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B Workshop Agenda Transgenic and Chimeric Neuroscience Research: Exploring the Scientific Opportunities Afforded by New NonHuman Primate ModelsâA Workshop October 4, 2018 Keck Center of the National Academies 500 Fifth Street, NW, Washington, DC Background: The translational disconnect from preclinical studies with predomi- nantly rodent animal models to human clinical trials remains a key challenge associated with lagging development of therapies for brain disorders. Since 2012, the Forum on Neuroscience and Nervous System Disorders has hosted a series of workshops examining different aspects of this challenge, includ- ing maximizing the translation of effective therapies from animal models to clinical practice and exploring the evidence needed to bring compounds that appear to be safe into human efficacy trials. While no animal model will fully recapitulate human nervous system disorders, nonhuman primates (NHPs)âsuch as marmosets and macaquesâhave shown promise in their ability to serve as models for complex brain disorders, given the phyloge- netic proximity and genetic similarity to humans, similarity of neuroana- tomical organization (e.g., a well-developed prefrontal cortex) and associated cognitive and behavioral functions, social cognition, and the abil- ity to study developmental phenotypes and prodromal disease states. 61 PREPUBLICATION COPY: UNCORRECTED PROOFS
62 TRANSGENIC NEUROSCIENCE RESEARCH Workshop Objectives: This 1-day public workshop will bring together experts and key stakehold- ers from academia, government, industry, and nonprofit organizations to exam- ine the scientific opportunities and challenges, as well as bioethical considerations, of genetically engineered nonhuman primate models for neuro- science research. Invited presentations and discussions will be designed to: â¢ Discuss the state of the science of transgenic and chimeric neurosci- ence research and emerging models for nervous system disorders, and explore the potential usefulness of such models to enhance understand- ing of behavior and higher cortical function and advance therapeutic development. â¢ Examine current tools and technologies used in rodent models (e.g., transgenesis, chimera, adeno-associated viruses (AAVs), gene therapy, etc.) and explore how they would need to be modified for use in other animal models, such as nonhuman primates. â¢ Consider bioethical principles and issues related to genetic engineering of animal models for nervous system disorders, and discuss potential metrics for determining the modelsâ readiness for nonhuman primate research. â¢ Discuss policies and infrastructure needed to advance research in this domain including, for example, training, recruitment of early career scientists, and the potential development of specialized research cen- ters and international collaborations. PREPUBLICATION COPY: UNCORRECTED PROOFS
APPENDIX B 63 DAY ONE: October 4, 2018 8:30 a.m. Welcome and Overview of Workshop FRANCES JENSEN, Perelman School of Medicine, University of Pennsylvania (Chair) Session I: Emerging Transgenic and Chimeric Nonhuman Primate Models for Neuroscience Research and Therapeutic Development for Nervous System Disorders Objective: - Discuss the state of the science of transgenic and chimeric nonhuman primate models for nervous system disorders and explore the potential usefulness of such models to enhance understanding of behavior and higher cortical function and in translational science to advance thera- peutic development. 8:45 a.m. Session Overview SARAH CADDICK, Thalamic (Moderator) 8:55 a.m. Speakers GUOPING FENG, Massachusetts Institute of Technology HIDEYUKI OKANO, Keio University School of Medicine; RIKEN Brain Science Institute YOLAND SMITH, Yerkes National Primate Research Center; Emory University ANGELA ROBERTS, University of Cambridge 9:55 a.m. Discussion Discussant: WILLIAM NEWSOME, Stanford University 10:30 a.m. BREAK PREPUBLICATION COPY: UNCORRECTED PROOFS
