE THE QUESTION OF QUESTION WHAT CAN WE CHANGE WITHIN A THREE-MONTH PERIOD, AND THAT'S A CHALLENGE. WHAT WOULD OUTCOME MEASURES BE? THREE GENERAL AREAS. SEIZURES, DEVELOPMENT WHICH IS BROADLY DEFINED, INCLUDES DOMAINS OF BEHAVIOR, COGNITION, SOCIALIZATION, QUALITY OF LIFE, CAREGIVER IMPRESSION OF CHANGE, PARENTAL STRESS AND FAMILY STRESS, BROADLY DEFINED NON-SEIZURE OUTCOMES. AND THEN BRIEFLY I'LL TALK ABOUT A TRADITIONAL BIOMARKER, THE EEG BACKGROUND. THERE'S GOING TO BE A WHOLE SESSION ON BIOMARKERS, WHICH ARE CLEARLY NEEDED IF WE'RE GOING TO ACCELERATE SUCCESS IN PRECISION MEDICINE TRIALS. NEXT SLIDE. SO, SEIZURES, LET'S REDUCE SEIZURES. WELL, I HAVE HEARD IT SAID MORE THAN ONCE, I WILL READ THE QUOTE, A PRECISION THERAPY FOR EPILEPSY WILL NOT BE BROUGHT TO MARKET UNLESS IT IMPROVES DEVELOPMENT. ALL RIGHT. THAT'S A LAUDABLE GOAL, RECOGNIZING IMPORTANCE OF NON-SEIZURES OUTCOMES, FRANKLY I HOPE THAT STATEMENT IS NOT TRUE BECAUSE THAT MAY BE SETTING THE BAR TOO HIGH. IT'S A BIG LIFT TO IMPROVE DEVELOPMENT IN A GENETIC EPILEPSY. I HOPE WE ACHIEVE IT. WE NEED TO ACHIEVE IT. BUT THE NEXT PHASE WE MAY NEED TO FOCUS ON SEIZURE REDUCTIONS UNTIL WE BETTER UNDERSTAND THE BIOLOGY. SO, IS SEIZURE REDUCTION MEANINGFUL? WELL, SEIZURE FREEDOM I THINK IS. I THINK AMBER AT THE BEGINNING OF THIS SESSION VERY EMPHATICALLY STATED THAT EPILEPSY IS TERRIBLE, FOR BOTH SEIZURE REASONS AND NON-SEIZURE REASONS. SO A THERAPY THAT COULD TRULY LEAD TO SEIZURE FREEDOM WOULD BE A BIG STEP FORWARD AND I THINK WOULD BE MEANINGFUL. WHAT ABOUT SEIZURE REDUCTIONS? THERE WERE SOME INTERESTING DATA PRESENTED AT THE CHILDING NEUROLOGY SOCIETY MEETING AND AES MEETING A FEW MONTHS AGO LOOKING AT SEIZURE REDUCTIONS AND THEIR CORRELATION TO QUALITY OF LIFE IMPROVEMENTS. AND THESE STUDIES BUILT ON THE FENFLURAMINE STUDIES, AND THEY FOUND THAT IN THEIR SHORT-TERM RANDOMIZED CONTROLLED TRIALS ABOUT A 45% SEIZURE REDUCTION WAS ASSOCIATED WITH IMPROVEMENT IN QUALITY OF LIFE. BUT IN THE LONGER OPEN LABEL STUDIES IT TOOK A 7 5% SEIZURE REDUCTION TO CONTINUE TO BE CORRELATED WITH QUALITY OF LIFE SO THIS MAY BE A MOVING TARGET. LONGER THE TIME FRAME, THE BIGGER THE REDUCTION IN SEIZURES MAY BE NEEDED. SO, IT'S CONTROVERSIAL HOW MUCH OF A SEIZURE REDUCTION IN A PRECISION MEDICINE THERAPY WOULD BE CONSIDERED MEANINGFUL. AND THEN THE HOLY GRAIL WOULD BE SEIZURES NEVER DEVELOP. NOW, OF COURSE, TO UNDERSTAND THAT WE REALLY HAVE TO ACHIEVE THAT, WE REALLY HAVE TO UNDERSTAND THE BIOLOGY, SO WE CAN INTERVENE PRIOR TO THE ONSET OF SEIZURES. NEXT SLIDE. SO, DEVELOPMENT, BROADLY DEFINED, AGAIN THINK OF THE THREE EPILEPSIES. SCN 1A DEVELOPMENT IS NORMAL, SEIZURES DEVELOP BETWEEN 6 AND 12 MONTHS OF AGE, AND DEVELOPMENTAL REGRESSION. KCN 2, ONSET EARLY IN LIFE. DEVELOPMENTAL CONSEQUENCES ARE ONGOING, AND KCNT 1 AS ONGOING SEIZURES AND DEVELOPMENTAL CONSEQUENCES FROM INFANCY, THREE DIFFERENT MOVING TARGETS ALREADY. WE KNOW FROM PAST EPILEPSY STUDIES THAT SHORT-TERM EPILEPSY INTERVENTIONS CAN IMPROVE SOME COGNITIVE DOMAINS LIKE ATTENTION, PROCESSING SPEED, FLUENCY, VERBAL LEARNING, COMPLEX EXECUTIVE FUNCTION AND CAN IMPROVE FINE MOTOR SKILLS. THAT'S GREAT. PROBLEM IS WE PROBABLY WANT TO STUDY INFANTS SO THOSE ARE NOT THE OUTCOME MEASURE WE CAN MEASURE IN INFANTS. THERE'S AN NIH TOOLBOX COGNITIVE BATTERY THAT HAS BEEN SHOWN TO BE RELIABLE AND VALID FOR PATIENTS WITH MENTAL AGE OF 5 YEARS AND UP BUT THAT'S PROBABLY TOO LATE FOR MANY EPILEPSIES WE WANT TO STUDY. SO THERE'S AN INCREASED FOCUS ON MEASURES FOR INFANTS AND TODDLERS WITH DEE. WHAT MEASURES DO WE HAVE? THERE ARE WELL-ESTABLISHED MEASURES OF ADAPTIVE BEHAVIOR, CHALLENGES CAN INTERVENTION INTRODUCE A CHANGE QUICKLY ENOUGH THAT YOU CAN MEASURE IT IN, SAY, THREE MONTHS? THERE ARE OTHER SCALES OF SOCIAL AND EMOTIONAL SKILLS IN INFANTS, TWO HAVE CATCHY NAMES, ITSEA AND BITSEA, INFANT TODDLER SOCIAL EMOTIONAL ASSESSMENT AND BRIEF INFANT TODDLER SOCIAL EMOTIONAL ASSESSMENT. >> TWO-MINUTE WARNING. >> THESE INSTRUMENTS WILL BE USED IN UPCOMING TRIALS AND MIGHT HAVE SHORT-TERM METRICS THAT CAN IMPROVE WITH TRIAL. LOTS OF ATTENTION ABOUT EYE CONTACT AND EYE TRACKING INSTRUMENTS. IT COULD BE THAT COGNITION BEGINS WITH EYE CONTACT AND EYE TRACKING IN INFANTS. AND IF YOU CAN STANDARDIZE AND MEASURE THAT YOU MAY BE ABLE TO SHOW IN INFANTS IMPROVEMENTS IN ATTENTION THAT COULD CORRELATE WITH IMPROVED COGNITION. NEXT SLIDE. THESE ARE THE EYE TRACKING GLASSES BEING STUDIED FOR ABSON SEIZURES BUT COULD BE ADAPTED FOR EYE TRACKING IN INFANTS. THIS IS MY BIOMARKER SLIDE, EEG BECOME GROUND, INFANTILE SPASMS, THE OUTCOME MEASURE IS CESSATION OF SPASM, RESOLUTION OF ARRHYTHMIA. ON THE RIGHT THE SLIDE IS NORMAL. LEFT IS BURBS -- BURST EXPRESSION. NORMALIZING IS GOOD, MAYBE NOT ENOUGH FOR APPROVAL BUT IT'S A GOOD STEP AND NEED MORE ATTENTION TO EEG AND OTHER BIOMARKERS. IN CONCLUSION MEANINGFUL OUTCOME MEASURES REQUIRE DETAILED UNDERSTANDING OF THE DISEASE, IN EVERY REGARD, THEY IN PART HAVE TO BE FEASIBLE IN SHORT-TERM TRIALS, REQUIRING LOTS OF INPUT FROM THOSE ON THE CALL, WE HAVE A LOT OF WORK TO DO. THANKS TO THESE ORGANIZATIONS AND PEOPLE FOR INFORMING MY THOUGHTS ON THIS TOPIC. I'LL TURN IT OVER TO DR. STANLEY CROOKE TO TALK ABOUT ACCELERATING BENCH TO BEDSIDE TRANSLATION. >> I'M PLEASED TO INTRODUCE N-LOREM TO YOU TODAY, A CHARITABLE FOUNDATION THAT I INITIATED ALMOST EXACTLY A YEAR AGO. NEXT SLIDE PLEASE. OUR MISSION AT N-LOREM IS TO TAKE ADVANTAGE OF THE TECHNOLOGY THAT WE CREATED AT IONIS TO BRING TREATMENT TO PATIENTS WITH RARE MUTATION AND PROVIDE TREATMENT FOR FREE FOR LIFE. I'LL SAY THAT AGAIN. FOR FREE, FOR LIFE. AND IT IS INDEED POSSIBLE TO DO THAT. IN FACT, IN PARALLEL WITH SETTING UP N-LOREM, WE HAD THE OPPORTUNITY TO HELP TWO INVESTIGATORS TREAT SEVERAL PATIENTS. NEXT SLIDE PLEASE. TIM YU AT HARVARD AND NEIL SCHNEIDER AT COLUMBIA, AND WENT OUT TO 13 PATIENTS, THREE AT TIM'S SHOP, TEN OF THESE MUTATION AOS PATIENTS AT NEIL RESPECT SHOP. IT IS FEASIBLE FOR US TO DO THIS. NEXT SLIDE. THE WAY TO THINK, WE'RE MIDDLEMEN, CONNECT THE NEED, PATIENT, INVESTIGATOR, IT DOES TAKE A RESEARCH INVESTIGATOR, TO THE ENGINE WE CREATED AT IONIS TO DISCOVER AND DEVELOP ASOs. SPECIFICALLY IT PROVIDES A SITE TO WHICH PATIENTS AND RESEARCH INVESTIGATORS CAN GO TO APPLY FOR TREATMENT, A PROCESS WE THINK ASSURES THAT WE MAKE SOLID DECISIONS THAT WE KNOW WHAT WE'RE TREATING AND WHY WE'RE TREATING IT, AND THESE PATIENTS ARE EXPOSED TO ONLY PRUDENT RISKS, THAT INCLUDES PRESENTATION OF THE CASE TYPICALLY WITH THE PHYSICIAN TO A COMMITTEE WE CALL ACCESS TO TREATMENT COMMITTEE WHICH IS COMPRISED OF ALL THE DISCIPLINES WE THINK WE NEED TO MAKE DIFFICULT JUDGMENTS WISELY. IF WE DECIDE TO TREAT, PATIENT CAN BE TREATED WITH AN ASO, WE THEN FUND DISCOVERY AND DEVELOPMENT OF THE ASO OF THAT ILLNESS, WE HELP THE INVESTIGATOR PREPARE AN INVESTIGATOR-INITIATED IND AND THEN IMPORTANTLY COMMITTED TO EVALUATING PERFORMANCE OF EACH ASO AND OVERALL PERFORMANCE AND WE THINK WE'LL DEVELOPED INTERESTING APPROACHES TO DO THAT. NEXT SLIDE PLEASE. TO TACKLE THIS, I BELIEVE THAT WE NEED FOUR ITEMS. AND I'VE BEEN WORKING ON THIS FOR FOUR YEARS. I REALIZED ABOUT FOUR YEARS AGO THAT TECHNOLOGY WAS IN PRINCIPAL CAPABLE OF DOING THAT, BUT THE TECHNOLOGY ALONE IS INSUFFICIENT TO TACKLE IT. AMONG THE STEPS THAT I FELT I NEEDED TO TAKE WAS DETERMINE WHETHER WE COULD PURSUE THIS WITH COMMERCIAL MODEL, THERE'S MUCH TO RECOMMEND IT, WE KNOW HOW TO USE IT, REGULATIONS ARE BUILT FOR THAT, BUT IF, EVEN IF ONE COULD DEVELOP A PATH TO APPROVAL, COMMERCIAL APPROVAL OF A DRUG FOR SINGLE PATIENT WHICH I THINK IS UNLIKELY IN THE DRUG DIVISION, THE COSTS HAVE TO BE CHARGED TO FAMILIES WOULD BE EXTREMELY HIGH. I THINK THAT'S WRONG. WE'RE A CHARITABLE ORGANIZATION. WE NEED ACCESS TO A GREAT DEAL OF INFORMATION. WE NEED ACCESS TO THE PATIENT, THE DIAGNOSIS, WE NEED A GREAT DEAL OF GENETIC INFORMATION. WE ALSO NEED TO KNOW MANIFESTATIONS OF THE DISEASE, ORGANS INVOLVED, INVESTIGATOR THAT'S CAPABLE OF MANAGING PATIENT UNDER INVESTIGATOR-INITIATED IND AND NEED INSTITUTION WILLING AND ABLE TO DO ALL THAT. FORTUNATELY I WAS INTRODUCED TO THE UNDIAGNOSED DISEASE NETWORK, SO I SPENT QUITE SOME TIME DEVELOPING A RELATIONSHIP WITH UDN, BUT IN THE FIRST YEAR LESS THAN HALF THE APPLICATIONS FOR TREATMENT WE HAD GOTTEN HAVE COME FROM UDN INSTITUTIONS, WHICH JUST SAYS LOTS OF INSTITUTIONS SEE THIS AS A KEY PROBLEM. AND THEN FINALLY YOU NEED A REGULATORY ENVIRONMENT THAT'S AT LEAST ACCEPTING. SO I SPENT MOST OF 2019 DEALING WITH -- DISCUSSING THIS WITH DRUG UNIT OF FDA, WE ARE PLEASED THAT THE FDA IS DEVELOPING NEW GUIDANCE FOR THIS BUT EVEN PRIOR TO GUIDANCE ISSUING WE THINK THAT IT'S POSSIBLE TO WORK WITH EACH OF THE DIVISIONS AND SOLVE SOME OF THE PROBLEMS SOME OF THESE PATIENTS HAVE. NEXT SLIDE. NOW, LOOKING MORE SPECIFICALLY AT THE TECHNOLOGY, OF COURSE, THE INTRINSIC EFFICIENCY OF TECHNOLOGY WAS NO SURPRISED TO ME, ONE OF THE MAIN REASONS I CREATED THE COMPANY TO PURSUE IT. BUT THAT'S NOT ENOUGH. YOU NEED THE VERSATILITY THAT WE HAVE TODAY AND TECHNOLOGY, MOST PEOPLE NOT PRACTITIONERS OF THE TECHNOLOGY DON'T UNDERSTAND WE HAVE NOW MULTIPLE POST-BINDING MECHANISMS TO USE, INCLUDING EVEN THINGS LIKE ASOs THAT CAN INCREASE TRANSLATION OF SPECIFIC PROTEINS, VALIDATED THROUGH ALL ROUTES OF ADMINISTRATION AND UNDERSTAND THEM IN DETAIL AND UNDERSTAND EACH BOARD THEY INTERACT WITH IN DETAIL. NEXT SLIDE. THE AUTOMATION THAT WE HAD AT IONIS IS CRITICAL. I THINK THE SINGLE-MOST CRITICAL ELEMENT WE HAVE IS THAT WITHIN A CHEMICAL CLASS ALL ASOs OF THAT CHEMICAL CLASS ARE BASICALLY THE SAME DRUG SO THERE'S HIGHLY CONSISTENT PERFORMANCE WITHIN THAT CHEMICAL CLASS, AT IONIS WE'RE DEVELOPING ESSENTIALLY FOUR MAJOR CHEMICAL CLASSES FOR DIFFERENT USES. AND SO WITHIN A CHEMICAL CLASS WE HAVE A VERY GOOD IDEA OF DOSE WE'LL NEED TO USE, WE KNOW WHAT ROUTE OF ADMINISTRATION WE SHOULD CHOOSE IS. WE KNOW THE DURATION OF EFFECT. AND BEGINNING ABOUT 15 YEARS AGO, WE ESTABLISHED DATABASES THAT INTEGRATE ALL THE SAFETY OBSERVATIONS FOR EACH CHEMICAL CLASS THAT WE'RE DEVELOPING FOR NON-HUMAN PRIMATES THROUGH ALL CONTROLLED HUMAN TRIALS. AND ACTUALLY SEVERAL OF THOSE DATABASES HAVE BEEN PUBLISHED, IN FACT I'M FIRST AUTHOR ON ALL THOSE PUBLICATIONS, AND THAT DATABASE IS AVAILABLE TO THE FDA. AND THAT'S CRITICAL I THINK TO THEM. FINALLY JUST THE POTENCY AND DURATION OF EFFECT OF MODERN ASOs IS EXTREMELY IMPORTANT. NEXT SLIDE PLEASE. NEXT SLIDE. NEXT SLIDE PLEASE. THANK YOU. SO THESE ARE THE ORGANS WE'RE FOCUSED ON TODAY. WHY THESE ORGANS? THESE ARE THE ONES WE KNOW THE BEST. WE UNDERSTAND THE SUBORGAN PK AND PD, HIGH POTENCY, COULD CONFIDENT OF POTENT RISK. ROUTES OF ADMINISTRATION SHOWN HERE, TWO SYSTEMIC FOR LIVER AND KIDNEY, ON THE FAR RIGHT IS TOTAL ANNUAL DOSE FOR A PATIENT. GMP FACILITY TODAY IT'S NOT POSSIBLE TO MAKE LESS THAN 10 GRAMS, SO GIVEN THE STABILITY, THESE DRUGS ARE EXTREMELY STABLE, DRY POWDER, YOU CAN SEE IF WE DO A SINGLE GMP RUN WE HAVE ENOUGH DRUG FOR A PATIENT FOR 10 TO 20 YEARS AT LEAST. SO THAT PART OF THE EQUATION IS ACTUALLY FAIRLY INEXPENSIVE. NEXT SLIDE. OF COURSE IT TAKES A VILLAGE TO DO THIS. WE NEED LOTS OF HELP. WE HAVE OUR RELATIONSHIPS WITH THE UNDIAGNOSED DISEASE NETWORK, THE MAIN COST CENTER IS ACTUALLY THE TOXICOLOGY STUDIES WE HAVE TO DO SO I SPOKE TO EACH OF THE CROs TO DO TOX STUDIES FOR US. EACH IS EXCITED TO PARTICIPATE IN THIS AND THEY ARE PERFORMING THESE TOX STUDIES AT SIGNIFICANT COST REDUCTIONS. >> TWO-MINUTE WARNING. >> BY 30% IN THE FIRST YEAR. AND THEN HELPING SEQUENCE, WE NEED MORE SEQUENCING THAN PROCEEDED. FIRST YEAR I EXPECTED FIVE APPLICATIONS, ONE TO TREAT, WE'RE NOW UP TO 47. WE EXPECT THOSE APPLICATIONS TO INCREASE VERY RAPIDLY IN THE COMING YEAR AND TO BEGIN TO COME FROM PLACES OTHER THAN CENTRAL NERVOUS SYSTEM AND REMARKABLY SO FAR WE'RE AGE TO DECIDE TO TREAT 30% OF APPLICATIONS WE RECEIVE, WE EXPECT THAT TO DECLINE OVER TIME BECAUSE WE HAVE SINGLE TECHNOLOGY. NEXT SLIDE. NEXT SLIDE PLEASE. AND THIS SLIDE IS RELEVANT TO THIS AUDIENCE, NOT SURPRISING THAT WE RECEIVED A GOOD MANY ION CHANNEL MUTATIONS IN THE CENTRAL NERVOUS SYSTEM, OF COURSE THESE OFTEN CAUSE EPILEPSIES, AND WE'RE MOVING TOWARDS TREATING A NUMBER OF THOSE, ALL THOSE PATIENTS ON THAT SLIDE. AND SO MY GOAL TODAY WAS TO MAKE YOU AWARE THAT N-LOREM EXISTS, AND IF YOU HAVE A PATIENT THAT YOU THINK MIGHT BENEFIT FROM WHAT WE CAN DO THEN WE LOOK FORWARD TO RECEIVING THE APPLICATION AND WORKING WITH YOU TO SEE IF WE CAN HELP YOUR PATIENT. THANK YOU. WELCOME BACK, EVERYBODY. I HOPE YOU HAD A GOOD BREAK, A GOOD EARLIER SESSION. WE'RE NOW GOING TO TURN THE FLOOR OVER TO DR. AL GEORGE TO MODERATE SESSION 3 ON MODELING HUMAN EPILEPSIES. HE COMES IN NORTHWESTERN UNIVERSITY, PROFESSOR OF PHARMACOLOGY AND DIRECTOR FOR CENTER