Report on the National Eye Institute Audacious Goals Initiative: Regenerating the Optic Nerve

Jeffrey L. Goldberg¹, William Guido², and the AGI Workshop Participants*

April 2015

¹Shiley Eye Center University of California San Diego La Jolla, CA 92093 jlgoldberg@ucsd.edu

²Department of Anatomical Sciences and Neurobiology University of Louisville Louisville, KY 40202 william.guido@louisville.edu

Download the National Eye Institute Audacious Goals Initiative: Regenerating the Optic Nerve report (PDF 230 KB) Read the report as published in Investigative Ophthalmology & Visual Science (IOVS) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110235/ Abstract

The National Eye Institute (NEI) hosted a workshop on November 19, 2014, as part of the Audacious Goals Initiative (AGI), an NEI-led effort to rapidly expand therapies for eye diseases through coordinated research funding. The central audacious goal aims to demonstrate by 2025 the restoration of usable vision in humans through the regeneration of neurons and neural connections in the eye and visual system. This workshop focused on identifying promising strategies for optic nerve regeneration. Its principal objective was to solicit input on future AGI-related funding announcements, and specifically to ask, where are we now in our scientific progress, and what progress should we reach for in the coming years? This report summarizes input from the meeting and serves as guidance for future funding of research that focuses on optic nerve regeneration.

Introduction

The NEI’s Audacious Goals Initiative (AGI) program initiated in 2012. At that time, the AGI began by soliciting big ideas suitable to bring the energy of the eye and vision research community into one or more audacious goals. Initially nearly 500 proposed ideas were reviewed by 80 outside extramural scientists, whittled down to 10 prizes, and divided into 7 groups. The single audacious goal chosen was to regenerate neurons and their neural connections in the eye and visual system, and this was subsequently separated into two primary goals, replacing degenerated photoreceptors, and regenerating axons in the optic nerve.

Injury to or neurodegeneration of the optic nerve underlies vision loss in many diseases, including glaucoma, ischemic and traumatic optic neuropathies, as well as retinal artery or vein occlusions, and many others. Normally, in humans and indeed in all mammals, there is no regenerative response, and the failure of injured or degenerating retinal ganglion cells (RGCs) to reconnect their axons through the optic nerve to their natural targets in the brain explains the irreversibility of such vision loss. Thus the AGI’s goal of restoring vision through promoting successful optic nerve regeneration recognizes the critical importance of understanding and reversing regenerative failure.

To understand progress to date in the sciences relevant to optic nerve regeneration, and more specifically to identify focal areas for funding, the NEI convened a workshop in November 2014 in Washington D.C. The workshop was chaired by Jeffrey Goldberg, University of California San Diego, and William Guido, University of Louisville. The meeting was sponsored by the NEI with planning oversight by the AGI Steering Committee and AGI Liaison Steven Becker.

Participants ( see appendix ) represented a variety of research areas relevant to optic nerve regeneration, from developmental neurobiology to visual processing. Over the course of a four-hour roundtable discussion, the workshop reviewed the current state of the science and addressed knowledge gaps in and barriers to scientific progress. It also identified key areas for discovery research. Here we capture the major points emphasized through the workshop as critical to achieving the goal of restoring vision by optic nerve regeneration.

Steps to optic nerve regeneration

The workshop organized its initial discussion by outlining what it will take to restore vision in optic neuropathies, and what must happen to rescue an injured or dying retinal ganglion cell (RGC). The workshop participants first outlined the factors necessary for promoting successful optic nerve regeneration and restoration of vision. These include RGC survival, axon growth and guidance, central target selection, and synapse formation and circuit integration.

Steps to Optic Nerve Regeneration Axon growth Synapse formation and circuit integration Gaps in scientific knowledge and barriers to progress

The workshop’s main focus was to identify and elaborate on the present gaps of knowledge in the area of optic nerve regeneration. Based on the workshop discussion we found that many knowledge gaps could be grouped into a few general areas: fundamental mechanisms underlying disease and injury-related regeneration, standardization and uniformity among different experimental models, species selection and translation to humans, and finally, measurable outcomes ( Box 1 ).