64 TRANSGENIC NEUROSCIENCE RESEARCH Session II: Technology, Research Methodology, and Assessment Tools for Transgenic and Chimeric Nonhuman Primate Models Objectives: - Examine how current tools and technologies developed in rodent mod- els (e.g., transgenesis, chimera, AAVs, gene therapy, in vitro fertiliza- tion, etc.) through the BRAIN Initiative and elsewhere might be modified for use in nonhuman primates. - Consider potential logistical and feasibility issues unique to nonhuman primate models (e.g., cost). 10:45 a.m. Session Overview ROBERT WURTZ, National Eye Institute (Scientist Emeritus) (Moderator) 11:00 a.m. Speakers MU-MING POO, Chinese Academy of Sciences BEN DEVERMAN, Broad Institute of Massachusetts Insti- tute of Technology and Harvard University JEAN BENNETT, University of Pennsylvania KAREN PARKER, Stanford University 12:00 p.m. Discussion - Why and how do you make that leap from rodents to nonhuman primates technically? - What are the logistical and feasibility issues in using ge- netic and chimeric technologies in nonhuman primate models for neuroscience research (e.g., cost)? - What tools and technologies are currently being used or needed to create these models? - What measures and assessment tools are needed (i.e., behavioral assessments)? Discussants: DAVID AMARAL, University of California, Davis ROBERT DESIMONE, Massachusetts Institute of Technology 12:30 p.m. LUNCH PREPUBLICATION COPY: UNCORRECTED PROOFS
APPENDIX B 65 Session III: Bioethical Considerations for Transgenic and Chimeric Nonhuman Primate Models in Neuroscience Research Objectives: - Explore bioethical principles and issues related to the genetic engineer- ing of nonhuman primate models or the creation of chimeric nonhuman primate models for neuroscience research. - Consider key questions that will necessitate nonhuman primate models for basic and translational research. - Discuss potential safeguards needed for transgenic and chimeric nonhu- man primate models of nervous system disorders to ensure proper ani- mal welfare. 1:30 p.m. Session Overview HENRY T. GREELY, Stanford University (Moderator) 1:40 p.m. Speakers MARGARET LANDI, GlaxoSmithKline STEFAN TREUE, German Primate Center; Georg-August University JEFFREY KAHN, Johns Hopkins University 2:25 p.m. Discussion - As NHPs deserve greater or different consideration than other nonhuman animal species used in research gener- ally, should there be particular considerations about their use in transgenic and chimeric neuroscience research? How should that be reflected in which research is carried out, and in the care of NHPs in research settings? - What criteria must be met in order to justify the use of nonhuman primates in transgenic and chimeric neurosci- ence research, that is, type and importance of research questions; unique aspects of nonhuman primates; data from other research models; clinical testing that cannot be performed in human subjects, etc.? - What are the possibilities that transgenic and chimeric neuroscience research in NHPs could confer some quali- tatively different aspect of cognition on the NHP? How PREPUBLICATION COPY: UNCORRECTED PROOFS
66 TRANSGENIC NEUROSCIENCE RESEARCH could that be assessed? What would be the significance if that were to happen? Discussant: MARINA EMBORG, Wisconsin National Primate Research Center; University of Wisconsinâ Madison 3:00 p.m. BREAK Session IV: Moving Forward: Policy and Infrastructure Needs to Advance Research Objectives: - Synthesize and discuss key highlights from the workshop presenta- tions and discussions, including identifying next steps and promis- ing areas for future action and research. - Discuss policies and infrastructure needed to advance research in this domain, including, for example, training, recruitment of early career scientists, and the potential development of specialized re- search centers and international collaborations. - Consider the roles of national primate research centers, govern- ments, private philanthropy, and other key stakeholders to advance this research. 3:15 p.m. Session Overview FRANCES JENSEN, Perelman School of Medicine, University of Pennsylvania (Chair) 3:25 p.m. Keynote MU-MING POO, Chinese Academy of Sciences 3:40 p.m. Panel Discussion JOHN MORRISON, California National Primate Research Center, University of California, Davis HIDEYUKI OKANO, Keio University School of Medicine; RIKEN Brain Science Institute JOSHUA GORDON, National Institute of Mental Health MARK FRASIER, The Michael J. Fox Foundation for Parkinsonâs Research PREPUBLICATION COPY: UNCORRECTED PROOFS
APPENDIX B 67 JOHN SPIRO, Simons Foundation Autism Research Initiative LISA STANEK, Sanofi 4:25 p.m. Discussion 5:15 p.m. Closing Remarks STEVEN HYMAN, Broad Institute of Massachusetts Institute of Technology and Harvard University 5:30 p.m. Adjourn Workshop PREPUBLICATION COPY: UNCORRECTED PROOFS