Council Members Present:
Dr. Eduardo Alfonso
Dr. Steven Bassnett
Dr. Marie Burns
Dr. Thomas Glaser
Dr. Jane Gwiazda
Dr. Dennis Levi
Dr. Carol Mason
Dr. Stephen McLeod
Dr. Douglas Rhee
Dr. Sylvia Smith
Dr. Russell Van Gelder
Dr. Monica Vetter
Dr. Rafael Yuste
Dr. Marco Zarbin
NEI Staff Present:
Dr. Houmam Araj
Dr. Neeraj Agarwal
Dr. Sangeeta Bhargava
Dr. Steven Becker
Ms. Pamela Bobbitt
Dr. Brian Brooks
Dr. Viviane Callier
Mr. Jay Colbert
Ms. Karen Colbert
Dr. Mary Frances Cotch
Ms. Ashley Dash
Ms. Linda Dingle
Mr. Don Everett
Dr. Shefa Gordon
Dr. Thomas Greenwell
Mr. Dustin Hays
Dr. Brian Hoshaw
Dr. Jeanette Hosseini
Dr. Ellen S. Liberman
Dr. Jessica Mazerik
Dr. George McKie
Dr. Sheldon Miller
Dr. Lisa Ann Neuhold
Dr. Maryann Redford
Ms. Karen Robinson-Smith
Dr. Gale Saunders
Dr. David Schneeweis
Dr. Belinda Seto
Dr. Grace L. Shen
Dr. Paul A. Sheehy
Dr. Paul A. Sieving
Ms. Karen Robinson Smith
Dr. Michael Steinmetz
Ms. Chantelle Stevenson-Brown
Ms. Melissa Trinchet
Dr. Santa Tumminia
Dr. Cheri Wiggs
Dr. Charles Wright
Dr. Jerome R. Wujek
Ms. Maria Zacharias
Other NIH Staff Present:
Dr. Michael Chaitin, CSR
Dr. Nataliya Gordiyenko, CSR
Dr. Paek Lee, CSR
Dr. Kristin Kramer, CSR
Members of the General Public Present at the Open Session:
Mr. James Jorkasky, National Alliance for Eye and Vision Research
Ms. Alison Manson, American Optometric Association
Mr. Matt Windsor, Association for Research in Vision and Ophthalmology
Call to Order and Opening Remarks
Dr. Paul Sieving, NEI Director
Dr. Sieving welcomed the Council members, new nominees (Drs. Alfonso, Mason and Van Gelder) and presenter (Dr. Burns).
NEI staff changes include the appointment of Dr. Brian Brooks as NEI Clinical Director as Dr. Ferris has stepped down. Dr. Sieving thanked Dr. Ferris for his long service in which he made large contributions to the intramural clinical research program and to many important clinical trials. Dr. Brooks’ training is as an ophthalmologist and medical geneticist. Dr. Viviane Callier was introduced as new science writer in the Office of Science Communications, Public Liaison & Education.
NIH is still funded by a Continuing Resolution so that budgets are somewhat less than FY16. More detail is provided in Ms. Colbert’s presentation immediately following.
Another important legislative action was the passage of the 21st Century Cures Acts which provides tools and resources to advance biomedical research. Notable features include
- The NIH Innovation Account for programs including BRAIN, the Precision Medicine Initiative, the Beau Biden Cancer Moonshot and a new regenerative medicine initiative
- Support for early-stage and diverse researchers
- New policies on privacy protection for human research, to encourage collaboration, data sharing, enhance rigor and reproducibility of scientific research, improve data on clinicaltrials.gov, and to reduce administrative burden for researchers
Dr. Sieving reviewed the status of two ongoing initiatives from NEI, the Audacious Goals Initiative (AGI) and the 3D Retinal Organoid Challenge, each to be addressed in more detail in later presentations to Council.
NIH is increasingly urged to determine efficiency and efficacy of funding. The NIH Office of Portfolio Analysis has developed an algorithm for assessing grant outcomes and impact. The relative citation ratio (RCR) evaluates the performance of a research article within its specific research field as determined by peer-group of other papers co-cited with it. The tool is publicly available through the iCite website (http://icite.od.nih.gov).
NIH continues its investment in the BRAIN Initiative. NEI grantees and vision research are involved with over 51% of the funding, indicating widespread recognition of the opportunities available in vision research.
Unsupervised and unregulated transplants of bone marrow stem cells into sub-retinal space for retinal diseases have garnered considerable public attention and consequent Congressional interest. In response, NEI convened a workshop in Bethesda on December 5 & 6th to stimulate the pathway to new therapies. The charge to participants was to evaluate state of the science and evaluate progress & challenges. Attendees included research and regulatory staff from government (NIH and FDA) as well as scientists and clinicians from academia, industry, and the nonprofit sector. Dr. Tumminia will provide a summary this morning.