FOR PHARMACOGENOMICS. AL, I TURN IT OVER TO YOU. >> THANK YOU, ANN. WELCOME BACK TO THE AFTERNOON. THIS IS SESSION 3, MODELING HUMAN EPILEPSIES, FOCUSING ON USE OF PRE-CLINICAL MODELS, TO SERVE AS SURROGATES OR PROXIES OR EVEN AVATARS FOR THE HUMAN BRAIN AND EPILEPSY SUSCEPTIBLE INDIVIDUAL. ONE EVER OUR GOALS THIS AFTERNOON IS TO ASSESS WHETHER WE NEED NEW MODELS OR ARE EXISTING MODELS SUFFICIENT TO HELP US ACCELERATE TOWARD DISCOVERY AND DEVELOPMENT OF NEW TREATMENTS FOR THE EPILEPSIES. WE'LL HAVE TWO TALKS FOLLOWED BY HOUR-LONG PANEL DISCUSSION, AND WE'LL HAVE BREAKOUT GROUPS IN THE REMAINING TIME. s I WANT TO INTRODUCE KIM NYE FROM TEST RESEARCH FOUNDATION, A PERSONAL STORY ON WHY EPILEPSY RESEARCH MATTERS. TAKE IT AWAY, KIM GOOD THANK YOU. I'M KIM NYE, SPEAKING ABOUT MY FAMILY'S PERSONAL JOURNEY WITH MODELING GENETIC EPILEPSY IN HOPE IT HIGHLIGHTS CHALLENGES WE'RE FACING. WHEN MY DAUGHTER WAS BORN IN 2003 SHE BEGAN HAVING SEIZURES SHORTLY AFTER BIRTH, FOR NO APPARENT REASON. DIAGNOSIS FROM BENIGN IDIOPATHIC TO CATASTROPHIC. MEDICATION, SURGERY, DIET, CLINICAL TRIALS AND RESEARCH FAILED TESSA FOR A DECADE. SHE WAS HAVING HUNDREDS OF SEIZURES A DAY BUT WE STILL HAD NO IDEA WHY. AT ONE POINT WE THOUGHT WE HAD A DE NOVO GENETIC DIAGNOSIS BUT HER DIAGNOSE WAS SWITCHED WITH ANOTHER, WE'RE BACK AT SQUARE ONE. AUGUST 26, 2013, OUR WORLD CAME CRASHING DOWN WHEN I GAVE BIRTH TO A BABY BOY NAMED COLSON, SEEMED HEALTHY BUT JUST LIKE BIG SISTER BEGAN HAVING SEIZURES AFTER BIRTH. HE WAS ONLY HOURS OLD, BUT I KNEW MY SON WOULD NEVER TALK OR DRESS HIMSELF. HIS BIRTH MADE THE MEDICAL PUZZLE EASIER, A RESEARCHER WAS ABLE TO FIND A GENETIC MARKER, SLC6A 5, DIAGNOSIS SHOULD NOT BE THE END JOURNEY BUT WE WE SHOULD TRANSLATE INTO TRIALS. WHEN THESE ATTEMPTS DIDN'T WORK WE DECIDED TO ORGANIZE OUR DISEASE COMMUNITY AND FUND RESEARCH. IN 2015 WE STARTED TESS RESEARCH FOUNDATION. BECAUSE IT WAS A NEWLY DISCOVERED DISORDER, THIS IS WHAT THE LANDSCAPE LOOKED LIKE WHEN WE STARTED. IT WAS A BUNCH OF ZEROES AND NOS, FEWER THAN TEN KIDS DIAGNOSED, NO FUNDING OR TOOLKIT IN PLACE. I KNEW THE FUTURE WAS BLEAK FOR MY NEWBORN SON. I DID NOT SEE HOPE IN RESEARCH LANDSCAPE. WHERE WAS THE INFRASTRUCTURE THAT COULD FIND THE ANSWERS WE NEEDED IN THE TIMELINE WE NEEDED THEM? NEXT SLIDE. WE FUNDED RESEARCH TO CREATE ANIMAL AND CELLULAR MODELS OF SLC13A 5, THE GOAL NOW TO MAKE THE GUINEA PIG BE THE GUINEA PIG. WE DID MAKE FISH, MICE, FLIES. WE'RE INTERESTED IN MECHANISM, DRUG SCREENING, REPURPOSING, METABOLISM-BASED THERAPY, GENE THERAPY. WE DON'T HAVE A PERFECT MODEL SYSTEM FOR SLC13A5 AND DEVELOPED MULTIPLE MODELS TO ACCEPT US ACCELERATE DISCOVERIES, FOR INSTANCE IT'S GOING TO BE DIFFICULT TO USE A ZEBRAFISH IN A GENE THERAPY PROJECT BUT FISH CAN BE USEFUL FOR DRUG SCREENING. WHAT HAPPENS WHEN ANIMAL MODELS DON'T BEHAVE LIKE HUMANS? THIS IS A MONOGENIC LOSS OF FUNCTION RECESSIVE DISEASE, THE KNOCKOUT MOUSE SHOULD BE A GREAT MODEL FOR US BUT THE KIDS BEGIN SEIZING AFTER BIRTH, AND CONTINUE TO HAVE MULTIPLE SEIZURE TYPES REFRACTORY TO MEDICATION, KNOCKOUT MOUSE HAS SPORE THETIC SEIZURES. DEVELOPMENTAL DELAYS DO NOT SEEM TO AFFLICT THE KNOCKOUT MOUSE AT ALL. NEXT SLIDE. FROM THE PATIENT ADVOCACY PERSPECTIVE MODELING RAISES MORE QUESTIONS THAN ANSWERS. HOW MUCH TIME AND FUNDING SHOULD BE PUT INTO THE CREATION OF HUMAN EPILEPSY MODELS? SHOULD WE KEEP MAKING MICE ON DIFFERENT BACKGROUNDS, DO WE MAKE MORE EXPENSIVE ANIMAL MODELS LIKE A FERRET OR PIG? OUR ORGANIZATION LARGELY STARTED OUT OF FEAR IF WE DIDN'T BUILD THE PRE-CLINICAL TOOLKIT IT WOULD NEVER GET BUILT. AND WHAT DO WE DO WHEN WE HAVE POTENTIALLY CUREATIVE TREATMENT BUT MEDIOCRE MOUSE? IN OUR CASE WILL WE GET OUR GENE REPLACEMENT THERAPY IN THE CLINICAL TRIALS IF THE CURRENT MOUSE MODEL IS AS GOOD AS IT GETS? DO MY CHILDREN'S LIVES DEPEND ON A MOUSE? I'M CLOSING WITH THE REFRAIN THAT I HOPE IS STARTING TO SOUND FAMILIAR. GO BACK ONE. THANK YOU. WE NEED TRANSFORMATIVE CHANGE. WE NEED TRANSFORMATIVE CHANGE FOR MY TESSA AND COLSON, MEREDITH, JACKSON, YAVI, ALAINA, SANJU AND AUBREY, ABHI AND MORE. >> THANK YOU, KIM. WE'LL HEAR FROM AMY BROOKS-KAYAL FROM UNIVERSITY OF CALIFORNIA DAVIS, GIVING AN OVERVIEW OF HOW RESEARCHERS HAVE MODELED HUMAN EPILEPSY GOING FROM ORGANOIDS TO NON-HUMAN PRIMATES AND EVERYTHING IN BETWEEN. >> THANKS, KIM, FOR A GREAT INTRODUCTION TO WHY THIS IS SUCH AN IMPORTANT ISSUE. NEXT SLIDE PLEASE. NEXT SLIDE PLEASE. GREAT. SO, I'VE BEEN ASKED TO COVER A VERY BROAD TOPIC, WHICH IS PRE-CLINICAL LARGELY NON-HUMAN MODELS OF EPILEPSY. AND I THINK THE FIRST QUESTION IS WHY DO WE NEED THESE MODELS. KIM DID A GREAT JOB EXPLAINING A NUMBER OF THE REASONS WHY THESE, THEY ARE ESSENTIAL IN EPILEPSY RESEARCH. WE NEED TO UNDERSTAND BASIC MECHANISMS OF THE DISEASE AND THAT REQUIRES STUDIES THAT ARE INAPPROPRIATE TO DO IN PATIENTS. WE NEED ANIMAL MODELS TO PROVIDE DRUG SCREENING FOR EFFICACY AND EQUALLY IMPORTANTLY TO EXAMINE WHETHER OUR MOLECULES ARE BIOAVAILABLE, WHEN GIVEN ORALLY OR IN THE BLOODSTREAM, WHETHER THEY CROSS THE BLOOD-BRAIN BARRIER, WHAT TOXICITIES THEY CREATE ONCE THEY ARE ADMINISTERED. AGAIN, THESE ARE ALL THINGS THAT ARE REALLY ESSENTIAL TO DO IN PRE-CLINICAL MODELS BEFORE INTRODUCING THEM INTO PATIENTS. BUT WHAT IS THE BEST MODEL? AND TO PARAPHRASE THE QUOTE THAT WE HEARD EARLIER, THE BEST MODEL OF THE HUMAN IS OBVIOUSLY A HUMAN. AND PREFERABLY THE SAME HUMAN. UNFORTUNATELY, THAT IS NOT PRACTICAL FOR THESE EARLY PRE-CLINICAL STUDIES. SO, I THINK WE HAVE TO TAKE IT AS A POINT OF FACT THAT ALL NON-HUMAN MODELS AND EVEN REDUCTIONIST MODELS BASED ON HUMAN CELLS ARE INHERENTLY IMPERFECT BECAUSE THEY ARE NOT THE HUMAN WITH EPILEPSY. THEY ARE ALL GOING TO HAVE LIMITATIONS. SO REALLY THE BEST NON-HUMAN OR PRE-CLINICAL MODEL FOR A GIVEN SET OF EXPERIMENTS DEPENDS ON SPECIFICALLY WHAT QUESTION YOU'RE ASKING. AND WHAT INFORMATION YOU NEED. AND YOU MAY NEED MULTIPLE DIFFERENT MODELS IN ORDER TO GET ALL OF THE INFORMATION THAT YOU NEED TO DETERMINE IF THE THERAPY IS GOING TO BE SAFE AND EFFECTIVE TO BRING INTO FIRST-IN-HUMAN STUDIES, IN PATIENTS. NEXT SLIDE PLEASE. SO, I ASKED ALL OF OUR PANELISTS TO HELP ME WITH THIS TALK, AND TO -- IN EACH OF THE MODELS THEY USED MOST COMMONLY THEY WILL SPEAK ABOUT RIGHT AFTER THIS TO GIVE ME BULLET POINTS OF WHAT THEY CONSIDER THE MOST COMMON AND EFFECTIVE USES FOR THESE MODELS, WHAT THEY SEE AS THE ADVANTAGES OF THESE MODELS AND WHAT THEY SEE AS LIMITATIONS OF THESE MODELS. WE'LL START WITH THE QUOTE/UNQUOTE HUMAN MODEL, HUMAN PLURIPOTENT MODEL, DERIVED FROM HUMAN FIBROBLASTS FROM PATIENTS WITH GENETIC EPILEPSIES OR OTHER GENETIC CONDITIONS IN OTHER AREAS. AND THEN THE CELLS CAN BE DEVELOPED INTO WHOLE VARIETY OF CELL TYPES INCLUDING NEURONS, GLIAS, GLIA, AND OTHER CELL TYPES YOU MIGHT WANT TO STUDY. THEY ARE USED TO STUDY STRUCTURAL BRAIN DEVELOPMENT, THEY ARE USED TO EXAMINE ELECTROPHYSIOLOGY OF CONNECTED NEURONS. YOU CAN DO CALCIUM IMAGING. YOU CAN DO DRUG SCREENING AND DRUG TESTING. YOU CAN ALSO DO GENETIC SCREENING IN THIS MODEL. THE ADVANTAGES ARE THAT THEY CONTAIN THE UNIQUE GENETIC BACKGROUND OF EACH PATIENT, AS WELL AS THEIR GENETIC -- THEIR SPECIFIC MUTATION. ONCE THESE CELLS ARE DERIVED THEY PROVIDE UNLIMITED SUPPLY OF MATERIAL TO STUDY, AND THEY CAN STUDY VERY SPECIFIC HUMAN NEURODEVELOPMENTAL FEATURES. THE DISADVANTAGE OF THE CULTURES IS THAT THEY ARE VERY MUCH A REDUCTIONIST SYSTEM. THEY TAKE A WHILE TO DEVELOP. AND THEY DON'T REALLY MATURE VERY FAR. BRAIN ORGANOIDS DO MATURE A BIT MORE, AND CAN BE MAINTAINED LONGER. BUT THEY ALSO STILL LACK IN VIVO NETWORK COMPLEXITY, STILL HAVE SLOW DEVELOPMENT AND, AGAIN, HAVE INCOMPLETE MATURATION. NEXT SLIDE PLEASE. NEXT SLIDE. MOVING UP A BIT IN COMPLEXITY WE GET TO DROSOPHILA. DROSOPHILA ARE USED PRIMARILY FOR GENETIC SCREENING, PARTICULARLY FOR EVOLUTIONARY CONSERVED GENES. THEY REPLICATE VERY QUICKLY. THEY HAVE SHORT LIVES, THEY HAVE LOW MAINTENANCE COSTS. THESE ARE INCREDIBLE ADVANTAGES FOR HIGH-THROUGHPUT GENETIC STUDIES. THEY HAVE A WELL-ESTABLISHED GENETICS SYSTEM. THERE'S A SOPHISTICATED GENETIC TOOLKIT AND RESOURCES. MANY GENES ARE ASSOCIATED WITH HUMAN DISEASE THAT HAVE ORTHOLOGS IN DROSOPHILA. AND THEY ARE A VARIETY OF SEIZURE-PRONE MUTANTS THAT CAN BE INDUCED TO HAVE SEIZURES. LIMITATIONS ARE, HOWEVER, THAT THE ANATOMY OF THE BRAIN IS OBVIOUSLY VERY DIFFERENT, VERY SIMPLISTIC. THEY HAVE DIFFERENT CARDIOVASCULAR AND RESPIRATORY SYSTEMS, FEVERS INDUCED, NOT SPONTANEOUS, GENES DON'T MAP IDENTICALLY TO HUMANS. YOU DON'T -- EEG DOES NOT CORRESPOND TO HUMAN BECAUSE OF DIFFERENCE IN COMPLEXITY. NEXT SLIDE. YOU CAN SEE A FLY SEIZING IN THE CORNER. ZEBRAFISH, VERY COMMONLY UTILIZED MODEL NOW, EMBRYOS CAN BE USED FOR SMALL MOLECULE SCREENING, GENETIC ANALYSIS, AND TO DEVELOP PERSONALIZED THERAPIES THROUGH INDIVIDUAL MUTATIONS THAT CAN BE MADE TO REPLICATE HUMAN GENE MUTATIONS AND THEN USED FOR DRUG SCREENING. THE ADVANTAGES, AGAIN, VERY RAPID LARGER GENE CONSERVATION THAN WE SEE IN THE FLIES, LOTS OF GENETIC RESOURCES, INEXPENSIVE AND EASY TO IMAGE BECAUSE THE EMBRYOS ARE TRANSPARENT. HOWEVER ANIMALS HAVE NO NEOCORTEX, GENES DON'T MAP IDENTICALLY TO HUMANS, SOME MUTANTS DON'T REPLICATE HUMAN DISEASE PHENOTYPE. NEXT SLIDE PLEASE. SO THEN WE GET TO PROBABLY THE MOST COMMON MODEL OF HUMAN GENETIC DISEASES, MOUSE GENETIC MODELS. THERE'S A LOT OF WORDS ON THIS SLIDE, WAYNE FRANKEL HAD A LOT TO SAY ABOUT THIS. BUT BASICALLY THERE ARE LOTS AND LOTS OF MOUSE MODELS ALREADY, OVER 360 MOUSE MUTANTS. 100 THAT HAVE CONSTRUCT VALIDITY. 85 MODELS FOR DEVELOPMENTAL AND ENCEPHALOPATHIES. ADVANTAGES ARE WE HAVE A NUMBER OF THESE MODELS. WE CAN IDENTIFY -- WE HAVE A LOT OF BACKGROUND INFORMATION. THERE ARE A LOT OF TOOLS THAT CAN CREATE VERY SPECIFIC MUTATIONS, SPECIFIC CELL TYPES, TURNED ON AND OFF AT VERY SPECIFIC TIMES. ALL OF THESE HAVE TREMENDOUS ADVANTAGES. AND THESE ARE HIGHLY ACCEPTED TOOLS. THE DISADVANTAGES, SOME OF THE GENETICS ARE DIFFICULT TO REPLICATE IN MOUSE, CNVs AND COMPLEX STRUCTURAL VARIANTS. YOU DON'T SEE ONE-TO-ONE CORRELATION WITH SEIZURE TYPES AND COMORBIDITIES, OBVIOUSLY SOME COMORBIDITIES ARE VERY DIFFICULT TO EVALUATE IN MICE SUCH AS COGNITIVE AND PSYCHIATRIC COMORBIDITIES. THE SMALL SIZE OF THE ANIMALS IS NOT CONVENIENT FOR SOME APPLICATIONS AND, AGAIN, BRAIN STRUCTURE, VERY DIFFERENT BRAIN STRUCTURE THAN HUMANS. AND HIGH THROUGHPUT SCREENS ARE MORE EXPENSIVE AND MORE CHALLENGING. NEXT SLIDE PLEASE. NEXT SLIDE PLEASE. WE ALSO USE RODENTS TO LOOK AT ACQUIRED EPILEPSIES, USING BOTH MICE AND RATS. WE HAVE A WHOLE ARRAY OF MODELS WHICH I'VE LISTED TO THE LEFT. MODELS OF TEMPORAL LOBE EPILEPSY INCLUDING ELECTRICAL AND CHEMICAL MODELS. MODELS OF POSTTRAUMATIC, STROKE, HYPOXIA, HYPOTHERMIA, FEBRILE STATUS IN YOUNGER CHILDREN AND A NUMBER OF OTHER FOCAL CORTICAL MODELS. THE ADVANTAGES OF THESE ARE THAT MANY OF THESE MODELS DO DISPLAY SPONTANEOUS SEIZURES AND HAVE SPONTANEOUS EPILEPSY, USED FOR SCREENING OF THERAPIES, YOU'VE HEARD ABOUT THE LARGE EPILEPSY THERAPY SCREENING PROGRAM RUN BY THE NIH THAT UTILIZES A NUMBER OF RODENT MODELS OF ACQUIRED EPILEPSY. HAVE REALLY BEEN THE BEDROCK OF A LOT OF OUR MECHANISTIC STUDIES, OF OUR TARGET IDENTIFICATION FOR THERAPY DEVELOPMENT. YOU CAN GENETICALLY MANIPULATE PARTICULARLY THE MICE TO ANSWER HYPOTHESIS-DRIVEN QUESTIONS AND EEG IS FEASIBLE IN RODENTS. DISADVANTAGES CHRONIC EEG IS VERY, VERY TIME CONSUMING TO INTERPRET AND VERY EXPENSIVE. THE ANIMALS FREQUENTLY HAVE FAIRLY RARE SEIZURES WHICH MEANS LONG RECORDING PERIODS AGAIN WITH LOTS OF EXPENSE AND BEING VERY TIME CONSUMING. BEHAVIORAL SEIZURES OFTEN ARE VERY SUBTLE AND DIFFICULT TO APPRECIATE. SOME MODELS DON'T PRODUCE SPONTANEOUS SEIZURES AT ALL, THERE ARE STRAIN DIFFERENCES. AGAIN THE BIGGEST ISSUE FOR ME AT LEAST IN RODENT MODELS COMPARED TO HUMANS IS THE INCREDIBLE DIFFERENCE IN THE STRUCTURES OF THE BRAINS. AGAIN, RATS LIKE MICE DON'T HAVE ANY GYREX. SO NOW WE'RE MOVING TO ANIMALS THAT HAVE GYRI. TO THE RIGHT IS A DOG WITH EPILEPSY, I'M SURE MANY OF YOU IF NOT ALL KNOW DOGS NATURALLY HAVE EPILEPSY, FAIRLY HIGH PREVALENCE. THEY FREQUENTLY DRUG RESISTANT. THEY HAVE A NUMBER OF -- IN ADDITION TO GENETIC EPILEPSIES CAN HAVE EPILEPSIES FROM ACQUIRED CAUSES JUST LIKE IN HUMANS, AND THERE ARE CANINE MODELS WHERE EPILEPSY IS INDUCED. LOTS OF DIFFERENT MODELS. THEY HAVE MUCH LARGER BRAINS AND GYRAL BRAINS, PARTICULARLY GOOD FOR STUDIES OF SURGERY, DEVICES TO ABORT OR ANTICIPATE SEIZURES, AND IT'S EASIER TO DO TRACKING AND SEIZURE DIARIES. COMMON PETS, PEOPLE ARE OFTEN INVESTED IN GETTING PETS TREATMENT. THEY ARE INTELLIGENT, SOCIAL, TRAINABLE. SO IT'S MUCH EASIER TO ASSESS COGNITIVE AND SOME SOCIAL COMORBIDITIES, AND THEY HAVE A LOT OF FEATURES OF INTRACTABLE EPILEPSY, DRUG RESISTANCE, COMORBIDITIES