Appendix C

Workshop Agenda

Neurodegeneration: Opportunities for Collaboration Across Disease-Specific Research and Development Communities—A Workshop

April 30-May 1, 2012

Pew DC Conference Center 901 E Street, NW, Washington, DC

Background: Neurodegenerative diseases are becoming increasingly prevalent in the United States due to the aging population. Implications of these diseases are grave, both for individual and family quality of life and for health care costs. Recent findings have revealed potential commonalities and parallelisms in genetic and cellular mechanisms across neurodegenerative diseases. Enhanced sharing of research findings and collaboration across research communities could potentially help advance basic scientific knowledge about each disease and about neurodegeneration and neurodegenerative diseases in general. Furthermore, enhanced basic scientific understanding could facilitate therapeutics development for neurodegenerative disorders, including therapeutics that may address more than one neurodegenerative disease. This workshop will explore commonalities across neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia, and identify potential opportunities for collaboration across the respective research and development communities. Speakers and participants will be invited from academia; pharmaceutical and biotechnology industries; government agencies such as the National Institutes of Health, the National Science Foundation, and the Department of Veterans Affairs; and disease advocacy groups.

Meeting Objectives: The objectives of this workshop are to look across the neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, ALS, and frontotemporal dementia—and



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Appendix C Workshop Agenda Neurodegeneration: Opportunities for Collaboration Across Disease- Specific Research and Development Communities—A Workshop April 30-May 1, 2012 Pew DC Conference Center 901 E Street, NW, Washington, DC Background: Neurodegenerative diseases are becoming increasingly preva- lent in the United States due to the aging population. Implications of these diseases are grave, both for individual and family quality of life and for health care costs. Recent findings have revealed potential commonalities and parallelisms in genetic and cellular mechanisms across neurodegen- erative diseases. Enhanced sharing of research findings and collaboration across research communities could potentially help advance basic scientific knowledge about each disease and about neurodegeneration and neuro- degenerative diseases in general. Furthermore, enhanced basic scientific understanding could facilitate therapeutics development for neurodegen- erative disorders, including therapeutics that may address more than one neurodegenerative disease. This workshop will explore commonalities across neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia, and identify potential opportunities for collaboration across the respective research and development communities. Speakers and participants will be invited from academia; pharmaceutical and biotechnology industries; gov- ernment agencies such as the National Institutes of Health, the National Science Foundation, and the Department of Veterans Affairs; and disease advocacy groups. Meeting Objectives: The objectives of this workshop are to look across the neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, ALS, and frontotemporal dementia—and 79

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80 NEURODEGENERATION • Identify and discuss commonalities related to genetic and cellular mechanisms. • Identify areas of fundamental science needed to facilitate therapeu- tics development. • Explore areas of potential collaboration among the respective research communities and sponsors. DAY ONE: April 30, 2012 8:00 a.m. Welcome and Opening Remarks Story Landis, Workshop Co-Chair Director National Institute of Neurological Disorders and Stroke John Trojanowski, Workshop Co-Chair Co-director, Center for Neurodegenerative Disease Research University of Pennsylvania 8:10 a.m. U.S. Department of Veterans Affairs and Neurodegeneration Research: Current Efforts and Future Goals Joel Kupersmith Chief Research and Development Officer U.S. Department of Veterans Affairs Session 1: Overview of common features across neurodegenerative diseases Session Objectives: The objectives of this session are to provide a genetic, clinical, and pathological framework to the notion that commonalities exist across neurodegenerative diseases. While this meeting focuses on discrete diagnostic entities, it is likely that this section may use examples from entities that cross these boundaries. Specifically, this session will • Provide an overview of the genetic complexity of different neurodegenerative diseases. • Discuss common and distinguishing features of the genetics of different neurodegenerative diseases. • Discuss the clinical heterogeneity of monogenic disorders.

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APPENDIX C 81 • Describe and discuss how pathology is likely to inform us about etiologic overlap between entities and provide illustrative examples of this overlap. • Discuss the rationale for looking across neurodegenerative diseases to advance scientific understanding and explore innovative approaches to therapeutics development. 8:20 a.m. Genetic Overlap and Complexity of Phenotypical Expression Andrew Singleton, Session Chair Senior Investigator, Laboratory of Neurogenetics National Institute on Aging 8:30 a.m. Pathological Overlap Dennis W. Dickson Professor of Laboratory Medicine and Pathology Mayo Clinic 8:40 a.m. Translational Route Challenges: Is Combining Diseases Informative or a Distraction? Adrian J. Ivinson Director, Harvard NeuroDiscovery Center Harvard Medical School 8:50 a.m. Discussion Among Speakers and Attendees Session 2: Protein aggregation in neurodegenerative diseases Session Objectives: The objectives of this session are to look at protein aggregation across the neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, and frontotemporal dementia—and • Highlight commonalities related to protein aggregation across these diseases, for example, autophagy. • Discuss promising opportunities for collaboration among the respective research communities. • Identify areas of fundamental research about protein aggregation that would facilitate biomarker and therapeutics development.