Council Discussion: Dr. Yuste noted that the 21st century Cures Act’s provision of funds for the BRAIN initiative provides a baseline for future operations but on the other hand, comes with oscillating levels of support. In all, it should be taken as a strong endorsement by Congress and may lead to an increase scope of operations. Dr. Zarbin noted that the NEI might consider incorporating experts at imaging brain function into outcome endpoints into AGI studies.
Consideration of Proceeding Minutes
Dr. Paul Sheehy, Executive Secretary and Director, Division of Extramural Affairs
The Executive Secretary asked for comments and corrections to the October 2016 Council minutes. There were none, and the minutes were unanimously approved.
Ms. Karen Colbert, Budget Officer, Office of the Director
Ms. Colbert noted that NIH is under a Continuing Resolution effective through April 28th (60% of FY17). We are proceeding conservatively, assuming a full-year CR with no increase over FY16. Non-competing awards are currently being made at 90% of the previously commitment, restorations through revised awards will be made when the final budget allocation is known.
The 21st Century Cures Act authorizes almost $5 billion over the next 10 years, however each year’s additional funds will require a new appropriation. Another notable feature is that support for Regenerative Medicine activities require matching funds.
She then reviewed NEI’s appropriation history. The historical allocation of the NEI appropriation continues: approximately 85% to the extramural program, 11% to the intramural program, and 4% to administration.
FY16 had an increase of 50 new Research Project Grants; these commitments will decrease the FY17 success rate. Without firm figures about our FY17 appropriation and the size of diversions to the Department and the NIH OD, our current best estimate FY17 success rate is 22%.
Council Discussion: Council members inquired about possible factors that contribute to fluctuations in the NEI success. Dr. Steinmetz replied that average R01 size and the mix of grant mechanisms and portfolio balance (scientific area) has been stable so that the primary determinant of success rate changes is the number of applications received.
Creating a Cellular Environment for Neuroregeneration
Cellular transplantation is a promising approach for diseases of the visual system. While there are many ways to grow cells in the laboratory, the consistent finding is that the majority die after transplantation. The goal of the workshop was to address the microenvironment of the posterior eye to identify the cells & signals involved in mediating survival and integration. The panel included experts in regeneration in the retina and other neural domains, glia and microglia, and inflammation.
The workshop was organized into three phases, breakout groups, summary of discussion and integration. There were three breakout groups, each directed at a specific theme (blood/retinal barriers and extracellular matrix, astrocytes and Müller cells, and microglia/inflammation). Each group was asked to consider the role of astrocytes and microglia, importance of vasculature/ECM/other cell types, use of scaffolds in regeneration and were asked to pick specific examples or mechanisms to answer the following questions
- What are the normal functions in maintaining retinal environment/homeostasis?
- How does this go awry in injury and disease - and what are the functional consequences?
- What are best strategies to intervene based on current knowledge/tools?
Blood/Retinal Barriers and Extracellular Matrix
Quite a lot is known about the ECM in the brain but its normal function in the retina is less well understood and the basis of and consequences of heterogeneity within the retina remain open questions. Other big questions remain regarding the normal function of the ECM, pericytes and choroidal endothelial cells. Regarding disease consequences, it was noted that the lack of a good animal model is a critical barrier.
Some important questions include: 1) How do pericytes change in pathology and trigger astrocytic reactivity and glial scarring; and 2) Can BRB be manipulated in a region-specific manner to modulate glial reactivity and neuroinflammation? Barriers include the negative consequences of the inhibitory features of the ECM so that tools to allow transplanted cells to circumvent the glial scar and/or facilitate synaptogenesis would be very valuable. Resources and policies to promote collaboration between primate centers, tissue sharing and data mining could be very helpful.
Astrocytes and Müller Cells
Our appreciation of the activities of glia in the nervous system has increased significantly in recent years but our understanding of their function in the retina is less well developed. We also know that Müller cells critical for physical and metabolic support to all retinal layers, set microenvironmental boundaries, and maintain the ECM. Important open questions about the normal function of astrocytes and Müller cells include: 1) What is the role of Müller cells at synapses; 2) Does the retina have a glymphatic system for extracellular drainage; 3) Are there subtypes of astrocytes in the retina, like the brain; and 4) What is the rate of normal phagocytosis by glia in healthy retina?
We know that gliosis makes it harder for cells to maintain homeostasis and that Müller cells are intermediary in retinal ganglion cell death. Important open questions include; 1) What are the signaling mechanisms in gliosis; 2) Can we identify druggable targets by gene expression profiling; 3) Does Müller cell dysregulation contribute to other retinal diseases; and 4) Could small molecules and/or transcription factors boost support functions and delay gliosis? We do have a good tool for targeting Müller cells but the lack of an analogous tool to manipulate astrocytes is a significant problem. Large scale efforts to identify where gene variants are expressed could be very beneficial.