SUCH AS SLEEP AND SUDEP. LIMITATION IS EXPENSE AND THEY ARE COMMON PETS SO GOING BEYOND TREATMENT STUDIES IN DOGS OFTEN MEETS, YOU KNOW, PEOPLE -- RESISTANCE BECAUSE OF THE CONCERN ABOUT ANIMAL TREATMENT. NEXT SLIDE PLEASE. THIS IS JUST A RECORDING SHOWING DOG SEIZURES LOOK LIKE HUMAN SEIZURES ON EEG. UP THE PHYLOGENETIC TREE PIG MODELS, PARTICULARLY UTILIZED FOR HEAD INJURY STUDIES, SPECIFICALLY CONTROLLED CORTICAL IMPACT STUDIES OF POSTTRAUMATIC EPILEPSY. AGAIN, IMPORTANT FOR MECHANISMS OF EPILEPTOGENESIS AND PARTICULARLY GOOD FOR STUDIES OF STRUCTURAL AND INJURY-INDUCED EPILEPSIES BECAUSE THEY HAVE GYRAL STRUCTURE SIMILAR TO HUMAN BRAINS. SEIZURES LOOK VERY MUCH LIKE HUMAN SEIZURES AND YOU CAN PUT MULTIPLE ELECTRODES ON PIGS BECAUSE OF THE SIZE OF THEIR HEADS AND BRAINS. AND THEY HAVE CLINICALLY RELEVANT NEUROIMAGING AND HISTOPATHOLOGY. YOU CAN FOLLOW SERIAL BLOOD AND CSF MEASUREMENTS AND THEY HAVE HIGHER LEVEL COGNITIVE AND SOCIAL FUNCTION THAT MAKES IT MUCH EASIER TO ASSESS COMORBIDITIES. LIMITATION, AGAIN, THEY ARE LARGE. THEY TAKE A LOT OF SPACE TO HOUSE. THEY ARE EXPENSIVE. AND EEG REALLY REQUIRES EXPERT INTERPRETATION AND, AGAIN, A LOT OF INVESTMENT OF BOTH TIME AND MONEY. NEXT SLIDE PLEASE. AND THEN FINALLY HIGHEST NON-HUMAN LEVEL WE GET TO NON-HUMAN PRIMATE, AND PARTICULARLY EPILEPTIC BABOONS, GENETIC PREDISPOSITION TO EPILEPSY INCLUDING PHOTOSENSITIVE SEIZURES AS WELL AS SPONTANEOUS SEIZURES, PARTICULARLY GENETIC GENERALIZED EPILEPSY. >> TWO-MINUTE WARNING. >> THEY HAVE A LOT OF THE SAME SEIZURES THAT WE SEE IN PATIENTS WITH SOME OF OUR GENETIC GENERALIZED EPILEPSY INCLUDING MYOCLONIC AND GENERALIZED CLONIC SEIZURES, CHILDHOOD OR JUVENILE ONSET, AGAIN CHARACTERISTIC OF MANY OF OUR GENERALIZED EPILEPSIES IN HUMANS. THEY HAVE PREDISPOSITION FOR SEIZURES AT SLEEP TRANSITIONS. THEY HAVE SCALP EEG WITH GENERALIZED SEIZURES THAT, AGAIN, REMINISCENT OF HUMAN EEG. AND MOST OF THE ANIMALS DEVELOP EPILEPSY BY AGE 5. YOU CAN USE THE EPILEPTIC BABOONS FOR EEG, IMAGING, DEVICE STUDIES OF EPILEPSY AND STUDIES OF SUDDEN UNEXPECTED DEATH IN EPILEPSY. A NUMBER OF ADVANTAGES. AGAIN, TRANSLATABILITY, SIMILARITY IN BRAIN STRUCTURE TO THAT OF HUMAN, AND OBVIOUSLY THEY HAVE QUITE HIGH LEVEL COGNITIVE AND SOCIAL BEHAVIORS THAT MAKE IT MUCH EASIER TO DO DETAILED ASSESSMENTS OF COGNITIVE AND POTENTIAL SOCIAL COMORBIDITIES. DISADVANTAGE, HUGE COST, EXTREMELY EXPENSIVE, VERY FEW PLACES IN THE COUNTRY ARE SET UP TO HOUSE PRIMATES AND USE PRIMATES. SO AVAILABILITY IS LIMITED. TRAINING TAKES A LONG TIME. AND SEIZURE INDUCED MORBIDITY IS A BIG CONCERN IN PRIMATES. THE OPPORTUNITIES IN THE FUTURE FOR BEING CONSIDERED ARE PROSPECTIVE STUDIES OF GENETIC, EPIGENETIC ETIOLOGIES OF EPILEPSY AND CORRELATING THAT WITH EEG NEURO IMAGING, BEHAVIOR AND MOLECULAR BIOMARKERS, SIMILAR TO THE TYPES OF STUDIES THAT WE DO IN HUMANS. STUDIES OF LONG-TERM SEIZURE DETECTION DEVICES AND NEUROSTIMULATION DEVICES, AND VALIDATION AND HONING OF ALGORITHMS USED FOR PATIENTS, HUMAN PATIENTS WITH GENERALIZED EPILEPSY IS AN EFFECTIVE POTENTIAL USE OF THE MODEL. VALIDATION OF SUDEP BIOMARKERS, THESE BABOONS HAVE SUDEP IF THEY HAVE UNTREATED GENERALIZED TONIC SEIZURES, LOOKING AT BIOMARKERS OF SUDEP IN THESE ANIMALS MUCH CLOSER TO HUMANS MAY GIVE US GOOD LEADS ON WHAT WE SHOULD BE LOOKING FOR FOR BIOMARKERS IN HUMANS, AND, AGAIN, -- >> TIME EXPIRED. >> LONGER LIFE, THEY HAVE DEVELOPMENTAL TRAJECTORY THAT CAN BE STUDIED. LAST SLIDE PLEASE. SO IN CONCLUSION, NON-HUMAN AND PRE-CLINICAL MODELS ARE ESSENTIAL TO UNDERSTAND BASIC MECHANISMS, SCREEN THERAPEUTIC ENTITIES, FOR EFFICACY AND TOXICITY, BEFORE GOING INTO FIRST-IN-HUMAN STUDY. ALL HAVE LIMITATIONS. WE'RE FORTUNATE TO HAVE MANY WE MAY BE ABLE TO USE IN COMBINATION TO BE MORE EFFECTIVE AND MITIGATE LIMITATION AND ENHANCE ADVANTAGES AND ULTIMATELY BEST HUMAN MODEL WILL VARY DEPENDING ON QUESTION BEING ASKED. THANK YOU VERY MUCH. >> GREAT. THANK YOU VERY MUCH, AMY. WE'RE SCHEDULED TO HAVE A 10-MEMBER PANEL DISCUSSION INCLUDING AMY AND KIM WHO YOU JUST HEARD FROM, AND FOR EVERYONE ELSE WHO IS SPEAKING ON THE PANEL I'D LIKE YOU TO TURN YOUR VIDEO CAMERAS ON AND WE'LL GO AROUND AND DO A VERY QUICK ALMOST LIKE A SPEED DATING TYPE OF INTRODUCTION. I WANT EVERYONE TO STATE THEIR NAME AND INSTITUTION AND THEN WHICH MODEL SYSTEM THEY USE AND MAYBE AN EXAMPLE OF A RESEARCH QUESTION THAT YOU USE THAT MODEL FOR. I'LL GIVE YOU ALL 30 OR 40 SECONDS TO DO ALL THAT. I'M GOING TO INTRODUCE EVERYONE IN THE ORDER IN WHICH THEY APPEAR ON MY SCREEN. AND KAREN, YOU'RE UP FIRST. >> THANK YOU. KAREN WILCOX, UNIVERSITY OF UTAH, ALSO P.I. OF THE CONTRACT FOR THE NINDS-FUNDED EPILEPSY SCREENING PROGRAM AND WE USE A LOT OF THE RODENT MODELS THAT AMY TALKED ABOUT IN HER PRESENTATION FOR EFFICACY AND TOLERABILITY OF NEW INVESTIGATIONAL COMPOUNDS AND MY BASIC SCIENCE REALM I USE INFECTION INDUCED MODEL OF EPILEPSY TO UNDERSTAND NEUROINFLAMMATION'S ROLE IN SEIZURE ACTIVITY. >> THANK YOU. NEXT ON MY SCREEN IS TOSHIHIRO. >> I'M IN UNIVERSITY OF IOWA, USING FRUITFULLY TO STUDY GENETIC AND ENVIRONMENTAL FACTORS THAT HAVE SIGNIFICANT IMPACT ON SEVERITY. WE'RE PARTICULARLY INTERESTED IN HOW SEIZURE PHENOTYPES, INCLUDING SPONTANEOUS SEIZURES, GENES INVOLVED IN RESPONSE AS WELL AS DIET AND GUT MICROBIOTA. THANK YOU. >> THANK YOU. NEXT IS GERRY. >> GERRY DOWNES, PROFESSOR AT UNIVERSITY OF MASSACHUSETTS AMHURST, USING ZEBRAFISH. WE'VE BEEN LOOKING SO FAR AT SOME MONOGENIC EPILEPSIES TO MODEL THOSE USING THE ZEBRAFISH SYSTEM, PARTICULARLY INTERESTED IN EXPLORING MORE OF THE mTOR SIGNALING PATHWAY AND USING ZEBRAFISH TO LOOK AT GENETIC INTERACTIONS. >> THANKS. NEXT IS JOHN. >> THANKS. GLAD TO BE HERE. JOHN WOLF, UNIVERSITY OF PENNSYLVANIA, MY LAB FOCUSES ON DISRUPTION OF COGNITIVE SYSTEMS FOLLOWING TBI AND EPILEPSY USING HIGH DENSITY ELECTROPHYSIOLOGY. MY COLLEAGUES AND I CREATED A PIG MODEL WHICH YOU HEARD ABOUT POSTTRAUMATIC EPILEPSY USING CONTROLLED CORTICAL IMPACT AND WE'RE IN THE PROCESS OF CHARACTERIZING THAT MODEL WITH SUPPORT OF THE V.A., DoD, AND CURE FOUNDATION. WE THINK THE MAJOR ROLE OF THE MODEL IS PROBABLY GOING TO BE TO STUDY MECHANISMS OF EPILEPTOGENESIS SINCE WE KNOW THE TIME WE'VE INITIATED EPILEPTIC-INDUCING EVENT HOPING TO BETTER UNDERSTAND THAT PROCESS AND DEVELOP NEW METHODS OF INTERVENTION, IN ADDITION WE HOPE THE NATURE WILL ALLOW FOR BETTER TRANSLATION AS WELL. >> THANK YOU, JOHN. WAYNE? >> WAYNE FRANKEL, COLUMBIA UNIVERSITY, AMY ALREADY KIND OF INTRODUCED ME. I'M A MOUSE GENETICIST, MOUSE MODELS FOR 30 YEARS, WE STARTED WITH POLYGENIC MODELS, IN THE GENOME PROJECT GOT GOING MORE INTERESTED IN GENETIC MODELS, WE DECIDED TO USE REVERSE ENGINEERING TO MAKE A NUMBER OF THEM IN MICE, CURRENTLY STUDYING SEVERAL OF THOSE MODELS AND WE'RE INTERESTED IN UNDERSTANDING THE ONSET IN MICE, BIOLOGICAL ONSET, EXPLORING MODES OF GENETIC AND RNA THERAPIES. >> THANK YOU, WAYNE. JACK? >> THANKS, AL. JACK PARENT, UNIVERSITY OF MICHIGAN, DEPARTMENT OF NEUROLOGY. MY LAB WORKS ON A NUMBER OF MODELS INCLUDING RAT, MOUSE, ZEBRAFISH, I'M HERE TODAY REPRESENTING 2D AND BRAIN ORGANOID HUMAN PLURIPOTENT MODELS TO STUDY EPILEPSY. >> HI, I'M AKOS, WORKING WITH BABOON MODEL FOR ALMOST 20 YEARS, AND WE'VE BEEN VERY I GUESS BLESSED WE HAVE A LARGE FOUNDATION, THE NATIONAL -- SOUTHWEST NATIONAL PRIMATE RESEARCH CENTER HERE THE LARGEST PEDIGREED COLONY OF BABOONS IN THE WORLD, MANY OF THEM HAVE ACTUALLY EPILEPSY, UP TO 15%, SO WE HAVE BEEN WORKING, DEVELOPING NEUROIMAGING PLATFORMS TO LOOK AT BRAIN STRUCTURE AND FUNCTION, BASICALLY LOOKING AT MANY OF THE BIOMARKERS THAT WE'RE ALSO SEARCHING FOR IN HUMANS, OF COURSE SEIZURE PREDICTION, AND NEUROSTIMULATION IS ALSO A VERY IMPORTANT TOPIC. FINALLY ONE OF THE IMPORTANT ONES IS THAT YOU CAN DO BASICALLY STUDIES OF NATURAL HISTORY, THESE ARE ANIMALS, UNFORTUNATELY UNTREATED, THEY HAVE SPONTANEOUS SEIZURES, MANY OF THEM WEEKLY SEIZURES, TO MONTHLY SEIZURES. AND WE'RE INTERESTED IN HOW EPILEPSY OF COURSE DEVELOPS IN THESE ANIMALS, WHAT IS THE MECHANISM UNDERLYING EPILEPTOGENESIS, ALSO HORMONAL AND NEURAL BEHAVIOR EFFECTS OF EPILEPSY. FINALLY WHAT ARE THE MECHANISMS UNDERLYING MOST OF THE BIOMARKERS THAT MAY DEMONSTRATE THE RISK FOR SUDDEN UNEXPECTED EPILEPSY. >> THANK YOU VERY MUCH. LAST BUT NOT LEAST, GREG. >> HI, THANKS FOR HAVING ME. GREG WORELL, DEPARTMENT OF NEUROLOGY, MAYO CLINIC, ROCHESTER, MINNESOTA. I'VE BEEN INTERESTED IN TRANSLATION OF DEVICES FOR TRACKING SEIZURES, DETECTING SEIZURES, FORECASTING SEIZURES, AND USING STIMULATION FOR THERAPY AND HAVE USED DOG -- NATURAL OCCURRING EPILEPSY IN DOGS AND DOG MODELS FOR PRE-CLINICAL WORK WITH DEVICES THAT THEN IS TRANSLATED TO HUMANS, AND WE'VE USEDs RESEARCH ANIMALS AS WELL AS PET DOGS WITH EPILEPSY, WHICH GETS YOU AROUND THAT VERY EXPENSIVE PART OF TAKING CARE OF THE ANIMALS IF THEY ARE OUT LIVING THEIR LIVES WITH THEIR OWNERS. SO, INTERESTING PLATFORM FOR DEVICE DEVELOPMENT. >> THANK YOU. WE HAVE QUITE A GREAT PANEL WITH A LOT OF EXPERTISE HERE. I'M TRYING TO FRAME A FEW BROAD QUESTIONS TO GET THE DISCUSSION GOING. AND THEY ARE BROKEN INTO TWO BROAD AREAS. ONE IS USING PRE-CLINICAL MODELS TO INVESTIGATE MECHANISMS OF EPILEPTOGENESIS AND THE OTHER IS USING THESE MODELS OBVIOUSLY FOR INVESTIGATING THERAPEUTIC OPPORTUNITIES AND TESTING THERAPIES. AND SO I WANT TO MAYBE START A LITTLE BIT WITH THE MECHANISTIC SIDE. I THINK THAT AGAIN JUST ONE KIND OF BROAD QUESTION WHICH WAS SORT OF HINTED AT IN SOME OF THE INTRODUCTORY MATERIAL FROM AMY WAS SOME OF THE MODELS PROBABLY ARE NOT IDEAL FOR EVALUATING CERTAIN TYPES OF COMORBIDITIES, IN ADDITION TO SEIZURES. SO SOME OF THE FOLKS ON THE PANEL THAT ARE INVESTIGATING LARGER ANIMAL MODELS I WOULD LIKE A LITTLE BIT OF DISCUSSION ABOUT HOW YOUR MODELS REPLICATE NON-CONVULSIVE COMORBIDITIES SEEN IN HUMANS. >> DO YOU WANT ME TO START? >> IT'S A GREAT QUESTION. ONE REASON WE DEVELOPED THE PIG MODEL WAS TO BEGIN TO LOOK AT COGNITIVE ASPECTS OF BOTH ROTATIONAL AND CONTUSION INJURY, AND SO ONE OF THE THINGS WE'VE BEEN WORKING HARD ON OVER THE PAST FEW YEARS IS DEVELOPING TASKS FOR THOSE ANIMALS THAT ARE HIGH ORDER, EPISODIC MEMORY. WE'VE ADAPTED A CONDITIONAL ASSOCIATION TASK USING TOUCH SCREENS WITH THE PIGS ORIGINALLY MRI BASED. WE'VE GOTTEN SOME FUNDING FROM THE V.A. WHERE WE CAN BASICALLY TRAIN THE ANIMALS TO DO THIS TASK AND INDUCE THE TBI, WATCH EPILEPSY PROGRESS AND SEE WHETHER THE NEURODEGENERATION AND/OR THE EPILEPSY IS LEADING TO CHANGES IN THE COGNITIVE PERFORMANCE ON THOSE TASKS. DEFINITELY SOMETHING THAT WE'RE HOPING TO TACKLE WITH THIS MODEL, ONE OF THE REASONS WE MOVED TO HIGH ORDER ANIMALS FOR THIS. WE'VE DONE SOME OTHER WORK WITH SPATIAL TASKS SUCH AS WHOLE BOARD WHERE THE PIGS WILL ROOT FOR THE RAISINETTES IN HIDDEN BOWLS, YOU CAN SEE HOW LONG IT TAKES FOR THE PIG TO REVERSE AND PICK UP THAT AGAIN. THE PROBLEM WITH THAT TASK WAS PIGS ARE SO GOOD AT THAT, THAT EVEN WITH A CCI OR ROTATIONAL INJURY AND PROBABLY EPILEPSY THEY WERE CAPABLE FINDING OUT WHERE THE OTHER FOUR RAISINETTES WERE, THAT'S WHY WE MOVED TO THE MORE COMPLEX TASK, YOU HAVE TO HAVE COMPLEX TASKS TO DETECT DIFFERENCES IN THESE TYPES OF ANIMALS, SO THAT'S WHERE WE ARE. >> WE'VE NOT DONE MUCH WITH COGNITIVE OR BEHAVIORAL TASK IN DOGS, ALTHOUGH AS MOST OF YOU REALIZE THERE'S A HUGE LITERATURE AROUND IT, A REALLY RICH OPPORTUNITY. WE'VE PUT WORK WITH CANINES HOW BRAIN STIMULATION AFFECTS SLEEP AND BEHAVIOR, BUT, AGAIN, IT'S PRETTY RUDIMENTARY AT THIS THIS POINT. GIVEN HOW INTELLIGENT DOGS ARE, THEIR ABILITY TO BE TRAINED, I THINK IT'S A RICH OPPORTUNITY, AS JOHN SAID. >> THIS IS WORK, I WANT TO SAY, THAT TIM ALLEN AT F.I.T. HAD DONE, WE BROUGHT HIM TO PENN, TO GIVE HIM CREDIT. >> IN THE BABOONS WE'VE DONE RUDIMENTARY TESTS, VERY LITTLE PUBLISHED. THERE ARE DEFINITE BEHAVIORAL DIFFERENCES BETWEEN THE EPILEPTIC BABOON AND BABOONS THAT ARE WITHOUT EPILEPSY. BABOON-- EPILEPTIC BABOONS ARE LESS AGGRESSIVE, LOOK A LITTLE BIT MORE INTROVERTED, SO THEY DO HAVE DIFFERENCES IF YOU TEST ON TEMPERAMENT TESTING, IF YOU LOOK, FOR EXAMPLE, AT THE HUMAN CONFRONTATION TESTING THAT THEY HAVE DIFFERENT RESPONSES BUT WE HAVEN'T REALLY DONE HIGHER COGNITIVE TESTING, OF COURSE IT'S SOMETHING THAT SHOULD BE DONE AND I HAVEN'T BEEN GEARED UP FOR THAT TYPE OF WORK SO FAR AND HAVEN'T HAD COLLABORATION EITHER BUT I THINK IT'S FASCINATING AND NEEDS TO BE DONE. >> NOT TO EXCLUDE OUR RODENT COLLEAGUES, CERTAINLY THERE IS A RICH ARRAY OF NEUROBEHAVIOR ASSAYS DONE ROUTINELY IN MICE, PROBABLY IN RATS AS WELL. AND I'M CURIOUS, KAREN, IN YOUR SCREENING PARADIGMS ARE THERE NON-CONVULSIVE OUTCOMES YOU ROUTINELY INTERROGATE? >> SO, WHAT WE ARE USING IS A TRADITIONAL IRWIN FUNCTIONAL OBSERVATION BATTERY FOR MANY COMPOUNDS, INTRODUCED OVER THE LAST COUPLE YEARS INTO OUR PROGRAM. THAT