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82 NEURODEGENERATION • Identify the next steps that research sponsors, investigators, and others should take to facilitate collaborative research and drug development in this area, including frameworks for partnerships and collaboration. 9:10 a.m. Overview of Status of the Field and Session Objectives John Dunlop, Session Co-Chair Vice President, Discovery Neuroscience Innovative Medicine Unit AstraZeneca Lucie Bruijn, Session Co-Chair Chief Scientist ALS Association 9:20 a.m. Proteostasis Challenges in Neurodegenerative Diseases Rick Morimoto Professor of Molecular Biosciences Northwestern University 9:30 a.m. Discussion Among Speakers and Attendees 9:45 a.m. The Selective Degradation of Misfolded Proteins and Protection Against Neurodegenerative Diseases Alfred Goldberg Professor of Cell Biology Harvard Medical School 9:55 a.m. Discussion 10:10 a.m. BREAK 10:25 a.m. Autophagy in Neurodegenerative Disease Ana Maria Cuervo Professor, Department of Developmental and Molecular Biology Albert Einstein College of Medicine 10:35 a.m. Discussion

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APPENDIX C 83 10:50 a.m. Protein Aggregation in ALS and Huntington’s Disease Claudio Hetz Professor, University of Chile Adjunct Professor, Harvard School of Public Health 11:00 a.m. Discussion 11:15 a.m. Development of Assay Systems in Observing Aggregates and Development of Small Molecules Steven Finkbeiner Director, Taube-Koret Center, Gladstone Institute  Neurodegenerative Disease Professor, University for of California, San Francisco 11:25 a.m. Discussion 11:40 a.m. Drug Discovery Efforts Warren Hirst Associate Research Fellow, Neurodegeneration & Neurologic Diseases Pfizer 11:50 a.m. Discussion 12:30 p.m. LUNCH session 3: mitochondrial pathology and neurodegenerative disease Session Objectives: The objectives of this session are to look at mitochondrial pathobiology across the neurodegenerative diseases—including Alzheimer’s disease and other dementias, Parkinson’s disease, and ALS—and to • Highlight differences and commonalities related to mitochondrial dysfunction and pathology across the diseases. • Discuss opportunities for the development of mitochondria- related biomarkers and therapeutic interventions. • Identify next steps that research sponsors, investigators, and others should take to facilitate collaborative research and drug development in this area, including frameworks for partnerships and collaboration.

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84 NEURODEGENERATION 1:30 p.m. Overview of Status of the Field and Session Objectives Lennart Mucke, Session Chair Director and Senior Investigator, Gladstone Institute of Neurological Disease Professor of Neurology and Neuroscience University of California, San Francisco 1:40 p.m. Systems Biology and Disease Vamsi K. Mootha Professor Department of Systems Biology, Harvard Medical School Department of Medicine, Massachusetts General Hospital 1:50 p.m. Discussion Among Speakers and Attendees 2:05 p.m. Neuronal Cell Death in Human Neurological Disorders and Their Animal/Cell Models Lee Martin Professor of Pathology, Neuroscience Johns Hopkins University 2:15 p.m. Discussion 2:30 p.m. Parkinson’s Disease Richard J. Youle Senior Investigator National Institute of Neurological Disorders and Stroke 2:40 p.m. Discussion 2:55 p.m. BREAK 3:10 p.m. ALS and Huntington’s Disease Neil Kowall Professor of Neurology and Pathology, Boston University Chief of Neurology, VA Boston Healthcare System 3:20 p.m. Discussion

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APPENDIX C 85 3:35 p.m. Alzheimer’s Disease Douglas C. Wallace Director, Center for Mitochondrial and Epigenomic Medicine Michael and Charles Barnett Chair of Pediatric Mitochondrial Medicine and Metabolic Disease The Children’s Hospital of Philadelphia 3:45 p.m. Discussion 4:45 p.m. Wrap-Up: Highlights and Key Themes of Day One Story Landis, Workshop Co-Chair John Trojanowski, Workshop Co-Chair 5:00 p.m. ADJOURN DAY ONE DAY TWO: May 1, 2012 8:00 a.m. Welcome and Objectives of Day Two Story Landis, Workshop Co-Chair Director National Institute of Neurological Disorders and Stroke John Trojanowski, Workshop Co-Chair Co-director, Center for Neurodegenerative Disease Research University of Pennsylvania session 4: neurodegenerative disease transmission and immune therapy Session Objectives: The objectives of this session are to • Provide an overview of the latest concepts on transmission of neurodegenerative diseases, including evidence that suggests that disease progression may occur through the cell-to-cell spread of pathological disease proteins. • Explore how targeting transmissible species of α -Synuclein as well as tau and Abeta using immune therapy may be used to treat Par- kinson’s disease and Alzheimer’s disease, respectively.

