National Academies Press: OpenBook
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R1
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R2
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R3
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R4
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R5
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R6
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R7
Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R8
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R9
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R10
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R11
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page R12

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Advancing Gene-Targeted Therapies for Central Nervous System Disorders Lisa Bain and Clare Stroud, Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Health and Medicine Division PREPUBLICATION COPY—Uncorrected Proofs

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This activity was supported by contracts between the National Academy of Sci- ences and Alzheimer’s Association; Cohen Veterans Bioscience; Department of Health and Human Services’ Food and Drug Administration (5R13FD005362- 02) and National Institutes of Health (NIH) (HHSN26300089 [Under Master Base #DHHS-10002880]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, and NIH Blueprint for Neuroscience Research; Department of Veterans Affairs (VA240-14-C-0057); Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Janssen Research & Development, LLC; Kavli Foundation; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (BCS-1064270); One Mind; Sanofi; Society for Neuroscience; Takeda Pharmaceuticals International, Inc.; The University of Rhode Island; and Wellcome Trust. Any opinions, findings, conclu- sions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: International Standard Book Number-10: Digital Object Identifier: https://doi.org/10.17226/25529 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2019 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2019. Advancing gene-targeted therapies for central nervous system disorders: Proceed- ings of a workshop. Washington, DC: The National Academies Press. https://doi. org/10.17226/25529. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of C ­ ongress, signed by President Lincoln, as a private, nongovernmental institu- tion to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the char- ter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engi­ eering, and Medicine to provide independent, objective analysis and n a ­ dvice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and ­ edicine M at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typi- cally include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and ­ pinions o contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

PLANNING COMMITTEE ON ADVANCING GENE THERAPY FOR NERVOUS SYSTEM DISORDERS1 STORY LANDIS (Co-Chair), Director Emeritus, National Institute of Neurological Disorders and Stroke LAMYA SHIHABUDDIN (Co-Chair), Sanofi ZESHAN AHMED, Eli Lilly and Company DAVID BREDT, Janssen Research & Development, LLC DANIEL BURCH, PPD Biotech JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai BEVERLY DAVIDSON, University of Pennsylvania Perelman School of Medicine JOSHUA GORDON, National Institute of Mental Health FRANCES JENSEN, University of Pennsylvania JOHN KRYSTAL, Yale University MARYANN REDFORD, National Eye Institute TODD SHERER, The Michael J. Fox Foundation for Parkinson’s Research HAO WANG, Takeda Pharmaceuticals CLINTON WRIGHT, National Institute of Neurological Disorders and Stroke Health and Medicine Division Staff CLARE STROUD, Director, Forum on Neuroscience and Nervous System Disorders SHEENA M. POSEY NORRIS, Program Officer PHOENIX WILSON, Senior Program Assistant ANDREW M. POPE, Senior Director, Board on Health Sciences Policy 1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rap- porteurs and the institution. v PREPUBLICATION COPY—Uncorrected Proofs

PREPUBLICATION COPY—Uncorrected Proofs

FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1 JOHN KRYSTAL (Co-Chair), Yale University STORY LANDIS (Co-Chair), Director Emeritus, National Institute of Neurological Disorders and Stroke SUSAN AMARA, Society for Neuroscience RITA BALICE-GORDON, Sanofi KATJA BROSE, Chan Zuckerberg Initiative EMERY BROWN, Harvard Medical School and Massachusetts Institute of Technology DANIEL BURCH, PPD, LLC JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai SARAH CADDICK, Gatsby Charitable Foundation ROSA CANET-AVILES, Foundation for the National Institutes of Health MARIA CARRILLO, Alzheimer’s Association E. ANTONIO CHIOCCA, Harvard Medical School (until July 2019) TIMOTHY COETZEE, National Multiple Sclerosis Society JONATHAN COHEN, Princeton University ROBERT CONLEY, Eli Lilly and Company JAMES DESHLER, National Science Foundation BILLY DUNN, Food and Drug Administration MICHAEL EGAN, Merck Research Laboratories JOSHUA GORDON, National Institute of Mental Health HENRY T. GREELY, Stanford University (until July 2019) RAQUEL GUR, University of Pennsylvania MAGALI HAAS, Cohen Veterans Bioscience RAMONA HICKS, One Mind RICHARD HODES, National Institute on Aging STUART HOFFMAN, Department of Veterans Affairs STEVEN HYMAN, Broad Institute of Massachusetts Institute of Technology and Harvard University FRANCES JENSEN, University of Pennsylvania GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke ALAN LESHNER, American Association for the Advancement of Science (Emeritus) HUSSEINI MANJI, Janssen Research & Development, LLC 1  The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. vii PREPUBLICATION COPY—Uncorrected Proofs