LOOKS AT A VARIETY OF AUTONOMIC RESPONSES, TOLERABILITY ISSUES, THE LIKE. WE DABBLED IN THAT SEVERAL YEARS AGO, OUR ADVISORY COMMITTEE, CONSULTANT BOARDS AND NINDS FELT IT WAS MORE IMPORTANT TO FOCUS WITH LIMITED RESOURCES ON SEIZURES, PER SE. WE LOOK AT TOLERABILITY ISSUES, SEDATION, BUT WE'RE CURRENTLY LOOKING AT COMORBIDITIES AT THIS POINT WITHIN THE PROGRAM. >> IN RATS AND MICE OUTSIDE OF ETSP THERE ARE BEHAVIORAL TASKS THAT CAN BE DONE TO ASSESS PRIMARILY COGNITION. YOU KNOW, MEMORY, MULTIPLE ASPECTS OF MEMORY CAN BE PRETTY EASILY ASSESSED. SOME ASPECTS OF SOCIABILITY CAN BE ASSESSED, A NUMBER OF RODENT MODELS FOR AUTISTIC BEHAVIOR, BUT THEY ARE LIMITED. THE SOCIAL BEHAVIORAL, OUR ABILITY TO ASSESS IN RODENTS IS MUCH MORE LIMITED THAN IT IS IN HIGHER ANIMALS. I THINK WE DO A GOOD JOB ASSESSING SPATIAL MEMORY IN RODENTS BUT I THINK CERTAINLY LANGUAGE AND SOCIAL BEHAVIOR CAN BE ASSESSED BUT IT'S LIMITED. >> HOW WELL DID THESE BEHAVIORS TRANSLATE TO HUMANS IN RESPONSE TO DRUGS AND SUCH? HAS THERE BEEN ANY GOOD EXAMPLES OF DRUG THERAPIES THAT IMPROVE THESE COMORBIDITIES IN A MOUSE MODEL OR ANY OTHER MODELS THAT HAVE BEEN SHOWN TO TRANSLATE? >> I DON'T THINK WE'RE GOING TO KNOW. SO THE ANSWER IS TO DATE, NO, BUT I DON'T THINK WE'RE GOING TO KNOW THE ANSWER TO THAT UNTIL WE GET OUR FIRST SUCCESSFUL THERAPY THAT DOES IMPROVE COGNITION OR SOCIAL BEHAVIORAL OR LANGUAGE IN PATIENT WITH EPILEPSY. WE DON'T HAVE THAT YET, WE DON'T HAVE TRUE VALIDITY IN ANYTHING WE'RE SEEING IN OUR RODENT MODELS. BUT THAT WOULD BE THE HOPE THAT WE'LL BE ABLE TO IDENTIFY SOME THERAPIES IN RODENT MODELS, POTENTIALLY TAKE THEM INTO PATIENTS WITH EPILEPSY AND THEN DETERMINE THE POTENTIAL VALIDITY OF ANYTHING WE SEE IN THE RODENTS. I THINK ONE OF THE THINGS THAT WILL HELP WITH THIS POTENTIALLY IS MAYBE NOT IN RODENTS BUT MORE IN THE DOGS, PIGS, BABOONS IS FUNCTIONAL IMAGING, IF WE CAN GET FUNCTIONAL IMAGING CORRELATES OF, YOU KNOW, DIFFERENT BEHAVIORAL TASKS THAT WE COULD ALSO LOOK TO SEE IF THERE'S SIMILAR FUNCTIONAL IMAGING CORRELATES IN HUMANS WITH EPILEPSY, THAT MAY HELP US TO ANSWER THESE QUESTIONS MUCH MORE EFFICIENTLY. >> SO, I LOOK AT THE BEHAVIOR AGAINST THE MODEL A LITTLE BIT MORE BROADLY. SO, WITH THE PERSPECTIVE THAT THE GENETIC MODEL CAUSES THE PHENOTYPES, PHENOTYPES OF SEIZURES, AND A VARIETY OF COMORBIDITIES, AND TO TEST FOR THEM BROADLY, BUT WORKING TOWARDS FINDING OUT WHAT DOES THE MOUSE VERSION OF THAT DISEASE REALLY LOOK LIKE. I UNDERSTAND FOR MANY COMORBIDITIES IT WILL NOT BE A DIRECT MATCH, BUT IT IS A REFLECTION OF THE GENETIC DEFECT IN THE RODENT, AND WITH RESPECT TO THE DRUGS, IF WHAT I CAN GATHER SO FAR THE GENETIC THERAPIES DO RESCUE COMORBIDITIES AND SEIZURES TO VARYING DEGREES. [ VIDEO DISTORTION ] THE SAME MAY NOT BE TRUE YET. >> THANK YOU, WAYNE. YOU WERE BREAKING UP AT THE END BUT WE GOT THE GIST, TRYING TO EMPHASIZE THERE HAVE BEEN EXAMPLES OF GENETIC THERAPIES AND MOUSE MODELS THAT DO AMELIORATE NON-CONVULSIVE COMORBIDITIES. THANKS. OKAY. I'M ALSO MONITORING THE CHAT HERE. THERE'S A GREAT QUESTION I THINK THAT WOULD BE WORTH DISCUSSING WHICH IS SOME MOUSE MODELS, WE'RE STILL ON RODENTS, FOR SOME GENES EITHER DON'T DEVELOP SEIZURES OR DEVELOP VERY MILD SEIZURES. WHAT ARE THE CURRENT -- WHAT ARE THOUGHTS AND PANEL ABOUT WHY THAT MIGHT BE THE CASE, WHAT ARE THE SORT OF COMMON REPORTED MECHANISMS FOR EXPLAINING THAT, LACK OF PHENOTYPE? AND THERE'S A LOT OF EXAMPLES WHERE THE HETEROZYGOUS MUTATION IN HUMAN IS ASSOCIATED WITH SEVERE EPILEPTIC ENCEPHALOPATHY FOR EXAMPLE BUT IN MICE YOU HAVE TO MAKE HOMOZYGOUS ANIMALS, ANY THOUGHTS ABOUT THAT? >> I STRUGGLE WITH THAT CERTAINLY. I THINK WE ALSO SEE THAT IN ACQUIRED EPILEPSY MODELS AS WELL. FOR EXAMPLE, IN OUR TYLER'S MURINE VIRUS MODEL THAT WE USE, INFECTION DISEASE MODEL OF EPILEPSY, IT WORKS, CAUSES MOST SEIZURES IN BLACK 6 J MICE, AND SO THERE'S A STRAIN DEPENDENT DIFFERENCE, IT CAUSES MULTIPLE SCLEROSIS PHENOTYPE IN OTHER MICE, AND JENNIFER'S WORK LOOKS AT THIS, A LOT TO BE SAID ABOUT BACKGROUND STRAINS FOR HYPEREXCITABILITY, WHETHER MUTATION IS ON THE CORRECT BACKGROUND. THAT CERTAINLY IS SOMETHING TO BE CONSIDERED WITH THE RODENT MODELS, MAYBE WAYNE HAS SOMETHING MORE PRECISE THAN ME BUT IT DOES HAPPEN IN ACQUIRED EPILEPSY MODELS AS WELL. >> WELL, I MEAN, CERTAINLY SOME SEIZURE PHENOTYPES ARE TOO RARE OR NON-EXISTENT TO EITHER MEASURE IN A MOUSE, AGAIN, SO LOOKING FOR ANY PHENOTYPE CAUSED BY GENETIC DEFECT, AMELIORATING THAT IS A STEP FORWARD. GENETIC BACKGROUND, YEAH, I MEAN JENNIFER, WE AND OTHER GROUPS WORKED ON THIS FOR A NUMBER OF YEARS, SOME PROGRESS HAS BEEN MADE IN IDENTIFYING BOTH MODIFIERS AND DIFFERENT BACKGROUNDS. BUT I THINK PREDICTABILITY OF WHICH BACKGROUND AND WHICH MODIFIER THAT'S GOING TO IMPACT, WHICH KIND OF EPILEPSY WITH GENETIC ONES IS NOT THERE, AND THERE ARE MANY DIVERSE MOUSE STRAINS AVAILABLE NOW, AND YOU CAN DO CRISPR IN PRINCIPLE IN ALL OF THEM, BUT CAN YOU REALLY [ AUDIO DISTORTION ]. >> YOU'RE BREAKING UP, WAYNE. >> SEIZURE REDUCTION, YOU KNOW. I'M GOING TO TURN OFF MY VIDEO. >> THAT'S PROBABLY A GOOD IDEA. BACK UP AND SAY WHAT YOU DID THE LAST 30 SECONDS. WE GOT MOST OF IT. >> YEAH, SO I FORGOT WHAT I WAS SAYING. ISN'T IT AWFUL? >> THAT'S OKAY. >> GENETIC MODIFIERS. >> YEAH, SO IT'S NOT REALLY EASY TO SCREEN ALL OF THOSE 20 OR SO DIFFERENT STRAIN BACKGROUNDS TO FIND THE ONE THAT WORKS, OR THAT MAKES ANY DIFFERENCE. WE TRIED THIS ON A SMALL SCALE WITH GABA 2 SUBUNIT OF GABA RECEPTOR A FEW YEARS AGO AND LOOKED AT FIVE VERY DIFFERENT STRAINS AND THERE WERE SUBTLE DIFFERENCES. WHEN YOU SEE THEM, THEY CAN BE STRONG BUT USING THAT IS A CHALLENGE AND IT'S A SCALE CHALLENGE. >> WELL, AND SPEAKING OF GENETIC MODEL SYSTEMS DROSOPHILA AND ZEBRAFISH ARE WIDELY USED GENETIC MODELS. IS THE GENETIC BACKGROUND IMPORTANT FOR YOUR MODELS? >> CAN I GO? >> YES PLEASE. >> SO, YEAH, IF YOU'RE INTERESTED IN -- SO EPILEPSY IS A COMPLEX DISEASE INVOLVING COMPLEX GENE AND ENVIRONMENT INTERACTIONS, AND WE ARE USING FRUIT FLIES BECAUSE WE CAN DO STRONG PIE PHYLO GENETIC SCREENING, STARTING WITH MUTANTS, KNOWN EPILEPSY GENE, ADDITIONALLY INDUCE MUTATION TO SEE THAT MUTATION CAN ENHANCE OR SEPARATE ORIGINAL PHENOTYPE. AND BY -- SO FAR GENETICS IS INBIASED STRATEGY SO IT CAN BE POWERFUL DRIVING FORCE FOR UNCOVERING NEW GENES AND BIOLOGICAL PATHWAYS IMPORTANT FOR EPILEPSY. OF COURSE, THAT GENE IDENTIFIED IN FLIES MAY NOT ALWAYS (INDISCERNIBLE) WITH HUMAN EFFORTS BUT CAN PROVIDE CANDIDATE GENE THAT CAN BE TESTED IN OTHER SYSTEMS. SO IN THAT CASE, I THINK TO MAKE FLY RESEARCH USEFUL FOR EPILEPSY RESEARCH IS GOOD COLLABORATION BETWEEN RESEARCHER, FLY RESEARCHERS WITH RESEARCHERS WHO USE MORE MODEL SYSTEM RELATED TO HUMAN EPILEPSY. >> IN ZEBRAFISH WE'RE DEFINITELY SEEING GENETIC BACKGROUND EFFECTS. SO A FEW YEARS AGO THERE'S BEEN SOME NICE BEHAVIORAL WORK, TO LOOK AT SOME OF THE MOST COMMONLY USED WILDTYPE STRAINS OF ZEBRAFISH, AND THEY HAVE PRETTY -- LIKE IN MICE, PRETTY DIFFERENT BEHAVIORAL PROFILES. SO IT IS SOMETHING THAT IS WORTH KEEPING IN MIND, WHEN PERFORMING GENETIC ANALYSIS USING ZEBRAFISH. I THINK, PERHAPS WE'LL GET TO THIS LATER ON, ONE OF THE BIGGEST MYSTERIES THAT I'VE BEEN THINKING ABOUT WITH ZEBRAFISH IS FREQUENTLY MAKING MUTANTS, MUTATIONS IN GENES THAT ARE VERY WELL CONSERVED, THAT HAVE PROMISING EXPRESSION PROFILES IN ZEBRAFISH, MEANING THEY ARE EXPRESSED AT HIGH AMOUNTS IN THE ZEBRAFISH BRAIN, BUT NOT SEEING CLEAR PHENOTYPES. AND I THINK THAT'S ALSO -- THERE COULD BE COMMON MECHANISMS BEHIND SOME OF THE LACK OF PHENOTYPE IN ZEBRAFISH, AND ALSO WHAT IS SEEN IN OTHER SYSTEMS LIKE MICE. I THINK THERE'S NICE WORK COMING OUT AND TRYING TO EXPLAIN WHY WE SOMETIMES AREN'T SEEING PHENOTYPES WITH USING ZEBRAFISH. >> ULTIMATELY THE GENETIC VARIABILITY WE'RE MOST INTERESTED IN IS OF COURSE HUMAN GENETIC VARIABILITY. JACK, YOU'RE USING A SYSTEM THAT COULD AFFORD YOU THE LUXURY OF LOOKING AT MULTIPLE DIFFERENT INDIVIDUALS, PERHAPS WITH THE SAME MUTATION OR DIFFERENT MUTATIONS, WHAT'S BEEN YOUR EXPERIENCE OBSERVING VARIABILITY AMONG LINES? >> SO, THERE'S A LOT OF GENETIC VARIABILITY WITH HUMAN PLURIPOTENT STEM CELLS WHICH MAKES USE OF ISOGENIC CONTROLS VERY IMPORTANT. AND WHAT YOU GET REALLY EXCITED, WE SEE A PHENOTYPE IN MULTIPLE LINES FOR MULTIPLE PATIENTS THAT ALL HAVE THEIR OWN UNIQUE GENETIC BACKGROUND, AND WE DON'T SEE IT IN UNRELATED OR ISOGENIC CONTROLS SO IT'S PART OF THE VARIABILITY WE SEE. >> WHAT'S REQUIRED TO LOOK AT THE SAME GENETIC MUTATION IN OTHER LINESS THAT SOMETHING YOU THOUGHT ABOUT DOING? >> WE DO DO THAT AND FOR OUR PROJECTS NOW WE'RE TALKING ABOUT ALSO DOING IT IN MALE AND FEMALE LINES AS WELL. ANYTHING YOU CAN DO TO REDUCE VARIABILITY, BECAUSE EVEN THE SAME MATERIAL FROM THE SAME PATIENT, DIFFERENT LINES FROM THE SAME PATIENT WILL SHOW VARIABILITY, SO YOU NEED TO DO AS MUCH AS YOU CAN TO CONTROL THAT. >> SO I'LL GO BACK TO SORT OF ONE OF THE PROVOCATIVE QUESTIONS IN THE PREAMBLE TO THE SESSION, DO WE NEED NEW MODELS OSH ARE EXISTING MODELS SUFFICIENT? OR DO WE NEED TO SOMEHOW INTEGRATE ACROSS MODEL SYSTEMS TO SYNERGIZE WHAT WE LEARN? >> YES AND YES. WE CAN ALWAYS USE NEW AND BETTER MODELS BUT I THINK IT'S REALLY IMPORTANT TO COMBINE DIFFERENT MODELS. THERE WAS A DISCUSSION IN THE CHAT ABOUT USING DIFFERENT MODELS FOR MECHANISM VERSUS COMORBIDITY AND I THINK ALSO TO VALIDATE STRENGTH OF PHENOTYPE IF YOU SEE IT IN DIFFERENT MODELS THAT STRENGTHENS YOUR CONFIDENCE SO I THINK THERE ARE DIFFERENT REASONS TO USE MULTIPLE MODELS. WAYNE'S BEEN LOOKING TO SAY SOMETHING. >> YEAH, I THINK IT WOULD BE HELPFUL, WE MAY NOT BE ABLE TO -- >> YOU'RE BREAKING UP AGAIN. >> MAY NOT BE ABLE TO -- WE MAY NOT BE ABLE TO UNDERSTAND WHY BUT IT WOULD BE USEFUL TO TRY TO UNDERSTAND. I'M NOT PUSHING FOR THIS BUT WHY, WE DON'T SEE SEIZURES IN, FOR EXAMPLE, MOUSE MODELS MODEL ORTHOLOGOUSLY A HUMAN DISEASE, DEVELOPMENT IS MUCH FASTER, EARLIER IN MOUSE. MICE DON'T LIVE LONG ENOUGH TO DEVELOP CERTAIN PATHOLOGIES. MAYBE THERE ARE OTHER EXPLANATIONS WE DON'T KNOW LEAK OVERRIDING INHIBITION THAT TAKES OVER AS THE MICE AGE. SO TO KNOW MORE ABOUT THAT COULD REALLY HELP INFORM US WHICH MODELS WE MIGHT CHOOSE AND/OR HOW TO RESOLVE SOME ISSUES IN THE MOUSE WE HAVE. YOU KNOW, RODENTS LACKING GYRI NOT WITH STANDING, I UNDERSTAND THAT OF COURSE. BUT IT WOULD BE NICE TO UNDERSTAND MORE OF THAT AND SOME OF IT SEEMS OBVIOUS, DEVELOPMENT IS FASTER AND EARLIER, BUT SOME MAY NOT BE SO OBVIOUS. >> A LOT OF INTERESTING QUESTIONS AND COMMENTS IN THE CHAT. I'M GOING TO VISIT THEM. I THINK WHEN WE BROUGHT UP THE QUESTION WHETHER WE NEEDED NEW MODELS, I NOTICE LORI POSTED THEY ARE DEVELOPING A NEW ZEALAND WHITE RABBIT WITH THE GERVASE MODEL, NOT OBSERVING SEIZURES IN THAT MODEL, QUITE INTERESTING. WHAT OTHER MODELS HAS ANYONE ON THE PANEL CONCEIVED OF OR HEARD OF AND THOUGHT OF THAT MIGHT BE VALUABLE IN THIS CONTEXT? >> OH BOY. >> KAREN, MUST HAVE EVALUATED A LOT OF THINGS. >> IN OUR PROGRAM WE MOVED TRYING TO IMPLEMENT MORE MODELS WITH SPONTANEOUS SEIZURES, A LONG CRITICISM OF THE SCREENING PROGRAM THAT WE USED MOSTLY ACCUSE SEIZURES. WE'RE TRYING TO ALWAYS EVOLVE AS PEOPLE COME ALONG WITH NEW MODELS, AND I THINK THE BENCHMARKS HAVE BEEN HELPFUL IN THAT REGARD BECAUSE THERE'S SO MANY ETIOLOGIES THAT WE HAVE FOR ACQUIRED EPILEPSIES AT ANY RATE, THINGS LIKE STROKE AND INFECTION AND STATUS AND THE LIKE. AND THE MORE MODELS WE GET TO KIND OF HONE IN ON THOSE ACQUIRED EPILEPSIES I THINK THE MORE INFORMATION WE CAN GATHER. I THINK THE OTHER THING I WANT TO POINT OUT, SOMETHING THAT HAS BEEN RAISED A FEW TIMES, THE ISSUE OF REPRODUCIBILITY. AND IN OUR PROGRAM WE'RE TRYING TO DO THAT. WE HAVE A SUBCONTRACT TO SEE -- UNIVERSITY OF WASHINGTON TO LOOK AT SOME OF THE NOVEL INVESTIGATIONAL COMPOUNDS TO SEE IF THEY BEHAVE SIMPLIFY SIMILARLY, DIFFERENT ALTITUDE, DIFFERENT HUMIDITY, DIFFERENT INVESTIGATORS, DIFFERENT SUPPLIERS, THE DATA HAS BEEN COMING BACK WELL. THE OTHER THING IS THE NEED FOR PRE-CLINICAL WORK, THINK ABOUT COMMON DATA ELEMENTS, CHANGING THE CONVERSATION BUT THE TRANSLATIONAL TASK FORCE CAME OUT WITH RECOMMENDATIONS IN THE EARLY 2010s, SUGGESTING THAT COMMON DATA ELEMENTS AND PRE-CLINICAL WORK WITH BE IMPORTANT SO PEOPLE CAN HOPEFULLY REPLICATE WHAT WE'VE DONE AS WELL. THAT'S ANOTHER AREA OF HOW TO REFINE THE ANIMAL MODELS WE DO HAVE. AND TRY TO LIMIT VARIABILITY WHEN IT'S POSSIBLE. NEW MODELS AS NEW MECHANISMS ARE UNDERSTOOD. >> COMMON DATA ELEMENTS, ARE YOU REFERRING TO THINGS LIKE ARRIVE GUIDELINES AND SUCH OR SOMETHING ELSE? >> YEAH, SO PUBLISHED A SERIES IN EPILEPSY CURRENT OR A SUPPLEMENT WHICH KIND OF DISCUSSED LIKE THE KINDS OF THINGS YOU WOULD WANT TO THINK ABOUT, DATA SHIPMENT ARRIVED, WHEN DID THE ANIMALS FIRST COME TO THE LABORATORY, WHEN DID YOU START THE PROCESS OF