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86 NEURODEGENERATION • Identify the next steps that research sponsors, investigators, and others should take to facilitate collaborative research and drug development in this area, including frameworks for partnerships and collaboration. 8:15 a.m. Overview of Status of the Field and Session Objectives John Trojanowksi, Session Chair Co-director, Center for Neurodegenerative Disease Research University of Pennsylvania 8:25 a.m. Transmission of Prions and Alzheimer’s Disease Abeta Amyloid Claudio Soto Professor of Neurology Director, Center for Alzheimer’s Disease and Related Brain Disorders The University of Texas Medical School at Houston 8:35 a.m. Discussion Among Speakers and Attendees 8:50 a.m. Transmission of Alzheimer’s Disease Abeta Amyloid Lary C. Walker Research Professor of Neuroscience Emory University 9:00 a.m. Discussion 9:15 a.m. Transmission of Alzheimer’s Disease Tau Amyloid Karen Duff Professor, Department of Pathology Columbia University 9:25 a.m. Discussion 9:40 a.m. BREAK

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APPENDIX C 87 10:00 a.m. Transmission of Parkinson’s Disease a-Synuclein Amyloid Virginia M.-Y. Lee The John H. Ware 3rd Professor in Alzheimer’s Research Department of Pathology and Laboratory Medicine Director, Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine 10:10 a.m. Discussion 10:25 a.m. a-Synuclein Immunization for Parkinson’s Disease Dora Games Head of Pharmacology Neotope Biosciences 10:35 a.m. Discussion 10:50 a.m. Tau Immunization for Alzheimer’s Disease and Related Tauopathies Peter Davies Head Litwin-Zucker Center for the Study of Alzheimer’s Disease and Memory Disorders The Feinstein Institute for Medical Research 11:00 a.m. Discussion 11:45 a.m. LUNCH Session 5: errors in rna Session Objectives: The objectives of this session are to • Discuss how errors in RNA-binding proteins are causes of neurodegenerative diseases, including ALS, frontotemporal dementia, and spinal muscular atrophy, as well as triplet nucleotide expansion as a risk factor in disease (e.g., ataxin and ALS).

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88 NEURODEGENERATION • Discuss disease mechanisms for diseases with toxic RNAs, including myotonic dystrophy and other triplet nucleotide repeats where there are toxic RNAs or aberrant translation of the expansions. • Explore potential biomarkers and therapies for RNA-binding protein errors in SMA, TDP-43, FUS, and C9orf72. • Discuss yeast models to identify therapeutics and the emerging roles of non-coding RNA networks in the pathogenesis of neurodegenerative diseases. • Identify the next steps that research sponsors, investigators, and others should take to facilitate collaborative research and drug development in this area, including frameworks for partnerships and collaboration. 12:45 p.m. Overview of Status of the Field and Session Objectives Don Cleveland, Session Chair Professor and Chair, Department of Cellular and Molecular Medicine Head, Laboratory for Cell Biology Ludwig Institute for Cancer Research University of California, San Diego 12:55 p.m. Overview of RNA Gain-of-Function Mechanisms in Neurodegenerative Disease Laura Ranum Professor of Molecular Genetics and Microbiology University of Florida 1:05 p.m. Discussion 1:20 p.m. Overview of Therapies for RNA-Binding Protein Errors Frank Rigo Assistant Director, Core Antisense Research ISIS Pharmaceuticals, Inc. 1:30 p.m. Discussion 1:45 p.m. Yeast Models to Identify Therapeutics Gregory A. Petsko Gyula and Katica Tauber Professor of Biochemistry & Chemistry Brandeis University

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APPENDIX C 89 1:55 p.m. Discussion 2:10 p.m. The Emerging Roles of Non-Coding RNA Networks in the Pathogenesis of Neurodegenerative Diseases Mark F. Mehler Alpern Professor of Neurology, Neuroscience and Psychiatry and Behavioral Sciences University Chair, The Saul R. Korey Department of Neurology Albert Einstein College of Medicine 2:20 p.m. Discussion 2:45 p.m. BREAK Session 6: future directions and next steps Session Objectives: A panel will synthesize and discuss key highlights from the workshop presentations and discussions, including • Identify key promising areas for future cross-disease research and collaboration. • Discuss opportunities for partnerships—public–private and across disease-specific communities—to advance neurodegeneration research and therapeutics development. • Discuss challenges to advancing research and therapeutics development for the neurodegenerative diseases and potential mechanisms to address these challenges. 3:00 p.m. Panel Discussion (Session Chairs from Previous Sessions): Story Landis, Session Co-Chair Director National Institute of Neurological Disorders and Stroke John Trojanowski, Session Co-Chair Co-director, Center for Neurodegenerative Disease Research University of Pennsylvania Andrew Singleton Senior Investigator, Laboratory of Neurogenetics National Institute on Aging

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90 NEURODEGENERATION John Dunlop Vice President, Discovery Neuroscience Innovative Medicine Unit AstraZeneca Lucie Bruijn Chief Scientist ALS Association Lennart Mucke Director and Senior Investigator, Gladstone Institute of Neurological Disease Professor of Neurology and Neuroscience University of California, San Francisco Don Cleveland Professor and Chair, Department of Cellular and Molecular Medicine Head, Laboratory for Cell Biology Ludwig Institute for Cancer Research University of California, San Diego 3:30 p.m. Discussion Among Speakers and Attendees 4:30 p.m. ADJOURN