Gaps in Scientific Knowledge and Barriers to Progress Mechanisms underlying regeneration Experimental models Animal models: Species selection Animal models: Translation to human disease Opportunities in how we do science

Closely related to these gaps in knowledge was the discussion of which of these are significant barriers to progress ( Box 2 ), which led to brainstorming how, as a field, scientists in a variety of areas might come together to make major progress towards optic nerve regeneration and vision restoration.

Opportunities in How We Do Science Development and dissemination of tools and technologies Building a culture of collaboration through grant mechanisms Areas for open-ended/non-hypothesis driven/discovery research A view to the future

At the end of the workshop, participants distilled the discussion into a consensus plan. Immediate goals included extending work to enhance regeneration in current animal models, to solve issues relating to axon guidance and central targeting, and to cross into human testing for both biomarker validation and for candidate therapeutic testing. Other first-move approaches included building resource centers and expanding functional or behavioral testing assays in pre-clinical models. The group appreciated that although disease pathophysiology remains an important separate goal, one therapeutic solution might ultimately address many different optic neuropathies, and that identifying candidate therapies should be a major focus of the AGI.

A View to the Future Box 1: Gaps in knowledge and other unknowns Gaps in Knowledge and Other Unknowns Box 2: Barriers to progress Appendix: AGI Workshop Participants

Aileen Anderson, Ph.D. Professor, University of California, Irvine Associate Director, Sue and Bill Gross Stem Cell Research Center Director, Reeve Foundation Spinal Cord Injury Core Facility Institute for Memory Impairments and Neurological Disorders Reeve-Irvine Research Center Institute for Immunology University of California, Irvine aja@uci.edu

Larry Benowitz, Ph.D. Professor, Departments of Neurosurgery and Ophthalmology Laboratories for Neuroscience Research in Neurosurgery F.M. Kirby Neurobiology Center Boston Children's Hospital Harvard Medical School larry.benowitz@childrens.harvard.edu

Deanna Benson, Ph.D. Professor, Department of Neuroscience Friedman Brain Institute Icahn School of Medicine at Mount Sinai deanna.benson@mssm.edu

Kapil Bharti, Ph.D. Earl Stadtman Tenure-Track Investigator National Eye Institute National Institutes of Health kapilbharti@nei.nih.gov

Mark Blumenkranz, M.D. (AGI Steering Committee) H.J. Smead Professor and Chair, Department of Ophthalmology Stanford University mark.blumenkranz@stanford.edu

Brian Brooks, M.D., Ph.D. Chief, Ophthalmic Genetics Branch and Visual Function Branch National Eye Institute National Institutes of Health brooksb@mail.nih.gov

Martha Constantine-Paton, Ph.D. Professor, Departments of Brain and Cognitive Science and Biology Investigator, McGovern Institute for Brain Research Massachusetts Institute of Technology mcpaton@mit.edu

Michael Crair, Ph.D. Professor, Departments of Neurobiology and Ophthalmology & Visual Science Director of Vision Core Program Yale University michael.crair@yale.edu

Jeffrey Diamond, Ph.D. Senior Investigator National Institute of Neurological Disorders and Stroke National Institutes of Health diamondj@ninds.nih.gov

John Dowling, Ph.D., A.B. (AGI Steering Committee) Gordon and Llura Gund Professor of Neurosciences Professor of Ophthalmology Harvard Medical School Harvard University dowling@mcb.harvard.edu

James Fawcett, M.D., Ph.D. Professor, Department of Clinical Neurosciences Cambridge Centre for Brain Repair University of Cambridge jf108@cam.ac.uk

David Feldheim, Ph.D. Professor, Department of Molecular, Cell, and Developmental Biology University of California, Santa Cruz feldheim@biology.ucsc.edu