INJECTING THEM BEFORE YOU GAVE THEM A DRUG, WHAT'S THE TEMPERATURE, WHAT'S THE INVESTIGATOR, THINGS YOU KEEP IN A NOTEBOOK BUT SYSTEMATIC, HOW IS THE DRUG MADE, WHAT WAS THE VEHICLE, LOTS OF THESE COMMON DATA ELEMENTS THAT ARE USED IN CLINICAL TRIALS, HOW CAN YOU RELATE THOSE TO PRE-CLINICAL WORK AS WELL. THAT'S SOMETHING THAT'S BEEN PUBLISHED ON A NUMBER OF OCCASIONS FROM THE TASK FORCE WORKING GROUP. I WOULD ENCOURAGE PEOPLE TO TAKE A LOOK AT THAT. >> ON THE TOPIC OF REPRODUCIBILITY, THERE'S BEEN A PUSH OR SUGGESTION I SHOULD SAY THAT ANIMAL CLINICAL TRIALS OF NEW THERAPEUTIC AGENTS OR PARADIGMS SHOULD BE HELD TO A SIMILAR STANDARD AS HUMAN CLINICAL TRIALS WHICH INCLUDES PRE-REGISTERING THE STUDY IN SOME FORM OR FASHION, MEANING THAT YOU PROPOSE THE STUDY TO THE Nth DEGREE WITH ALL OF THE -- WITH ALL OF THE THOUGHT PROCESS BEHIND RATIONALE STUDY DESIGN, THE SAMPLE SIZE CALCULATION, EVEN STATISTICAL ANALYSIS AND OUTCOMES, AND YOU PARK THAT SOMEWHERE THAT'S PUBLICLY AVAILABLE, AND THEN YOU HOLD YOUR FEET TO THE FIRE. YOU DON'T DEVIATE FROM THAT IN SOME WAY. AND SO HAS THAT CREPT INTO ANYONE'S WORK AT THIS POINT? AGAIN, I'M KIND OF HOVERING AROUND THE RODENT PEOPLE BUT DOESN'T HAVE TO BE REQUIRED. GO AHEAD. >> HI. YES, SPEAKING OF NEW MODEL, HAS ANYBODY HEARD ABOUT THE NATIVE MOLE RAT FOR EPILEPSY RESEARCH? THE NAKED MOLE RAT IS VERY ORDINARY SPECIES, AND THEY DON'T HAVE CANCER AND THEY ARE VERY RESISTANT TO OXIDATIVE STRESS. AND MAYBE WE CAN INCREASE TO INTRODUCE SEIZURE-RELATED MUTATION IN THAT ANIMAL, AND IF THEY DON'T SHOW SEIZURE MAYBE WE CAN STUDY WHY THEY DON'T SHOW SEIZURE. SO I THINK IT'S A GOOD IDEA TO TEST VERY UNUSUAL MODEL, TEST THE EPILEPSY. I CANNOT DO THAT BUT SOMEBODY MAY DO IT. >> YEAH, IN THE ERA WE'RE IN NOW WITH GENOME EDITING BEING SO EFFICIENT, WHETHER WE SHOULD BE CLIMBING UP THE PHYLOGENETIC TREE TO TRY TO MAKE KNOCK-IN MUTANTS IN LARGER ANIMALS. WHEN GREG WAS TALKING ABOUT THE DOG MODEL, AND I HAD THIS THOUGHT WHEN AMY WAS PRESENTING ON DOGS, WHAT DO WE KNOW ABOUT GENETICS OF DOG EPILEPSY? >> YEAH, NOT A GREAT DEAL, BUT IT'S ALWAYS SURPRISING TO ME HOW SIMILAR IT IS TO HUMANS. NED PATTERNSON LOOKED IN DETAIL AND DOGS COMING INTO THE CLINIC, DIDN'T FIND A GREAT DEAL BUT CLEARLY THERE ARE BREEDS OF DOGS AND FAMILIES OF DOGS THAT CLEARLY HAVE A GENETIC COMPONENT. I MEAN, AND SO THAT'S BEEN REASONABLY WELL BORNE OUT, JUST LIKE IN HUMANS. BUT TH MAJORITY OF DOG WITH EPILSY, MORE SRADICALLY OCCURRING, NO MILY HISTORY, IF YOU WI, OR HAVE A BRAIN TOR OR GOT HIT BY A CAR OR THE WHOLE LITTER GOT A VIRAL ENCEPHATIS, SO, YOU KNOW, IT'S REALLY INTESTING IN THAT REGARD. SO I TNK JUST LIKE WITH HUMAN EPILEPSY, THERE ARE MANY CAUSES AND IT'S -- YOU KNOW, OFTEN HARD T SORT THAT OUT. SOMEONE HAD A -- WHAT ABOUT THE ETHICS OF DNG LARGE ANIMAL TRIALS? I THINK THAT WAS -- BUT IN THESE NATURALLY CURRING EPILEPSIES IT AN INTERESTING OPPORTUNITY. THEIRST DOG THAT WE PUT ANTERIORUCLEUS BRAIN STIMULATOR, THE OER WANTED T KNOW IS THIS DANROUS? WE'VTRIED IT ON A FEW THOUSAND HUNS, IT SMS TO WORK. MAYBWE CAN MAKE SOME PROGRESS WITH YOUR DOG, REVERSE TRANSLATION, IF YOU WILL. THERE ARE SOM REALLY RICH OPPORTUNITIES THERE. OCCURRING EPILEPSIES, AS JOHN POINTED OUT EPIPSY MODELS. >> EVEN IF THERE WERE ONE OR TWO LARGER PRIMATES IN THREE OR FOUR OR FIVE, O COULD MAKE AN INSTMENT IN MAKING A GENETICALLY ORTHOLOGOUS MODEL, THAT COULD BE REALLY -- CERTAINLY I WOULD SAY WORTH OF EFFORT BECAUSE THERE'S SO MANY THINGS YOU COULD TEST IN THOSE WITH RESPECT TO AT LEAST GENETIC THERAPIES, DELIVERY SIZE, DO YOU HAVE ENOUGH VIRUS, INTRATHECAL GOOD ENOUGH FOR ASOs? SO CERTAINLY AN ARGUMENT FOR SOME INVESTMENT MAY BE SIGNIFICANT TO ASK A FEW QUESTIONS WE NEED TO KNOW FOR OTHER REASONS. >> YEAH, I THINK THE THERAPY QUESTIONS, THE NEED FOR LARGE ANIMAL MODEL, ARE REALLY IMPORTANT, WHETHER IT BE SCOTT'S WORK WITH THE SEA LION, IT'S A NICE TRANSLATION TO SOMETHING THAT COULD BE A HUMAN THERAPY, SAME WITH BRAIN STIMULATION. IT'S GOING TO BE VERY DIFFERENT, LEARNING FROM RODENTS, SAY, VERSUS LEARNING FROM A LARGE MAMMAL. I AGREE, THAT'S IMPORTANT. WHETHER IT'S A GENETIC ETIOLOGY OR, YOU KNOW, AN ACQUIRED ETIOLOGY. >> I THINK THIS BRINGS US BACK TO SORT OF THE ORIGINAL POINT WHICH IS THAT WHICH MODEL IS BEST DEPENDS ON WHAT YOU'RE DOING, RIGHT? SO WE WERE TALKING ABOUT, AL, YOU BROUGHT UP REGISTERING STUDIES, DOING DOUBLE BLIND STUDIES FOR PRE-CLINICAL THERAPEUTIC TRIALS. EVEN IN RODENTS THAT IS HUGELY EXPENSIVE TO DO THOSE TYPES OF STUDIES. IF YOU TRIED TO BRING THAT IN TO A PRIMATE OR EVEN A DOG MODEL, YOU WOULD NEED HUNDREDS EVER ANIMALS TO DO THAT EFFECTIVELY. SO, THERE'S CERTAINLY -- WE CERTAINLY SHOULD BE DOING I THINK MORE IN LARGER ANIMALS, BUT I THINK WE HAVE TO BE VERY SELECT ABOUT WHICH STUDIES WE TAKE INTO THEM AND I DON'T THINK I WOULD JUMP OVER RODENTS AT LEAST IN THOSE INITIAL TOXICITY AND EFFICACY STUDIES WHERE ALTHOUGH EXPENSIVE AND DIFFICULT, YOU CAN DO HUNDREDS OF ANIMALS WITH, YOU KNOW, 15 TO 25 TO 30 OR MORE ANIMALS PER GROUP IN A CONTROLLED BLINDED FASHION, WHICH I JUST CAN'T IMAGINE WOULD BE FEASIBLE IN DOGS, PIGS, OR BABOONS. >> IT'S MOSTLY RODENT STUDIES PEOPLE POINTED OUT AS BEING PARTLY RESPONSIBLE FOR THE IRREPRODUCIBILITY OF SOME CLINICAL DATA, PRE-CLINICAL DATA. I THINK THAT'S WHERE THIS PRE-REGISTRATION ISSUE HAS BEEN BROUGHT UP. >> I THINK THAT'S VERY -- PRE-REGISTRATION MAKES A LOT OF SENSE AND IT DOES HOLD PEOPLE'S FEET TO THE FIRE, AND IT WOULD MAKE IT A LOT EASIER, ARGUMENT AFTER ARGUMENT WITH POSTDOCS, WHY THEY HAVE TO BE BLINDED. THERE'S A LOT OF ADVANTAGE TO PRE-REGISTERING TO MAKE SURE YOU'RE DOING EVERYTHING AS EFFECTIVELY AS POSSIBLE. >> RIGOR IS STILL AN ISSUE WITH OTHER STUDIES, EVEN SEIZURE STUDIES, BEHAVIORS, EVEN CEOs PAID LOTS OF MONEY TO DO THIS, STATISTICS. >> I WAS NOTICING SOME BABOON-RELATED AND ALSO I THINK GREG MENTIONED THAT ALSO WITH THE ETHICAL ISSUES. YES, INDEED I THINK IT'S VERY DIFFICULT TO MANAGE I THINK A LARGER ANIMAL OR NON-HUMAN PRIMATE WHO HAS VERY BAD EPILEPSY WITHOUT -- AND JUST DO OBSERVATIONAL OR NATURAL HISTORY STUDY AND THEN WHERE YOU KNOW THEY ARE INJURING THEMSELVES, YOU KNOW, THEY ARE OF COURSE NOT JUST -- THEY ARE AT RISK FOR A LOT OF COMPLICATIONS, EVEN SOCIAL PROBLEMS, SOCIAL ISOLATION. SO IT IS I THINK A VERY GOOD QUESTION ABOUT THE ETHICAL AND SETTING IS VERY IMPORTANT, OF COURSE, WHAT GREG MENTIONED, THAT HE HAS MANY OF HIS DOG STUDIES INVOLVED DOGS AT HOME. OF COURSE THOSE ANIMALS ARE BEING TREATED VERY WELL, BEING OBSERVED VERY CLOSELY. BUT I THINK THAT'S AN ISSUE. OF COURSE WE DO HAVE TO PAY ATTENTION TO THAT QUITE A BIT. YOU NEED TO HAVE A VERY RESPONSIVE VETERINARY GROUP FOR THAT. THE OTHER QUESTION WAS IS THE GENETICS FIGURED OUT FOR THE BABOON, WE'RE JUST RIGHT NOW FINALLY PUBLISHING A PAPER, BASICALLY SUBMITTING IT, IT'S IN THE FINAL WORKS, WE SAW THAT THERE WAS A STRONG ASSOCIATION WITH THE RB FOX 1 GENE, THE GENE SEEN AS SUSCEPTIBILITY GENE, ALSO IN HUMAN GENERALIZED EPILEPSIES, FOCAL AND GENETIC. GENERALIZED EPILEPSIES. AND WE SEE ALSO QUITE A FEW -- STRONG ASSOCIATION OF PROTEIN DAMAGING SNPs, INVOLVED IN NEURODEVELOPMENTAL ASPECTS. SO JUST TO ANSWER THAT QUESTION. >> THANK YOU. I'M CURIOUS, JOHN, WITH WORKING ON PIGS WHETHER YOU FACE THE SAME ETHICAL QUANDARIES AS PEOPLE WORKING ON NON-HUMAN PRIMATES AND DOGS BECAUSE PIGS ARE MORE OR LESS IN THE FOOD CHAIN. >> VERY GOOD QUESTION. HAPPY TO ADDRESS IT. WE WERE CONCERNED IN THE BEGINNING TO ADDRESS THE POINT RAISED, CONCERNED IN THE BEGINNING WHAT CLINICAL HEALTH OF THE ANIMALS WOULD BE AFTER WE DID THESE INJURIES AND WERE INTERESTED TO FIND THESE ANIMALS DEVELOP A PARTIAL EPILEPSY BEFORE THEY MOVE ON TO ANY TYPE OF GENERALIZED OR BEHAVIORAL SEIZURES. SO INTERESTINGLY THE TYPE OF INJURY WE'RE DOING, A UNILATERAL CORTICAL IMPACT LEADS TO A BEHAVIORAL SEIZURE THAT IS VERY MILD AND DOES NOT INITIALLY, YOU KNOW, TEND TO LEAD TO PROBLEMS FOR THE ANIMAL OR THE NEED FOR INTERVENTION. SO IF WE WERE TO TAKE THOSE ANIMALS OUT LONGER IT MIGHT PROGRESS TO SOMETHING MORE TONO CLONOI, 90% ARE PARTIAL EPILEPSIES, WE'VE BEEN AID ABLE TO MODEL. IT BECAME EVIDENT WE WERE NOT -- WE DID NOT HAVE TO BE AS CONCERNED ABOUT SOMETHING LIKE A SUDEP OCCURRING OFF HOURS, FOR EXAMPLE, BUT WE'RE MONITORING THESE PIGS ROUTINELY FOR A GREAT DEAL OF TIME. I THINK IT HELPS. TO ANSWER YOUR QUESTION, I DO THINK IT HELPS THE AN MILLIONS ARE IN THE FOOD CHAIN. FARMING STANDARDS ARE TERRIBLE, FACTORY FARMING, ET CETERA, OUR ANIMALS ARE EXTREMELY WELL CARED FOR AND WE DO AS BEST WE CAN TO TAKE CARE OF THE ANIMALS IN A WAY THE TECHNICIANS REALLY DO GET ATTACHED TO THEM. WE'RE DOING BEHAVIOR WITH THEM EVERY DAY, INTERACT WITH THEM, THEY HAVE SOCIAL INTERACTIONS WITH OTHER PIGS. WE FEEL STRONGLY THE WORK WE'RE DOING IS ETHICAL AND FRANKLY MORE ETHICAL THAN FORMING -- FARMING GOING ON RIGHT NOW. IT HELPS OUR POSITION BUT I THINK IT IS SOMETHING THAT SHOULD ALWAYS BE DISCUSSED AND SHOULD ALWAYS BE ACTIVELY ADDRESSED. >> THANK YOU. >> I WANTED TO MAKE A QUICK COMMENT COMING UP IN THE CHAT, GREG ALLUDED TO, PAUL BUCK MASTER LOOKING AT THE POISON SEA LIONS, A COMPLEX BRAIN, WITH THE GYRA AND VERY DEVASTATING SEIZURES ONCE THEY BECOME POISONED AND WOULD NEED TO BE OTHERWISE BE PUT DOWN, THAT'S ANOTHER AREA OF NATURALLY OCCURRING LARGE MAMMALS. >> WE'VE TALKED ABOUT MODEL SYSTEMS, IT'S COME UP THERE'S PROBABLY AN UNREALIZE THE OPPORTUNITY TO INTEGRATE ACROSS MODEL SYSTEM. I WANT TO GIVE KIM THE OPPORTUNITY TO GIVE US INFORMATION ABOUT THE WORK THAT YOU DESCRIBED IN CREATING MULTIPLE DIFFERENT SPECIES MODELS AND HOW SUCCESSFUL WAS IT TO GET INVESTIGATORS WORKING ON THOSE INDIVIDUAL MODELS TO SHARE THEIR RESULTS AND HOW DID YOU ENABLE THAT IF IT WAS SUCCESSFUL? >> YEAH, I THINK WE'RE LUCKY, WE HAVE THIS AMAZING GROUP OF INVESTIGATORS THAT'S BEEN EAGER TO COLLABORATE AND COMMUNICATE. WE HAVE PROJECTS LIKE WITH OUR iPSCs, ORGANOIDS THAT STAKEHOLDERRED, OUR iPSC PROJECT STARTED AT UNC, NOW GONE TO -- SENT TO AT LEAST HALF A DOZEN LABS, THE PROJECT FURTHER IN AUSTRIA. WE'VE BEEN LUCKY. WE HOST ANNUAL -- THIS IS A ROLE A LOT OF PATIENT ADVOCACY GROUPS ARE TAKING ON, REALLY SPURRING THAT COLLABORATION AND COMMUNICATION BETWEEN AND AMONG RESEARCHERS WHO ARE LOOKING AT MODEL SYSTEMS OF THE SAME DISEASE IN DIFFERENT ANIMALS OR MODELS AND I THINK THE ANNUAL RESEARCH ROUNDTABLES THAT SO MANY PATIENT ADVOCACY ORGANIZATIONS HOST, THAT'S REALLY ONE OF THE MAIN GOALS IS TO SHARE INFORMATION ABOUT THESE MODEL SYSTEMS FOR THEIR DISEASE. >> I KNOW THAT JACK IS FAMILIAR WITH THE GERVASE SYNDROME FOUNDATION, ONE OF THE THINGS THEY HAVE CATALYZED, ONE OF THE BENEFITS OF FOUNDATIONS DRIVING RESEARCH AS THEY BRING PEOPLE TOGETHER. >> THEY HAVE BEEN A MODEL ORGANIZATION FOR THAT. AND IT'S GOTTEN A BANG FOR THE BUCK GETTING RESEARCHERS INTERESTED IN GERVASE SYNDROME OVER THE LAST DECADE. BEEN DOING IT 11 YEARS. >> I'M GETTING QUESTIONS, DO OUR KIDS' LIVES DEPEND ON MICE? I'M CURIOUS TO HEAR WHETHER ANYONE ON THE PANEL HAS THOUGHTS ON THE IMPORTANCE OF THE MOUSE IN GENETIC EPILEPSIES. >> KAREN? >> I'M WRESTLING WITH THAT. I WOULD HOPE NOT, THAT THERE CAN BE STRATEGY -- ANOTHER EXAMPLE LOOKING AT FDA-APPROVED DRUGS USING DROSOPHILA OR ZEBRAFISH STRAIN, SCOTT AND HIS GROUP HAS GONE FROM ZEBRAFISH, FDA DRUGS INTO CLINICAL TRIALS IN PATIENTS WITH GERVASE SYNDROME, SETTING UP FOR CLINICAL TRIALS. THAT'S LEAPT RIGHT OVER MICE AND RODENTS, AND BY LOOKING AT ALREADY APPROVED DRUGS, CERTAINLY ANOTHER STRATEGY. >> I CAN IMAGINE WITH THE EMERGENCE OF GENETIC THERAPIES INCLUDING ASOs, THAT PROBABLY LANDING IN A MOUSE IS AS FAR UP THE PHYLO GENETIC TREE AS YOU CAN GO BECAUSE THE GENETIC DEFECT IS NOT THERE IN OTHER MODEL SYSTEMS. >> RIGHT. >> I WAS GOING TO COMMENT, WE'VE BEEN TALKING ABOUT THIS IN THE CHAT, PROBABLY STRONGLY AFFECTED BY MY NEIGHBOR IN MY OFFICE WHO STUDIES MARMOSETS, AND, YOU KNOW, MARMOSETS, AS FAR AS I UNDERSTAND, THIS IS NOT MY AREA OF EXPERTISE, COULD POSSIBLY OFFER THE ABILITY FOR SOME GENETIC AMENABILITY, FOR DIFFERENT CONDITIONS IN WHICH OTHER MODELS HAVE NOT WORKED BUT AS DISCUSSED IN CHAT THERE ARE A VARIETY OF ETHICAL CONCERNS BUT PROBABLY SOMETHING WORTH CONTINUING TO DISCUSS. >> MARMOSET MODELS COULD -- OF COURSE THEY DON'T HAVE NATURAL EPILEPSY BUT COULD BE AS YOU SAID FOR GENETIC INDUCED EPILEPSY, COULD BE VERY USEFUL BECAUSE THEY HAVE A VERY SHORT LONGEVITY, VERY FAST -- THEY HAVE A VERY FAST REPRODUCTION CYCLE, YEAH. >> I MEAN, ONE SUGGESTION, ONE POSSIBILITY TO TAKE A COUPLE OF WELL KNOWN -- >> WAYNE, TURN YOUR VIDEO OFF. >> TO TAKE SOME OF THE ONES BEST WELL KNOWN TO NOT HAVE, FOR EXAMPLE, SEIZURES OR SEIZURES THAT WE EXPECT IN, FOR EXAMPLE, MICE OR RATS, AND TRY THOSE IN A NUMBER OF MODELS. IT'S ALREADY STARTED THE RABBITS DO OR DON'T HAVE