CAROLINE MONTOJO, The Kavli Foundation ATUL PANDE, Tal Medical STEVEN PAUL, Voyager Therapeutics, Inc. EMILIANGELO RATTI, Takeda Pharmaceuticals International, Inc. DOUGLAS SHEELEY, National Institute of Dental and Craniofacial Research TODD SHERER, The Michael J. Fox Foundation for Parkinson’s Research DAVID SHURTLEFF, National Center for Complementary and Integrative Health PAUL SIEVING, National Eye Institute NORA VOLKOW, National Institute on Drug Abuse ANDREW WELCHMAN, Wellcome Trust DOUG WILLIAMSON, Lundbeck STEVIN ZORN, MindImmune Therapeutics, Inc. Health and Medicine Division Staff CLARE STROUD, Forum Director SHEENA M. POSEY NORRIS, Program Officer PHOENIX WILSON, Senior Program Assistant BARDIA MASSOUDKHAN, Financial Associate ANDREW M. POPE, Senior Director, Board on Health Sciences Policy viii PREPUBLICATION COPY—Uncorrected Proofs

Reviewers This Proceedings of a Workshop was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: JEAN BENNETT, University of Pennsylvania Perelman School of Medicine VIVIANA GRADINARU, California Institute of Technology Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by ELI ADASHI, Brown University. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully consid- ered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. ix PREPUBLICATION COPY—Uncorrected Proofs

PREPUBLICATION COPY—Uncorrected Proofs

Contents 1 INTRODUCTION AND OVERVIEW 1 Workshop Objectives, 2 Organization of the Proceedings, 3 2 EXPLORING THE CURRENT LANDSCAPE OF CENTRAL NERVOUS SYSTEM GENE-TARGETED THERAPIES 5 Approved Gene-Targeted Therapies for Monogenic Central Nervous System Disorders, 6 Unsuccessful Gene Therapy Trials: Lessons Learned, 14 3 GENE-TARGETED THERAPY APPROACHES FOR CENTRAL NERVOUS SYSTEM DISORDERS: OPPORTUNITIES AND CHALLENGES 17 Delivery of Gene-Targeted Therapies to the Central Nervous System, 19 Identifying Therapeutic Targets, 23 4 TRANSLATING GENE-TARGETED THERAPIES FROM BENCH TO BEDSIDE 27 Enabling Translation with Pre-Clinical Models, 28 Clinical Trial Design Challenges for Gene-Targeted Therapies, 29 Regulatory Pathways, 32 Manufacturing Capacity, 35 xi PREPUBLICATION COPY—Uncorrected Proofs

xii CONTENTS 5 MEANINGFUL ENGAGEMENT OF PATIENTS AND FAMILIES 37 Facilitating Patient and Family Engagement, 39 Access, Cost, and Equity, 42 6 FUTURE DIRECTIONS IN THE DEVELOPMENT OF GENE-TARGETED THERAPIES 45 New Technologies on the Horizon, 46 Diverse Expertise Needed to Tackle Delivery Challenges, 50 Moving Beyond Monogenic Disorders, 52 Targeting Non-Coding RNAs, 54 Potential for Pre-Competitive Collaboration, 55 Final Remarks, 56 APPENDIXES A References 59 B Workshop Agenda 65 C Registered Attendees 73 PREPUBLICATION COPY—Uncorrected Proofs

Next: 1 Introduction and Overview »
Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop Get This Book
×
Buy Paperback | $45.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

On April 23 and 24, 2019 the Forum on Neuroscience and Nervous System Disorders convened a workshop titled "Advancing Gene-Targeted Therapies for Central Nervous System Disorders" in Washington, DC. This public workshop brought together experts and key stakeholders from academia, government, industry, philanthropic foundations, and disease/patient-focused nonprofit organizations to explore approaches for advancing the development of gene-targeted therapies for central nervous system (CNS) disorders, and implications of developing these therapies. Participants explored lessons learned from both successful and unsuccessful clinical development programs; new knowledge about the genetic underpinnings of brain disorders; the current status and future potential of gene-targeted therapies for CNS disorders; challenges and potential solutions for translating preclinical findings to approved therapies; and patient and caregiver perspectives. They also discussed what will be needed to develop these therapies for common disorders such as Alzheimer's and Parkinson's disease, as well as neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism. The workshop included approaches that target both DNA and RNA, as well as gene products using viral vectors, antisense oligonucleotides, and RNA interference. This publication summarizes the presentations and discussion of the workshop.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!