Laura Frishman, Ph.D. Professor, College of Optometry University of Houston lfrishman@uh.edu

Jeffrey Goldberg, M.D., Ph.D. (Co-Chair) Professor and Director of Research, Shiley Eye Center Department of Ophthalmology University of California, San Diego jlgoldberg@ucsd.edu

Dan Goldman, Ph.D. Professor, The Molecular & Behavioral Neuroscience Institute University of Michigan neuroman@umich.edu

William Guido, Ph.D. (Co-Chair) Professor and Chair, Department of Anatomical Sciences and Neurobiology University of Louisville william.guido@louisville.edu

Marc Hammarlund, Ph.D. Assistant Professor, Department of Genetics Program in Cellular Neuroscience, Neurodegeneration, and Repair Yale University marc.hammarlund@yale.edu

Zhigang He, Ph.D., B.M. Professor, Kirby Program in Neuroscience Children's Hospital Boston zhigang.he@childrens.harvard.edu

Andrew Huberman, Ph.D. Assistant Professor, Division of Biological Sciences and Ophthalmology Department of Neurosciences University of California, San Diego ahuberman@ucsd.edu

Yishi Jin, Ph.D. Professor of Neurobiology, Neurobiology Section, Division of Biological Sciences Department of Cellular and Molecular Medicine, School of Medicine University of California, San Diego, and Howard Hughes Medical Institute yijin@ucsd.edu

Leonard Levin, M.D., Ph.D. Professor and Chair, Department of Ophthalmology McGill University Department of Ophthalmology and Visual Sciences University of Wisconsin leonard.levin@mcgill.ca

Wei Li, Ph.D. Senior Investigator National Eye Institute National Institutes of Health liwei2@nei.nih.gov

Yaping Joyce Liao, M.D., Ph.D. Director of Neuro-Ophthalmology Department of Ophthalmology Stanford University yjliao@stanford.edu

Richard Masland, Ph.D. Professor of Ophthalmology Massachusetts Eye and Ear Infirmary Professor of Neurobiology Harvard Medical School richard_masland@meei.harvard.edu

Robert Nickells, Ph.D. Professor and Vice Chair for Research Department of Ophthalmology and Visual Sciences University of Wisconsin nickells@wisc.edu

Pamela Raymond, Ph.D. (AGI Steering Committee) Stephen S. Easter Collegiate Professor Department of Molecular, Cellular, and Developmental Biology College of Literature, Science, and the Arts University of Michigan praymond@umich.edu

Joshua Sanes, Ph.D. (AGI Steering Committee) Director, Center for Brain Science Professor, Department of Molecular and Cellular Biology Harvard University sanesj@mcb.harvard.edu

Paul A. Sieving, M.D., Ph.D. Director National Eye Institute National Institutes of Health pas@nei.nih.gov

Stephen Strittmatter, M.D., Ph.D. Professor of Neurology and Neurobiology Director of Cellular Neuroscience, Neurodegeneration, and Repair Yale University stephen.strittmatter@yale.edu

Veronica Tom, Ph.D. Assistant Professor, Department of Neurobiology and Anatomy Drexel University vtom@drexelmed.edu

W. Martin Usrey, Ph.D. Professor, Center for Neuroscience University of California, Davis wmusrey@ucdavis.edu

Robert Wurtz, Ph.D. Chief, Visuomotor Integration Section Laboratory of Sensorimotor Research National Eye Institute National Institutes of Health bob@lsr.nei.nih.gov

Rafael Yuste, M.D., Ph.D. Director, Neurotechnology Center Columbia University rmy5@columbia.edu

Don Zack, M.D., Ph.D. Professor, Wilmer Eye Institute Johns Hopkins University donzack@gmail.com

Fengquan Zhou, Ph.D. Associate Professor, Departments of Orthopaedic Surgery and Neuroscience Johns Hopkins University School of Medicine fzhou4@jhmi.edu

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