SEIZURES IN THE CHATS BUT MAYBE A SMALL PRIMATE WOULD. SO IT MIGHT BE A CASE FOR A PILOT STUDY FOR GENETIC MODELS ACROSS A FEW ORGANISMS TO SEE BECAUSE IF WE DON'T HAVE ANSWERS AS TO WHY RODENTS DON'T DEVELOP THEM AND SOME STUDIES COULD GIVE US THAT ANSWER THAT COULD BE HELPFUL. >> IT'S A QUESTION WHETHER YOU'RE ATTEMPTING TO LOOK AT EPILEPTOGENESIS OR HOW TO INTERVENE AFTER SEIZURES HAVE ALREADY DEVELOPED IN THAT MODEL BECAUSE IF SEIZURES ARE ALREADY THERE YOU HAVE TO MONITOR AND SURVIVE WITH A SEIZING MARMOSET BUT IF YOU'RE LOOKING AT HOW GENETICS LEAD TO THAT PARTICULAR EPILEPSY DEVELOPING YOU CAN STUDY IT DURING THE EPILEPTOGENESIS, NOW MY RAT IS SEIZING AND I'LL TRY TO UNDERSTAND WHAT'S GOING ON IN THE CIRCUITRY OR SOMETHING OF THAT NATURE. JUST A DIFFERENT PERSPECTIVE IN TERMS OF EPILEPTOGENESIS. >> PROVIDING THAT OPPORTUNITY TO LOOK AT THE BRAIN'S FUNCTION AND STRUCTURE BEFORE THE FIRST SEIZURE IS EVIDENT, THIS IS SORT OF THE BIOLOGICAL ONSET THAT WAS COINED EARLIER. SO JUST IN THE LAST COUPLE MINUTES I'D LIKE EVERYONE TO COMMENT ON WHAT THEY THINK WOULD HELP ACCELERATE PROGRESS IN YOUR AREAS TOWARD IMPLEMENTING OR TESTING THERAPEUTIC STRATEGIES THAT YOU THINK WOULD BE WORTH DISCUSSING. I WON'T CALL ON ANYBODY, JUST BLURT IT OUT. >> I THINK WE'VE SEEN A NUMBER OF COMMENTS IN THE CHAT ABOUT HAVING FUNDING AVAILABLE FOR NOT JUST DOING MORE RIGOROUS STUDIES BUT HAVING RIGOROUS REPRODUCTION OF THE STUDIES BY MULTIPLE LABS, AND I WOULD ARGUE THAT THAT MAKES SENSE ACROSS, YOU KNOW, STUDIES IN THE SAME SPECIES AND EVEN MORE SO WITH BEING ABLE TO SEE IF RESULTS ARE REPLICABLE IN HIGHER ORDER SPECIES BUT THAT'S GOING TO BE A VERY EXPENSIVE PROPOSITION. THINK WE HAVE THE EPILEPSY RESEARCH WORK FORCE BUT I DON'T THINK WE HAVE THE FUNDING. THAT WOULD BE A CHALLENGE FOR WALTER. WALTER AND VICKY AND COLLEAGUES, WHETHER IT BE POSSIBLE TO GET THAT SORT OF SYSTEM SET UP AND PROVIDE THE FUNDING NECESSARY FOR IT. >> TWO-MINUTE WARNING. >> THANK YOU. OTHER COMMENTS ON THAT THEME? HOW TO ACCELERATE PROGRESS? >> WE TALKED ABOUT IT AS A GROUP ON OUR PRE-CALL MEETING FOR THIS WHICH IS, YOU KNOW, SOMEHOW WE NEED TO INTEGRATE THESE MODELS ACROSS A SPECTRUM SO THAT WE CAN -- IF THERE'S A PARTICULAR ACQUIRED EPILEPSY OR PARTICULAR TYPE OF EPILEPSY WE NEED TO INTEGRATE ACROSS LEVELS OF MODELS TO EXAMINE MECHANISMS AND LOOK AT POTENTIAL TREATMENT. SO I THINK ONLY GOVERNMENT ORGANIZATION CAN DO THAT. WE'RE STILL PROBABLY MOSTLY SILOED IN OUR OWN MODELS AND OUR OWN EXPERIMENTS, BUT I THINK LOOKING AT THE LONGITUDINAL ASPECT IN TERMS OF MODELS THEMSELVES FOR PARTICULAR ASPECTS OF EPILEPSY WOULD BE EXTREMELY HELPFUL. >> I THINK THAT IDEA THAT I'M SAYING THE SAME THING THAT AMY SAID EARLIER, AND JOHN'S JUST SAYING, THE IDEA OF USE OF RODENTS, MOUSE ORGANOIDS, BUT STEADY PROGRESSION, BEFORE YOU GO TO HUMANS I THINK IS OFTEN -- VERY OFTEN NOT DONE AND WOULD BE VALUABLE. OBVIOUSLY I'M LOBBYING FOR SOMETHING THAT I DO BUT I DO IT BECAUSE I THINK IT'S USEFUL. YOU KNOW, FOR TRACKING SEIZURES, FORECASTING SEIZURES, TRYING TO DELIVER THERAPIES THAT YOU'RE GOING TO USE IN HUMANS, YOU KNOW, YOU NEED A LARGE BRAIN TO DO THAT. IT WOULD BE GREAT TO HAVE A GENETIC MODEL TRANSLATED INTO A LARGER ANIMAL OR IDENTIFIED IN A LARGER ANIMAL TO TEST SOME OF THESE THERAPIES. >> TIME HAS EXPIRED. >> I WANT TO THANK EVERYONE ON THE PANEL, THAT WAS A ROBUST DISCUSSION, AND COVERED A LOT OF GROUND, I MUST SAY I'M SO IMPRESSED BY THE FLURRY OF CHATS. I HAD TROUBLE KEEPING UP THEY WERE COMING SO FAST AND FURIOUS. >> WELCOME BACK, EVERYONE. IT'S 4:20 EASTERN TIME. AND WE'RE SCHEDULED TO HAVE OUR BREAKOUT GROUP REPORTING SESSION I HAVE A LIST OF THE MODERATORS FROM ALL THE INDIVIDUAL GROUPS. AND I'VE JUST BEEN INSTRUCTED TO CALL THEM UP IN ALPHABETICAL ORDER BY LAST NAME. SO, FIRST ON MY LIST IS MIA. >> LET ME SHARE MY SCREEN WITH YOU ALL. ARE YOU ABLE TO SEE MY POWERPOINT SCREEN? >> YES. >> OKAY. SO, OUR GROUP FOUND IT VERY HELPFUL TO HAVE THE STRUCTURED PANEL DISCUSSION AND INFORMATION SUMMARIZING ALL THE DIFFERENT ANIMALS, ANIMAL MODELS, WANTED TO GIVE THAT FEEDBACK. I THINK IN TERMS OF GAPS IN OPPORTUNITIES, I THINK THERE WAS UNIFORM CONCERNS ABOUT THE CHALLENGES AROUND SHARING DATA ACROSS DIFFERENT LABS, THAT INCLUDES BOTH THE CLINICAL AS WELL AS SOME OF THE MORE BASIC SCIENCE DATA. PEOPLE ALSO TALKED ABOUT THE CHALLENGES OF NOT HAVING ENOUGH CLINICAL TRIALISTS COLLABORATING EITHER WITH OR WITHIN ANIMAL MODELS LABS AND HOW THAT ADDITION TO BASIC ANIMAL MODEL LABS MIGHT BE VERY WELCOME IN TERMS OF INITIATING TRANSLATIONAL STUDIES. PEOPLE ALSO TALKED ABOUT THE DIFFICULTIES WHEN HUMAN AND ANIMAL STUDIES COME TOGETHER FOR PROPOSALS. FOR EXAMPLE, HOW SOMETIMES IT'S VERY CHALLENGING THROUGH TRADITIONAL R01 MECHANISM, FOR EXAMPLE, TO GET FUNDED IF YOU'RE PROPOSING ANIMAL AND HUMAN EXPERIMENTS, OFTEN BECAUSE OF THE GAPS BETWEEN HUMAN AND ANIMAL MODELS, AND SOMETIMES REVIEWERS HAVE A DIFFICULT TIME RECONCILING THOSE LIMITATIONS. SO THERE COULD BE SOME NOVEL APPROACHES TO TRY TO ADDRESS THAT, WHETHER IT'S THROUGH FUNDING MECHANISMS OR SPECIAL INITIATIVES SUDEP CENTERS WITHOUT WALLS BEING ONE EXAMPLE AND THINKING ABOUT OPPORTUNITIES. WE TALKED ABOUT NATURALLY OCCURRING ANIMAL MODELS, AND WE TALKED A LITTLE BIT ABOUT VERY NOVEL NATURALLY OCCURRING EPILEPSIES IN SEA LIONS. IN TERMS OF ACCELERATING RESEARCH, PEOPLE THOUGHT IT WOULD BE HELPFUL TO HAVE FUNDED INITIATIVES TO BRING BASIC SCIENCE LABS DOING PRE-CLINICAL TRIALS TO HAVE ACCESS AND MAINTENANCE OF DATA AROUND EEG DATA, TREATMENT TRIALS, AND REALLY CURATING THAT TYPE OF DATA AND JUST HAVING THE MAINTENANCE OF IT CAN BE VERY CHALLENGING, PARTICULARLY WHEN YOUR PROJECT ENDS SO HAVING SOME SORT OF PROJECT MEMORY OR WHETHER IT'S THROUGH DISEASE-SPECIFIC ADVOCACY GROUPS TRYING TO MAINTAIN BIOINFORMATICS AROUND ANIMAL MODELS OR CLINICAL DATA. PEOPLE TALKED ABOUT HOW CHALLENGING IT IS SOMETIMES TO REPRODUCE EXPERIMENTS AND MAKING SURE THAT THE EXPERIMENTAL PROCEDURES ARE REPRODUCIBLE AND PROVIDING THAT INFORMATION TO ENSURE THAT OCCURS AND HOW THAT INFORMATION COULD BE SHARED AND TRANSMITTED ACROSS CENTERS. AND BY AGENCIES COLLABORATING TOGETHER, EITHER INTRAAGENCY ACROSS NIH OR ACROSS EFFICACY ORGANIZATIONS TO CATALOG ANIMAL MODELS AVAILABLE, NOT JUST WITHIN EPILEPSY BUT ACROSS ALSO OTHER DISEASES SUCH AS ALZHEIMER'S DISEASE OR MAYBE EVEN AUTISM. WE FELT THAT IN TERMS OF IMPACTS OF RESEARCH, THIS IS A WIN ACROSS THE BOARD FOR RESEARCHERS, ADVOCATES, FAMILIES, CLINICIANS, AND SO WE REALLY FELT THAT REALLY TRYING TO BRIDGE CLINICAL AND BASIC SCIENCE ANIMAL RESEARCH TOGETHER WOULD BE A HUGE WIN FOR EVERYBODY. >> GREAT. THANK YOU VERY MUCH, MIYA. NEXT UP IS DATLAP. SORRY IF I'M BUTCHERING EVERYONE'S NAME. DATLAP, I WANTED TO CALL UP. >> OKAY. CAN YOU HEAR ME. >> YES, WE CAN. >> WE HAD A LIVELY DISCUSSION, IDENTIFIED A COUPLE GAPS IN MODEL SYSTEMS THAT ARE NEEDED OR NEED TO BE EXPANDED, ONE IS MODEL REFRACTORY EPILEPSY TO MOVE MORE FROM ACUTE TO SPONTANEOUS SEIZURE MODELS, THE CAVEAT IS CONTINUED SEIZURE MODELS ARE MORE EXPENSIVE. WE NEED MORE AND BETTER MODELS TO STUDY EPILEPTOGENESIS. THERE'S CURRENTLY LACK OF TOOLS TO STUDY ALL OF THEM, WE NEED TO IDENTIFY BIOMARKERS OF MECHANISMS. A BIG ISSUE IS REPRODUCIBILITY OF MODEL DATA, AS IN OTHER AREAS LIKE SPINAL CORD OR TRAUMATIC BRAIN INJURY THERE HAVE BEEN -- THERE'S BEEN A HUGE DISAPPOINTMENT IN THAT PRE-CLINICAL DATA THAT WAS THE BASIS FOR CLINICAL TRIALS, NOT REPRODUCIBLE. IT'S UNKNOWN WHAT THE STATUS IS IN THE FIELD OF EPILEPSY. WE NEED TO PAY MORE ATTENTION TO COMMON DATA ELEMENTS. SO WHAT WE CAN DO TO ACCELERATE THE RESEARCH TO LEVERAGE EXISTING RESOURCES, WE NEED TO UNDERSTAND THE BASIC BIOLOGY, AND WE NEED TO USE AND DEVELOP TOOLS TO STUDY NETWORK BEHAVIOR. WE NEED TO LOOK AT BIOMARKERS OF MECHANISMS. WE ALSO NEED STANDUPS FOR BRAIN BRECK LEVEL CONCENTRATIONS, BRING NEW TECHNOLOGIES INTO EXISTING MODELS, AND POSSIBLY HAVE TO ADD COLLABORATORS TO HELP WITH NEW TECHNOLOGIES, NEED MORE AND BETTER REPOSITORIES FOR POSITIVE LARGE SCALE DATASETS AND MOST IMPORTANTLY ALSO NEED REPOSITORIES FOR NEGATIVE DATASETS. WE SHOULD LOOK AT MORE THAN JUST ONE OUTCOME, LOOKING NOT JUST AT SEIZURES BUT AT THE WHOLE COMPLEXITY OF EPILEPSY INCLUDING COMORBIDITIES, FIELD WOULD BENEFIT BY PARTNERSHIPS BETWEEN CLINICIANS AND SCIENTISTS TO DEVELOP AND TO USE MODEL SYSTEMS. KEY FOR THAT IS COLLABORATION, TRUST AND GOALS. AN IMPORTANT ASPECT WE DISCUSSED WAS NEED FOR OPEN-END QUESTIONS AND DATA, AS OPPOSED TO HYPOTHESIS DRIVEN RESEARCH WHICH CAN BE BIASED, INCLUDING ELECTROPHYSIOLOGIC DATASETS, POSSIBLY NEED MACHINE LEARNING TO DEAL WITH LARGE SCALE DATASETS. A SUGGESTION WAS MADE TO CREATE NIH SUPPLEMENTS TO SUPPORT FUNDING FOR REPRODUCIBILITY AND REPLICATION STUDIES. SO, WHO WOULD BE MOST IMPACTED BY THIS RESEARCH, OBVIOUSLY ALL PERSONS WITH EPILEPSY, BUT ON THE OTHER HAND ALSO CLINICAL TRIALS AND FUNDERS, PRE-CLINICAL STUDIES WERE DONE THIS WOULD SAVE RESOURCES FOR THE MOST PROMISING STUDIES, SO THAT'S WHAT I HAD TO REPORT. >> THANK YOU VERY MUCH. NEXT UP IS BEN. TAKE IT AWAY, BEN. >> SORRY ABOUT THAT. AM I SHARING MY SCREEN? >> YOU ARE. >> OKAY, GREAT. WE HAD A VERY LIVELY DISCUSSION, I PROBABLY CAPTURED ABOUT 40% OF IT, AND I HAVE TO THANK JC WAGMAN FOR BEING THERE TO WRITE THINGS DOWN. WE CAME UP WITH THE BIGGEST GAPS AND OPPORTUNITIES, ONE CENTRAL TEAM WHAT QUESTIONS ARE APPROPRIATE TO ASK WITH SPECIFIC MODELS, FOR INSTANCE WE HAD A GOOD DISCUSSION ABOUT USING NON-HUMAN PRIMATES FOR COGNITIVE AND BEHAVIORAL COMORBIDITIES, THAT YOU REALLY CAN'T USE RODENTS AND OTHER MODELS FOR. AND WE ALSO CAME UP WITH A CAVEAT THAT PERHAPS WE'RE ASKING TOO MUCH OF THE RODENT MODELS. WE'RE TRYING TO GET TOO MANY COMPLEX BEHAVIORS OUT OF THEM. AND THAT MIGHT NOT BE APPROPRIATE. WE ALSO BROUGHT UP A LIVELY DISCUSSION OF ORGANOIDS AND HOW THEY CAME INTO COMPLEX, IF YOU LOOK AT NUMBER 4, WE CAME UP WITH THEM TO BE VERY GOOD BRIDGE MODELS, ESPECIALLY FOR DRUG SENSITIVITY AND SCREENING. ANOTHER QUESTION CAME UP WAS IF WE'RE ASKING TOO MUCH FROM THE RODENT MODELS, WHEN IS IT APPROPRIATE TO MOVE FROM ONE MODEL TO A MORE COMPLEX MODEL, AND CAN WE -- WHICH MODEL DO WE NEED TO GO TO. WE DON'T HAVE TO GO FROM RODENTS TO CLINICAL OR RODENTS TO PRIMATE, CAN WE DO PIG OR DOG MODELS IN BETWEEN? BEFORE WE DO THAT, ONE OF THE POINTS WE BROUGHT UP, CAN WE VALIDATE FINDINGS WITH A SECOND MODEL WITHIN THE SAME SPECIES? THAT IS, IF WE FIND SOMETHING IN A POLY CARPY MODEL CAN WE USE A DIFFERENT MODEL OF SEIZURES TO RECOMMENDLY INDICATE THE STUDIES? ONE CAVEAT CAME UP PARTICULARLY WITH RODENT MODELS PARTICULARLY AS THEY EVOLVE SOME MAY GET TOO NARROW, PARTICULARLY WITH INTRAAMYGDALA INJECTION, IS THAT TOO NARROW A MODEL, AS WE'VE DEVELOPED FROM SOME OF THE MORE GENERALIZED SEIZURE MODELS. HOW TO ACCELERATE THIS RESEARCH JUST LIKE WAS SAID, ONE OF THE THINGS THAT CAME UP A LOT WAS FUNDING TO HAVE A SECOND LAB REPLICATE FINDINGS. RIGHT NOW THERE'S REALLY NO MECHANISM FOR THAT, AND THEY THINK THAT WOULD BE -- THE GROUP THOUGHT THAT BE WOULD A GOOD WAY TO INCREASE RIGOR AND HELP MOVE THINGS FORWARD. ANOTHER THING WOULD BE TO DEFINE NEEDED INFORMATION. WHEN YOU NEED TO MOVE FROM A RODENT MODEL TO A HIGHER MODEL. AND ALSO WHAT WOULD BE NEEDED TO HELP SELECT WHICH MODEL WOULD BE APPROPRIATE. WOULD A CANINE MODEL BE BETTER THAN A PIG MODEL? ANOTHER IDEA THAT CAME UP WOULD BE A WORKSHOP PROPOSED TO HELP WITH CROSSTALK BETWEEN RESEARCHERS WHO USE RODENT SYSTEMS AND RESEARCHERS WHO USE HIGHER MODELS, THE PIG, THE CANINE, THE NON-HUMAN PRIMATE WITH EPILEPSY. WHO WOULD BENEFIT MOST, I CANNOT SEE. PRE-CLINICAL RESEARCH WOULD BENEFIT FROM THE EXTRA STUDY SUPPORT, PARTICULARLY FOR REPLICATION OF THEIR DATA, AND ACCESS TO MORE COMPLEX MODEL SYSTEMS. PERHAPS WE COULD HAVE A MECHANISM FOR SOMEBODY WHO DOES HAVE FUNDING FOR RODENT MODELS FOR OTHER MODEL SYSTEMS, MORE STANDARDIZED PRE-CLINICAL STUDIES TO BENEFIT CLINICAL RESEARCHERS. >> THANK YOU VERY MUCH. NEXT UP IS CHRIS. >> HEY, EVERYBODY. LET ME SHARE MY SCREEN. OKAY. >> LOOKS GOOD. >> GREAT. SO, YEAH, WE HAD A GREAT DISCUSSION. I WANT TO THANK AMANDA WHO HELPED ME KEEP TRACK OF EVERYTHING. GAPS AND OPPORTUNITIES, WE TALKED ABOUT COMORBIDITIES AND HOW IMPORTANT WE THINK IT IS TO IDENTIFY THE RIGHT ASSAY TO HAVE SIGNIFICANCE TO HUMAN EPILEPSY. THERE'S RODENT BEHAVIORAL ASSAYS PEOPLE DO BUT THERE'S REAL OPPORTUNITIES TO DRAW FROM, YOU KNOW, TRIALS OR TESTS THAT ARE MORE RELEVANT TO THE HUMAN CONDITION AND HUMAN DYSFUNCTION IN EPILEPSY, AND TRY TO CORRELATE THOSE WITH RODENT STUDIES. THERE'S A REALLY INTERESTING IDEA THAT CAME UP WHICH WAS ARE THERE MOLECULAR ELECTROPHYSIOLOGIC OR IMAGING SURROGATES MORE READILY TRANSLATABLE THAN A BEHAVIORAL ASSAY SO CAN WE GET AROUND BEHAVIORAL TESTS, STILL BE RELEVANT TO COMORBIDITY. AND ONE IDEA THAT CAME UP THERE WAS USE OF SLEEP WHICH IS A REALLY HEAVILY STUDIED AREA BOTH IN PEOPLE AND IN RODENT MODELS AND A LOT OF MODELS. THAT WAS SOMEWHERE WE HAD A LOT OF EXCITEMENT. WE ALL AGREED THERE'S A LOT OF GOOD MODELS FOR A LOT OF TYPES OF EPILEPSY WE FELT THAT THERE NEEDS TO BE IMPROVEMENT IN MODELS OF NEOCORTICAL EARLY ONSET AND LATE ONSET EPILEPSY, SO THOSE ARE THINGS WE DON'T THINK WE HAVE GREAT MODELS ACROSS THE BOARD. ALONG THOSE LINES EVEN IN MODELS WHERE WE KNOW A LOT, WE WOULD LIKE TO KNOW MORE ABOUT WHERE SEIZURES START AND HOW THEY PROPAGATE, SO FOR EXAMPLE IN MODELS OF TRAUMATIC BRAIN INJURY. WE TOUCHED ON USING ORGANOIDS FOR NON-GENETIC EPILEPSIES, INJURY-BASED EPILEPSIES OR INFECTION, OPPORTUNITIES THERE, AND THE CHALLENGES THAT OPPORTUNITIES IN USING ORGANOIDS TO UNDERSTAND ECTOGENESIS. THAT'S SOME GAPS AND OPPORTUNITIES. HOW CAN WE LEVERAGE THIS TO ACCELERATE THINGS? ONE THING THAT KEPT POPPING UP IN OUR DISCUSSION WAS USING ALL GENETIC RESOURCES, ONE IDEA THAT'S TANTALIZING IS SEIZURE RESISTANTS STRAINS OF MICE TO UNDERSTAND WHAT MAKES THEM RESISTANT, AND COMBINING MULTIPLE MOUSE STRAINS OR COLLABORATIVE COST, MOUSE BREEDING APPROACHES TO SPECIFICALLY UTILIZE GENETIC DIVERSITY IN A STUDY SO YOU CAN IDENTIFY CHANGES THAT ARE MOST MEANINGFUL TO THE DISEASE PROGRESSION. WE TALKED ABOUT HOW WE CAN FACILITATE OR EMPOWER REPRODUCIBILITY. WE ACTUALLY TOUCHED ON THE IDEA THAT FOR A LOT OF ASPECTS OF EPILEPSY RESEARCH WE HAVEN'T FAILED TO MAKE IT TO A CLINICAL TRIAL OR FAILED TO BE REPRODUCIBLE LARGELY BECAUSE MAYBE WE HAVEN'T TAKEN TOO MANY COMPOUNDS TO LARGE SCALE CLINICAL TRIALS. SO WE KIND OF PUSHED BACK A LITTLE BIT ON THAT IDEA THAT WE'RE NOT DOING REPRODUCIBLE SCIENCE BUT ALSO RECOGNIZE THAT IT'S IMPORTANT TO ACCEPT THESE THINGS IN THE MOST ROBUST WAY POSSIBLE. WE TALKED ABOUT DISTINGUISHING DISCOVERY AND PRE-CLINICAL SCIENCE. I THINK THAT'S SOMETHING IMPORTANT TO DELINEATE BETWEEN AS WE TALK ABOUT REPRODUCIBILITY. A LOT OF BASIC SCIENTISTS, MYSELF INCLUDED, DO DISCOVERY SCIENCE FIGURING THINGS OUT AND AT SOME POINT THAT WOULD TRANSITION TO A PRE-CLINICAL STUDY ONCE YOU KNOW, FOR EXAMPLE, EFFECT SIZE OF THE THING YOU'RE STUDYING OR THE VARIABILITY IN YOUR OUTCOME. SO THAT'S SOMETHING THAT AS WE THINK THIS THROUGH HAVE TO KEEP IN MIND. LIKE OTHER GROUPS WE TALKED ABOUT IMPORTANCE OF FUNDING MULTIPLE SITES, HAVING MECHANISMS IN PLACE TO IDENTIFY STUDIES THAT ARE APPROPRIATE FOR REPRODUCING AND PUBLISHING AND GETTING THOSE STUDIES DONE. WE TALKED A LITTLE BIT ALSO ABOUT WHAT I THINK IS AN INTERESTING IDEA OF USING A COMBINATION OF PHENOTYPIC SCREENING, WHETHER IT'S IN SLICE CULTURES OR ZEBRAFISH, A LOT OF PHENOTYPIC SCREENS WE DO USING THAT INFORMATION AND THOSE COMPOUNDS THAT WE IDENTIFY AND COMPLEMENTING THEM WITH OUR UNDERSTANDING OF DISEASE AND DRUG MECHANISMS, SO THOSE ARE KIND OF TWO ENDS OF THE SPECTRUM, PEOPLE DO THINGS DIFFERENTLY DEPENDING HOW THEY ARE USING THEIR MODEL FOR SCREENING FOR DRUG, TO IDENTIFY NEW EPILEPTIC DRUGS AND OPPORTUNITY TO CONNECT TO GET MECHANISTIC INSIGHT WHILE DOING HIGH-THROUGHPUT SCREENING. AND ONE THING I THOUGHT WAS REALLY NICE, POTENTIAL TANGIBLE OUTCOME, 100% AGREE WITH, PEOPLE ARE WORKING IN ANIMAL MODELS AND NOT REALLY THAT INFORMED OF THE CLINICAL REALITY, AND CLINICIANS ARE SUPER SPECIALIZED IN SPECIFIC TYPE OF EPILEPSY OR SPECIFIC NEUROLOGICAL DISORDER AND THOSE TWO WORLDS ARE NOT TALKING TO EACH OTHER. SO WITH THE IDEA OF MAKING ANIMAL MODELS AS REALISTIC AS POSSIBLE, USABLE AS POSSIBLE, AND TO HAVE BASIC SCIENTISTS DOING THEIR WORK AND SETTING UP THEIR EXPERIMENTS IN A WAY THAT ALLOW LATER CLINICAL TRIAL IMPLEMENTATION, WE THOUGHT IT'S NICE TO HAVE CURATED REVIEWS WHERE YOU'RE CONNECTING BASIC SCIENTISTS AND CLINICIANS HIGHLY SPECIALIZED IN SPECIFIC ASPECTS OF A MODEL OR SUBSYNDROME OF EPILEPSY. AND AS I MENTIONED, WHO WOULD BE IMPACTED MOST WITH THIS? I THINK AS WE'RE TALKING ABOUT MODELS, THE PATIENTS THAT SUFFER FROM EPILEPSY THAT AREN'T WELL MODELS ARE THE ONES THAT ARE GOING TO BENEFIT THE MOST SO WE TALKED ABOUT A FEW NEOCORTICAL, LATE ONSET, OTHER PHARMACO RESISTANCE AS WELL, WHERE IT'S HARD TO MODEL, WE DON'T NECESSARILY KNOW THE MECHANISM SO IT CAN BE HARD TO MODEL. YEAH, HAD A GREAT CONVERSATION AND LOOKING FORWARD TO HEARING FROM THE OTHER GROUPS. >> THANKS, CHRIS. NEXT UP IS ELIZABETH. >> HELLO. OKAY. SO, WHAT WE HAD HERE WAS VERY SIMILAR TO WHAT SOME OF THE OTHER GROUPS HAVE SHARED. WE TALKED ABOUT SOME OF THE GAPS AND OPPORTUNITIES, LARGER ANIMAL MODELS, HOW TO APPLY FINDINGS FROM ONE MODEL OF EPILEPSY TO OTHER EPILEPSIES, AND ALSO HAVING TRUE MODELS OF REFRACTORY EPILEPSY AND SEIZURES. WE FOUND OR DISCUSSED A LOT OF THESE MODELS MAY NOT BE REPRESENTING WHAT WE ARE TRYING TO MODEL AND SO IMPROVING THE ACTUAL MODELS THAT WE'RE USING MAKING SURE THEY FIT THE HUMAN DISEASE THAT WE ARE TRYING TO FIGURE OUT. SECOND, A DISCUSSION ABOUT ACADEMIC CULTURE PUTTING UP BARRIERS TO TRUE COLLABORATION SO TEAM SCIENCE IS A POPULAR TERM BUT NOT ALWAYS TRULY EMBRACED BY TENURE REVIEW COMMITTEES SO THAT'S ONE OF THE BARRIERS, FOR EXAMPLE JUNIOR RESEARCHERS WORKING WITH SENIOR RESEARCHERS, COLLABORATIONS ACROSS INSTITUTIONS, WE SEE SOME OF THAT, THERE ARE SOME BARRIERS TO THAT THAT WE THINK IS SORT OF PUT UP WITH THE SORT OF STRUCTURE OF OUR ACADEMIC CULTURE. ADVOCACY GROUPS, FUNDING THE RESEARCH, HAVING NO ROAD MAP FOR IT FOR HOW AND WHERE TO PUT THE MONEY AND FRANKLY THAT THEY ARE SORT OF HAVING TO PUT THE MONEY THERE, AND THAT IF THEY DON'T DO IT POSSIBLY LIKE AS WE HEARD KIM SAY IN THE BEGINNING, WILL THE RESEARCH EVEN GET FUNDED IF ADVOCACY GROUPS DON'T COME TOGETHER FOR IT. EXCESSIVE COST OF ANIMAL RESEARCH PARTICULARLY FOR LARGE ANIMAL WORK. AND THEN YOU KNOW NEEDING TO CONSIDER WHETHER SOMETHING IS ANTI-SEIZURE VERSUS ANTI-EPILEPTOGENESIS, GENETIC VERSUS POSTTRAUMATIC AND OVERALL IMPROVING YIELD AND PRE-CLINICAL TO CLINICAL PIPELINE, VERY FEW MAKE IT ALL THE WAY THROUGH AND PERHAPS THAT'S BECAUSE WE'RE NOT FOCUSING ON THE RIGHT THINGS IN THE PRE-CLINICAL AREA. SOME OF THE THINGS WE TALKED ABOUT TO ACCELERATE RESEARCH ARE IMPROVING SHARED RESOURCES, THERE WAS CONVERSATION ABOUT THIS BEFORE AS WELL. FOR EXAMPLE, EEG DATA ACROSS MODEL SYSTEMS, IF THERE'S SOME WAY THIS COULD BE UPLOADED, PEOPLE TO HELP IDENTIFY AND VALIDATE COMMON BIOMARKERS, FUNDING INITIATIVES TO BRING THESE MODELS TOGETHER TO BRING JUNIOR AND SENIOR INVESTIGATORS TOGETHER AND BASIC AND CLINICAL SCIENCE, AND ENCOURAGING THAT MAY REQUIRE CHANGES AT THE LEVEL OF TENURE REVIEW COMMITTEES, SO THAT'S A BIGGER ASK BUT SOMETHING THAT MAY BE NECESSARY IN ORDER TO TRULY ACCELERATE THIS. AND THEN NUMBER 3 IS IN THE VEIN OF IMPROVING YIELD OF PRE-CLINICAL TO CLINICAL PIPELINE, MAYBE THERE ARE GRANTS AND PUBLICATIONS THAT ARE STRETCHING THE TRUE TRANSLATIONAL NATURE OF THE WORK. THEY ARE MAKING IT SEEM LIKE IT'S APPLIED TO PEOPLE WITH EPILEPSY WHEN PERHAPS IT'S NOT AND REALLY NEEDING TO BE MORE CRITICAL ABOUT THAT TO IMPROVE THE QUALITY OF THE PRE-CLINICAL WORK THAT'S DONE. VALIDATION OF TREATMENT OF BIOMARKERS BETWEEN LABS. AND THEN THE LAST ONE, THIS IDEA OF SETTING UP CENTERS OF TECHNICAL EXCELLENCE THAT COULD DO SCREENING WORK FOR MULTIPLE GROUPS AS PART OF A CENTRALIZED INFRASTRUCTURE SO GROUPS COULD SEND ANIMALS THERE FOR TESTING AND LABS WOULD BE ABLE TO OUTSOURCE SOME OF THAT TECHNICAL WORK SO THEY CAN THEN FOCUS ON, YOU KNOW, MORE ON THE OTHER ASPECTS OF THE SCIENCE AND HAVE SOMEBODY TRAINED TO DO TECHNICAL WORK DOING. IF THEY SAY WE WANT TO DO THIS WITH OUR MODEL, OH, THERE'S THIS OTHER MODEL DOING SOMETHING SIMILAR, THAT COULD HELP WITH SOME COLLABORATIONS. REALLY EVERYONE WOULD BE IMPACTED BY THE RESEARCH INCLUDING THE ADVOCACY GROUPS. >> THANK YOU VERY MUCH. MOVING ON, NEXT UP IS BRIAN. BRIAN KLEIN, THERE YOU ARE. REMEMBER TO UNMUTE. >> OKAY. CAN YOU SEE MY SCREEN? >> YES. >> GREAT. SO WE HAD A GOOD DISCUSSION AROUND THIS, IN TERMS OF THE GAPS AND OPPORTUNITIES WE STARTED OUR DISCUSSION AROUND SOME OF THE AREAS OF RIGOR THAT WERE BROUGHT UP, AND THINKING ABOUT THAT TRANSLATABILITY OF THE DIFFERENT MODELS, AND THE NEEDING TO AVOID FALSE NEGATIVES WITH RESEARCH THAT WE'RE DOING. AND SOME OF THE POINTS THAT WERE DISCUSSED WAS THE NEED TO BE ABLE TO FIRST OF ALL PULSE NEGATIVE DATA AS DISCUSSED, PRE-REGISTRATION OF PRE-CLINICAL STUDIES. THE OTHER ASPECT EXPLORATORY VERSUS TRANSLATIONAL STUDIES, THESE ELEMENTS WOULD BE APPLIED, ENCOURAGING USE OF COMMON DATA ELEMENTS, TO MAKE SURE THAT YOU'RE CAPTURING THE METHODOLOGY APPROPRIATE LEVEL OF DETAIL TO UNDERSTAND WHY STUDY WAS A NEGATIVE STUDY. AND ALSO PROPERLY RESOURCING INVESTIGATORS SO THEY CAN POWER THEIR STUDIES, ALSO TO CONFIRM IN TERMS OF THERAPIES, EFFICACY IN FEMALE ANIMALS. AND THEN REPLICATION OF TRANSLATIONAL STUDIES, NOT ONLY CONFIRMATION WITHIN THE SAME SPECIES BUT ALSO BEING ABLE TO REPLICATE THE EFFECTS ACROSS DIFFERENT SPECIES. SO THE OTHER GAP THAT WAS BROUGHT UP IS NEED TO INVESTIGATE IN MODELS ACROSS THE LIFESPAN OF THE SPECIES, AS WELL AS THE TIME COURSE SINCE THE ONSET OF THE DISEASE ESPECIALLY WHEN LOOKING AT BOTH IN TERMS OF THERAPIES TO STOP FOR ANTI-SEIZURE THERAPIES AS WELL AS DISEASE PREVENTION. THE THIRD ASPECT THAT WAS DISCUSSED HERE UNDER GAPS AND OPPORTUNITIES WAS ANIMAL MODELS TRANSLATABLE TO HUMAN CLINICAL TRIALS. AGAIN, HERE THE POINT THAT WAS BROUGHT UP IS THE NEED FOR MORE RESISTANT SEIZURE MODELS AND THE OTHER ASPECT OF IT IS THAT FOR THERAPIES THAT ARE ABLE TO DEMONSTRATE EFFICACY, THIS SHOULD BE GENERALIZABLE IN MORE THAN ONE MODEL OR IN SPECIES. SO, GOING ON TO HOW CAN WE ACCELERATE THE RESEARCH OR LEVERAGING EXISTING RESOURCES, ENCOURAGING COLLABORATIVE TEAM APPROACHES THAT UTILIZE DIFFERENT MODELS, EXPERTISE IN TECHNIQUES TO ADDRESS SPECIFIC QUESTIONS, AND TRANSLATIONAL STUDIES. THIS GETS INTO THE FACT THAT, YOU KNOW, ONE PARTICULAR LAB OR P.I. CAN'T HAVE THE RESOURCES TO LOOK AT DIFFERENT MODELS, NOR HAVE THE BREADTH OF TECHNICAL EXPERTISE TO INTERROGATE THESE MODELS IN DIFFERENT WAYS SO AGAIN HAVING MORE TEAM APPROACHES TO BRING IN RESOURCES, THIS COULD INCLUDE COLLABORATIONS IN TERMS OF FACILITATING PATIENT ADVOCACY GROUPS THAT ARE OUT THERE, YOU KNOW, WORKING IN THIS AREA, AS WELL AS PRIVATE ENTERPRISES. SO THE OTHER ASPECT HERE WAS TO FACILITATE ANALYSIS OF EEG DATA TO REDUCE RESOURCE BURDEN AND REDUCE POTENTIAL BIAS, MANY MODELS THAT ARE SEIZURE MODELS NOW BEING USED ARE USING EEG DATA AS AN ENDPOINT AND THIS WOULD BE SOMETHING THAT WOULD BE VERY HELPFUL IN TERMS OF BEING ABLE TO FACILITATE THIS KIND OF RESEARCH IN MEASURING THESE ENDPOINTS. AND THEN THE THIRD ONE THAT WAS DISCUSSED WAS NEED TO ENCOURAGE REPORTING THAT ARE ALREADY EXISTING RESOURCES THAT ARE AVAILABLE OUT THERE IN THE COMMUNITY, AND THIS WAS AGAIN COMING BACK TO SOME DISCUSSIONS THAT I'VE HEARD FROM OTHER GROUPS IS THAT WHETHER IT BE FUNDING AGENCIES OR JOURNALS OR WITHIN DEPARTMENTS IN TERMS OF PROMOTION IS THAT THIS NEEDS TO BE ENCOURAGED WIDELY IN ORDER TO GET THE COMMUNITY TO INCLUDE THESE KINDS OF DATA ELEMENTS, FOR THE RESEARCH THAT'S BEING CONDUCTED. LASTLY WHO IS GOING TO BE IMPACTED BY THIS RESEARCH, OF COURSE THE EPILEPSY RESEARCH COMMUNITY WOULD BENEFIT AS WELL AS PATIENTS THEMSELVES AND HAVING IMPROVED TRANSLATION AND THERAPIES AVAILABLE TO THEM. >> THANK YOU, BRIAN. NEXT WE'LL HEAR FROM LAURA. >> HI, EVERYBODY. I'LL SHARE MY SCREEN. >> BRIAN, YOU MAY HAVE TO STOP SHARING YOUR FIRST. >> OKAY. >> LET'S SEE. HERE WE GO. CAN YOU SEE THIS? >> THAT'S GOOD. >> YEAH, OKAY. SO, WE HAD A GREAT LIVELY DISCUSSION. I FEEL LIKE I ONLY CAPTURED HALF, AS A PREVIOUS MODERATOR SAID. AND A LOT OF WHAT WE DISCUSSED IS VERY SIMILAR TO WHAT OTHER GROUPS HAVE COME UP WITH, THERE SEEMS TO BE COMMON THEMES. THE FIRST IS THAT WE NEED RIGOROUS RESEARCH IN THIS AREA. WE NEED BLINDED, CONTROLLED, AND REPLICATED STUDIES ACROSS SPECIES INCLUDING HIGHER ORDER MODELS. AND HOW DID WE DO THIS, WE NEED TO BRING TOGETHER LARGER CONSORTIA TOGETHER, FOR EXAMPLE THROUGH THE CENTERS WITHOUT WALLS OR NETWORKS SIMILAR TO THE UTSP, TO KEEP CRITICAL INFRASTRUCTURE IN PLACE FOR LONGER TIME AND TO BRING IN THE DIFFERENT EXPERTS THAT WOULD BE NEEDED TO SET UP SOMETHING LIKE THIS. THE SECOND -- WE NEED TO SHARE MODELS THROUGH, FOR EXAMPLE, THROUGH NIH-SUPPORTED CENTRAL REPOSITORY, IN ORDER TO FACILITATE RIGOROUS HIGH-QUALITY RESEARCH. THE SECOND POINT IN TERMS OF GAPS IS -- THIS WAS MENTIONED BY SOME OTHER GROUPS, NEED TO DEFINE WHAT IS NECESSARY IN DEVELOPING A NEW MODEL. AND HOW MANY MODELS DO WE NEED TO TEST A DRUG? AND IF WE HAVE MULTIPLE MODELS, HOW DO WE RECONCILE DIFFERENCES IN OUTCOMES ACROSS THESE MODELS? AND TO ADDRESS THAT, YOU KNOW, WE NEED TO UNDERSTAND, AND I THINK WE NEED TO UNDERSTAND THE UNDERLYING MECHANISMS AND PATHWAYS THAT LEAD TO THESE PHENOTYPES ACROSS THE DIFFERENT MODELS AND SPECIES. SO THAT WE CAN REALLY UNDERSTAND, OKAY, THIS PHENOTYPE IN THIS MODEL REALLY -- THE MECHANISM INVOLVES THIS MECHANISM AND WE CAN UNDERSTAND WHAT IT MEANS IN ORDER TO TRY TO DETERMINE WHICH MODELS ARE GOING TO BE THE MOST INFORMATIVE. ALONG THAT SAME LINE, WE NEED TO DO COMPARATIVE STUDIES OF VIDEO EEG ACROSS DIFFERENT MODELS AND SPECIES, IN ORDER TO UNDERSTAND HOW, YOU KNOW, THESE OUTCOMES, HOW DO THEY COMPARE IN DIFFERENT MODELS AND SPECIES. AGAIN, WITH STUDIES THAT WOULD REALLY GET SOME OF THE UNDERLYING MECHANISMS. WE NEED -- THE GROUP TALKED QUITE A BIT ABOUT DEVELOPING BETTER MODELS TO UNDERSTAND THE COMORBIDITIES ASSOCIATED WITH THE EPILEPSIES. DEPRESSION, ADHD, COGNITIVE FUNCTION, AUTISM, SUDEP, AND THERE'S QUITE A BIT OF DISCUSSION THAT THESE KINDS OF COMORBIDITIES AND BEHAVIORS ARE VERY DIFFICULT TO MODEL IN RODENTS BECAUSE, YOU KNOW, THEY JUST DON'T HAVE THE CIRCUITRY, THEY HAVEN'T EVOLVED CIRCUIT CIRCUITRIES OR BRAIN STUDIES SO WE HAVE TO BRING IN HIGHER ORDER, YOU KNOW, PIGS AND DOGS AND NON-HUMAN PRIMATES MORE TO UNDERSTAND THOSE COMORBIDITIES, AS WELL AS IT WAS MENTIONED THAT, YOU KNOW, THIS IS NOT A PRE-CLINICAL MODEL BUT NATURAL HISTORY REGISTRIES OF PATIENTS WITH EPILEPSIES COULD BE, YOU KNOW, STUDIED AND FOLLOWED IN ORDER TO STUDY -- UNDERSTAND THESE COMORBIDITIES BETTER. AND THEN FINALLY WE NEED BETTER MODELS TO STUDY THE EPIGENETIC MECHANISMS IN THE EPILEPSIES, AND THAT WAS -- [ AUDIO DISTORTION ] I TALKED WITH WAYS TO ACCELERATE, DIVERSE MODELS, RODENTS, HIGHER ORDER, SURGICALLY RESECTED TISSUES. YOU KNOW, WE NEED TO UNDERSTAND UNDERLYING MECHANISMS, DEVELOP CLEAR STANDARDS TO ADVANCE THERAPEUTICS SIMILAR TO WHAT THE NINDS ETSP HAS DONE, YOU KNOW, DEVELOP CLEAR GO/NO-GO CRITERIA TO STUDY THERAPEUTIC AND INVOLVE DISEASE FOUNDATIONS IN CONSORTIUM ACTIVITIES. WHO BENEFITS? EVERYBODY, PATIENTS, CLINICIANS, RESEARCHERS. >> PERFECT. THANK YOU, LAURA. THREE TO GO. NEXT IS VIJI. . >> LET ME SEE IF I CAN SHARE MY SCREEN. SO WE HAD A DISCUSSION, MANY TOPICS COVERED ARE SIMILAR TO SOME OF THE ONES THAT WERE DISCUSSED, I'D REALLY LIKE TO THANK LOU FOR TAKING GOOD NOTES TO MAKE SURE I WAS ABLE TO COVER EVERYTHING WE DISCUSSED. SOME OF THE GAPS AND OPPORTUNITIES AS WE'VE DISCUSSED BEFORE, THE LACK -- DIFFICULTY IN REPRODUCING ANIMAL DATA HAS LED TO DIFFICULTY IN TRANSLATABILITY, TO HAVE MORE CONSORTIUM-BASED APPROACHES TO STUDY MULTIPLE MODEL SYSTEMS AND DO MORE CROSS-MODEL VALIDATION, THIS WOULD OF COURSE INVOLVE MORE FUNDING MECHANISMS IN ORDER TO GET THAT TO HAPPEN AND ALSO ABILITY TO PUBLISH SUCH DATA. THE OTHER THING THAT WE SPENT A LOT OF TIME DISCUSSING WAS ANALYSIS OF COMORBIDITIES WHICH IN TERMS OF BOTH DISEASE PROGRESSION AND THERAPEUTIC ENDPOINTS AND PATIENT ADVOCACY GROUPS, THE COMORBIDITIES ARE AN IMPORTANT FACTOR TO CONSIDER EVEN WHILE DOING, YOU KNOW, THERAPEUTIC STUDIES. THE PROBLEM OF COURSE AS WE DISCUSSED WAS THE FACT THAT IT IS VERY DIFFICULT TO DO THESE COMORBIDITY STUDIES AND BEHAVIORAL STUDIES VERY VARIABLE FROM LAB TO LAB. THEY ARE DIFFICULT TO DO IN RODENT MODELS, THIS BROUGHT UP THE OPPORTUNITY FOR DOING SOME KIND OF, YOU KNOW, UNBIASED APPROACHES LIKE MACHINE LEARNING OR DATA MINING APPROACHES WHICH ARE NOW BEING USED TO ACTUALLY ANALYZE BEHAVIORAL DATA AND THIS MIGHT GIVE A COMMON PLATFORM TO MAKE THESE STUDIES ON COMORBIDITIES MUCH MORE FEASIBLE IN FUTURE. THE OTHER ISSUE WAS LEVERAGING EXISTING ANIMAL MODELS FOR BIOMARKERS AND HERE, AGAIN, MINING DATA, DOING THESE LONG-TERM EEG STUDIES OR BIOMARKER STUDIES WOULD -- WHICH CAN BE VALIDATED ACROSS LABS TO INCLUDE REPRODUCIBILITY WOULD BE IMPORTANT. THE OTHER THING THAT WE DISCUSSED WHICH IS KIND OF COMING FROM SOMETHING THAT HAPPENED IN THE CANCER FIELD WAS TO STOP GROUPING EPILEPSIES, LESS BASED ON PHENOTYPES BUT MORE BASED ON MECHANISMS, UNDERLYING MECHANISMS. THAT WAY IT WOULD MAKE IT EASIER TO CONSOLIDATE MODEL SYSTEMS IN ORDER TO STUDY MECHANISTICALLY THESE EPILEPSIES SO THIS WOULD BE BETTER ENABLED BY PERIODICALLY BRINGING TOGETHER PEOPLE WORKING ON MODEL SYSTEMS AT DIFFERENT LEVELS, DIFFERENT MODEL SYSTEMS WITH ADVOCACY GROUPS TO SEE WHERE THE EMPHASIS NEEDS TO BE, WHICH MODEL SYSTEMS CAN BE BETTER USED TO ADDRESS SOME OF THE KEY QUESTIONS THAT THED ADVOCACY GROUPS WANT ADDRESSED. THE OTHER ISSUE WE DISCUSSED WITH iPSC LINES GIVES US AN OPPORTUNITY TO ACTUALLY INCLUDE MORE ANALYSIS OF GENDER DIVERSITY AND UNDERREPRESENTED POPULATIONS WHICH WE CANNOT DO IN TRADITIONAL ANIMAL MODELS AS WELL BUT OF COURSE THE CONCERN IS THAT GETTING THAT DATASET OR GETTING THAT POPULATION TO GET THESE LINES IN GENETIC EPILEPSIES WHICH MIGHT BE RARE WOULD BE REALLY DIFFICULT SO THOSE ARE BOTH THE THINGS TO, YOU KNOW, FOR FUTURE TO LOOK INTO, INCORPORATING THAT IN OUR iPS LINES. IN TERMS OF LEVERAGING EXISTING RESOURCES, THERE WAS A PUSH FOR MORE DATA SHARING TO ENABLE ANALYSIS OF EXISTING DATA, AND KIND OF PUTTING SOME TEETH BEHIND THE, YOU KNOW, GENERAL IDEA THAT ONCE PUBLISHED THE DATA HAS TO BE SHARED. REPOSITORIES FOR iPSC LINES, INCORPORATING BIOINFORMATICS AND MACHINE LEARNING WITH EXISTING DATA REPOSITORIES SO WE CAN MINE EXISTING DATA RATHER THAN DOING EXPERIMENTS ALL OVER AGAIN. ANOTHER EMPHASIS WAS ON FUNDING LIFESPAN STUDIES SO WE COULD DO DISEASE PROGRESSION, THIS WOULD REQUIRE A LONGER FUNDING MECHANISM, IF POSSIBLE, AND TAPPING INTO EXISTING MODELS OF EPILEPSY AND PHENOTYPIC VARIATION IN GENETIC MODELS OVER THE DISEASE LIFESPAN TO ACTUALLY STUDY DIFFERENTIAL OUTCOMES AND WHY, YOU KNOW, SOME MECHANISMS OF HOMEOSTASIS LEAD TO THE SAME INSULT WITHOUT DEVELOPMENT OF EPILEPSY, WHEREAS OTHER DEVELOP EPILEPSY, GETTING AT DIFFERENTIAL MECHANISMS MIGHT HAVE BEEN THERAPEUTICS, OBVIOUSLY THE BENEFIT IS FOR THE GREATER -- THE PATIENT POPULATION AND RESEARCH COMMUNITY AS WELL. >> GREAT. THANK YOU VERY MUCH. AND NEXT IS BRETT, BRETT SMITH. >> STOP SHARING. >> CAN YOU SEE THAT? >> YES, WE CAN. THANK YOU. >> GREAT. SO FIRST I WANT TO THANK SOPHIE HILL FOR TAKING GREAT NOTES, WE HAD A LIVELY DISCUSSION, AND THEY HELPED CONSOLIDATE AT THE END. I APPRECIATE THAT. I NOTE WE HAD SEVERAL TRAINEES IN THE GROUP THAT BROUGHT UP REALLY EXCELLENT POINTS, AND ALSO OUR DISCUSSION WAS KIND OF GUIDED BY THE -- WE HAD SEVERAL REPRESENTATIVES FROM PATIENT ADVOCACY GROUPS THAT HELP GUIDE THIS CONVERSATION AND HELPED KEEP US ON TRACK. SO IN TERMS OF GAPS, A LOT OF STUFF WE WENT OVER WAS REMARKABLY SIMILAR TO WHAT'S BEEN REPORTED ALREADY SO I'M GO QUICKLY. WE THOUGHT WE WERE MISSING A LARGE INTEGRATED EFFORT TO COMBINE AND COMPARE KNOWLEDGE ACROSS DIFFERENT MODELS INCLUDING DIFFERENT SPECIES. WE ALSO THOUGHT THERE SHOULD BE A BETTER REPRESENTATION OF VERY SPECIFIC, INCLUDING MOST SEVERE KINDS OF EPILEPSIES AND THE THOUGHT WAS THAT WHILE CURRENT ANTI-SEIZURE MEDICATIONS ARE FAIRLY EFFECTIVE THEY ARE NOT EXACTLY TARGETING THOSE REFRACTORY EPILEPSIES WELL, SO THOSE WOULD BE IMPORTANT TO DEVELOP. THERE WAS CONCERN WE SHOULD START LOOKING AT MODELS THAT ARE PREDICTIVE, SO IN TERMS OF ACQUIRED EPILEPSIES ESPECIALLY, MODELS THAT CAN BE ACTUALLY USED TO PREDICT EPILEPTOGENESIS AND LOOK FOR BIOMARKERS AND MIGHT BE INDICATIVE OF THAT, THE SAME GOES FOR SUDEP. THESE ARE THINGS IN THE POPULATION WHERE IT'S RELATIVELY RARE BUT THE SAME INJURY, THE SAME SET OF SEIZURES CAN CAUSE DIFFERENT OUTCOMES AND WE'D LIKE TO DEVELOP MODELS TO PREDICT THOSE OUTCOMES. AND FINALLY, TO IDENTIFY MECHANISMS UNDERLYING THE VARIABILITY WITHIN AND BETWEEN MODELS, THOSE THAT WORK WITH MODELS KNOW THE SAME ONE REPEATED TEN TIMES MIGHT GIVE YOU WIDELY VARIABLE RESULTS, UNDERSTANDING WHY THAT HAPPENS BEYOND TECHNICAL THINGS, COMPETENCE IN THE LAB, REAGENTS OR THINGS LIKE THAT, ARE THERE OTHER THINGS THAT CAN CONTRIBUTE TO THAT? SO ONE THING THAT WAS THOUGHT TO THAT MIGHT ACCELERATE RESEARCH IS THAT INCENTIVIZING PUBLICATION OF NEGATIVE RESULTS OR REPLICATION STUDIES BEFORE, BROUGHT UP BEFORE WITH MANY CAVEATS. WE CAN PREDICT A LOT, NOT THE LEAST OF WHICH WAS THAT WOULD MEAN FORMING RESEARCH GROUPS NOT DEPENDENT ON TRAINEES WHO NEED TO -- OR EVEN FACULTY WHO NEED TO USE THESE STUDIES TO HELP THEIR CAREERS AND BUILD THEIR CAREERS. SORT OF A DIFFERENT RESTRUCTURING, IT'S NOT SIMPLE. WE HOPE TO SUPPORT UNDERSTANDING OF GENETIC SUSCEPTIBILITY, COMPARING RESULTS ACROSS SPECIES AGAIN WOULD REQUIRE SUPPORT FOR COLLABORATIVE STUDIES, MAYBE VERY LARGE COLLABORATIVE STUDIES. WE HOPE TO -- I'LL SAVE 4 FOR LAST, WE HOPE TO IMPROVE INTEGRATION OF STUDIES THAT INVOLVED INDUSTRY, PRIVATE, GOVERNMENT, ET CETERA. SUPPORT. IN OTHER WORDS, RATHER THAN NIH FUNDING EVERYTHING OR JUST GETTING INPUT FROM ONE GROUP, MAYBE CROSSING OVER SO THESE CAN BECOME MORE TRANSLATIONAL OR MORE EASILY TRANSLATIONAL ONCE SOMETHING GETS INTO THE PIPELINE AND FINALLY IT WAS BROUGHT UP A FEW TIMES, EMPHASIZED THAT FOCUSING ON MODELS NEEDS TO BE WELL DEFINED TO UNDERSTAND WHAT WE'RE STUDYING SO FOCUSING ON BETTER UNDERSTANDING MECHANISMS IS DIFFERENT THAN PRE-CLINICAL RESEARCH AND IDENTIFYING THE UTILITY OF YOUR MODELS FIRST IS SOMETHING THAT NEEDS TO BE DONE UP FRONT. AND I THINK THOSE HAVE ALL BEEN MENTIONED BEFORE, MOST. SO WE THOUGHT PATIENTS ESPECIALLY WITH INTRACTABLE OR REFRACTORY EPILEPSIES WOULD BENEFIT AND PEOPLE AT RISK FOR DEVELOPING EPILEPSIES. >> SUPER, BRETT. VERY WELL. LAST BUT NOT LEAST DELIA. >> I THINK -- >> BRETT, YOU MAY HAVE TO STOP SHARING YOUR SCREEN FIRST. >> LET'S SEE IF I CAN STOP SHARING. HERE IT IS. SORRY. >> CAN YOU SEE MY SCREEN? >> WE CAN'T AT THIS POINT. >> HMM. CAN YOU SEE IT NOW? >> WE CAN BUT IT'S CUT OFF. I DON'T KNOW IF YOU CAN -- THAT'S GOOD. PERFECT. >> OKAY. SO, WE ALSO HAD A VERY GOOD DISCUSSION AND PRETTY MUCH WE COVERED THE SAME AREAS AS EVERYBODY ELSE. IN TERMS OF GAPS AND OPPORTUNITIES, WE TALKED ABOUT PROBABLY -- IT'S NOT SO MUCH A NEED OF DEVELOPING NEW MODELS BUT RATHER DEFINING BETTER CHARACTERIZING EXISTING MODEL AND IN PARTICULAR DEFINING THE FEATURES THAT ARE OR NOT RECAPITULATED WELL BY SPECIFIC MODELS. ANOTHER IMPORTANT AREA WAS RIGOR AND REPRODUCIBILITY. ANOTHER POINT WAS EVENTUALLY USING LARGE ANIMAL MODELS FOR GENETIC EPILEPSY AS ONLY EXAMPLE OF POSSIBLY ADVANTAGE OF DEVELOPING MODELS, AND THIS ESPECIALLY WITH RESPECT TO NON-SEIZURE OUTCOMES AND THE COMPLEX BRAIN STRUCTURE. ANOTHER IMPORTANT ASPECT DISCUSSED WAS NEED FOR BETTER CHARACTERIZATION OF NON-COMBATIVE SEIZURES, NEED OF DEVELOPING SOFTWARE FOR AUTOMATIC SEIZURE DETECTION, AND LASTLY THE NEED OF ACCESS, MORE ACCESS TO HUMAN SAMPLES AND DATA SO THAT WE CAN DO A -- CREATE ALIGNMENT BETWEEN DIFFERENT MODELS AND DIFFERENT MODEL. LEVERAGE OF EXISTING RESOURCES, WAYS TO ACHIEVE THIS, WE TALKED ABOUT THE NEED FOR RESOURCES TO DEVELOP NEW MODELS, ON MULTIPLE BACKGROUNDS AND SPECIES, AND THIS IS INCENTIVIZE FOR REPRODUCIBILITY STUDIES AND THIS IS -- I'M GLAD THIS WAS ACTUALLY BROUGHT UP BY ALMOST EVERYBODY. THE CREATION OF BIGGER REPOSITORIES TO STORE DATA, ESPECIALLY EEG DATA, EEG VIDEO DATA, WHICH WILL FACILITATE SHAKER AND ANALYZING INVESTIGATORS AND ANOTHER IMPORTANT ASPECT WAS TO STANDARDIZE AND BETTER DEFINE THE DATA COLLECTION STANDARDS WHICH WILL FACILITATE COMPARISON AMONG LABS. AND OF COURSE ALL PATIENTS WITH EPILEPSY WOULD BENEFIT FROM THIS RESEARCH AND ESPECIALLY FOLLOWING THE REPRODUCIBILITY STUDIES AND VALIDATION STUDIES IN MULTIPLE LABS SO WE THINK THAT THIS WILL IN PARTICULAR IMPROVE SUCCESS OF THE CLINICAL TRIALS. THIS WILL ALSO BENEFIT ALL SCIENTISTS AND DATA SHARING WILL FACILITATE ESTABLISHMENT OF COMMON FEATURES ACROSS MODELS. AND I WOULD LIKE TO THANK CHRIS FOR TAKING WONDERFUL NOTES AND THANK EVERYBODY FOR THE VERY GOOD DISCUSSION. >> GREAT. THANK YOU VERY MUCH. THAT WAS TEN GROUPS THAT REPORTED OUT. DID WE MISS ANYBODY? IF NOT, THEN I THINK WE WILL BE CONCLUDING THIS SESSION. I DON'T KNOW, ANN, DO YOU WANT TO SAY ANY CONCLUDING REMARKS AND GET US READY FOR TOMORROW? >> VICKY WILL CLOSE US OUT FOR THE DAY, BUT THANK YOU, AL, FOR THE GREAT SESSION. >> GREAT. THANK YOU. >> YEAH, THANK YOU, EVERYONE. I'D LIKE TO THANK ALL THE MODERATORS, SPEAKERS AND DISCUSSANTS. AND ALSO THE MODERATORS AND NOTE TAKERS IN THE BREAKOUT GROUPS. IT'S BEEN A TREMENDOUS DAY. LOTS OF INFORMATION. LOTS OF GREAT IDEAS. LOTS OF GREAT EXCHANGE OF IDEAS IN THE CHAT SO THANK YOU. WE'LL BE SAVING THOSE CHATS SO WE CAN LOOK BACK AT THE EXCHANGE OF INFORMATION THERE AS WELL. SO JUST REMINDER, TOMORROW WE'LL START AT 10:30 A.M., PROMPTLY. SO PLEASE SIGN IN A BIT EARLY SO THAT YOU'RE ON AND WE'LL ADDRESS BIOMARKERS FOR THE HUMAN EPILEPSIES IN THE MORNING AND THEN HARNESSING BIG DATA TO DRIVE EPILEPSY RESEARCH AND CLINICAL CARE IN THE AFTERNOON. SO WITH THAT, I WILL WISH YOU ALL A GOOD EVENING AND LOOK FORWARD TO SEEING YOU AGAIN TOMORROW. THANK YOU.