Microglia and neuroinflammatory cells are notable for their dynamic morphology in response to changes in the external environment. The functions mediated by these cells include clearing apoptotic cells and aberrant synapses in development, maintaining synaptic morphology and function in adulthood, and phagocytosing dead and dying cells. Important open questions include: What determines 1) morphology, density, and dynamics; 2) their lifespan and homeostasis; 3) consequences of normal aging on microglial function; 4) the rate of normal phagocytosis in healthy retina; and 5) Could small molecules and/or transcription factors boost support healthy functions and delay phagocytic transformation?
It is known that microglia and neuroinflammatory cells have both helpful and harmful roles in different conditions. Important questions remain about 1) signaling mechanisms in activation and in the resolution of inflammation; 2) commonalities and specializations of microglial involvement in pathology; and Can microglia be programmed to migrate to and deliver support or remove debris, as needed? Current barriers include lack of methods for studying cells in their native environment, labeling techniques, methods to functionally categorize cells, and how signaling changes in development and disease.
Integration of Findings and Recommendations
Common needs identified by the working groups included improvements in our
- understanding of normal functions,
- ability to define cell type specificity and heterogeneity: during development, aging and disease, in both animals and humans
- ability to identify age-dependent and environmental factors that change the microenvironment (independent of disease)
Necessary tools and resources include:
- ways to control glial and microglial states
- better animal models for disease
- centralized, managed database for expression profiles, human donor tissue, etc
- efficient, in vivo cell-type specific labeling and manipulation, esp. microglia
- ways to efficiently incorporate microglia into organoid studies for transplantation
Council Discussion: Dr. Van Gelder noted that neuroregeneration is much more robust in lower vertebrates and asked whether the committee discussed their potential as model systems. Dr. Burns said that they will certainly be addressed in the forthcoming white paper. Dr. Smith asked about ways to ‘prime’ the environment to improve survival and Dr. Zarbin noted several strategies are being explored, including in humans. Council noted the recent introduction of a variety of virus serotypes that target different cell types. Council members noted that several of the tools and resources that were identified would be appropriate for support under programs in the BRAIN initiative.
Dr. Steve Becker, An Update on the NEI Audacious Goals Initiative
Dr. Becker reviewed the history, structure and activities of the Audacious Goals Initiative. It started with a challenge competition soliciting ideas from the vision community that led in 2013 to selection of the Audacious Goal of regenerating neurons and neural connections in the eye and visual system, targeting photoreceptors and retinal ganglion cells. Activities to date include:
- Two RFAs, the first focused on functional imaging and the second on regeneration factors. The investigators meet annually and share data extensively using standardized formats to promote cross-validation.
- State of the science meetings held annually at ARVO and SfN.
Seminar series held on the NIH Campus.
Dr. Santa Tumminia, Overview of the recent NEI Workshop: “Clinical Application of Stem Cell Therapies for Human Eye Disease”
As noted by Dr. Sieving in his opening remarks, stem cell transplants for retinal diseases are increasing. Multiple factors, including the rapid evolution of the science of stem cells, previous council interest in NEI’s role in the clinical use of stem cells, and congressional interest in stem cell therapies led the NEI to recently convene a workshop on stem cells and their application to human eye diseases. Attendees included research and regulatory staff from government (NIH and FDA) as well as scientists and clinicians from academia, industry, professional societies, and the nonprofit sector.
The charge to participants was to evaluate state of the science of stem cell biology and therapeutic development, progress & challenges for purposes of stimulating the pathway to the safe clinical application of stem cell treatments. To that end, the meeting was designed to explore what we know currently about the feasibility of the different stem cell types to treat eye disease and what we need to know to achieve safe clinical application. The first session consisted of a series of presentations addressing:
- The properties, sources & biology stem cells with further consideration of their advantages/disadvantages for use in ocular clinical trials
- Standards for products subject to FDA Premarket Approval (e.g., standardization, methods for cell generation, validation)
- Physician Community Perspective on the Clinical Application of Stem Cells
- Ethics of Un-regulated/Non-monitored Stem Cell Usage
- Lessons learned from an established therapy.
Speakers and participants then met in a series of moderated breakout sessions that were then presented to the full group, discussed and next steps identified. Important themes included:
Replacement vs. Rescue/Repair Strategies
- Challenges include survival of the transplanted cells and integration in the microenvironment where host cells are degenerating. Recent reports using photoreceptor precursors suggest that additional research is warranted to understand the mechanism(s) underlying positive results observed to date.
- Several ongoing approaches incorporate the use of a scaffold to maximize RPE cell longevity and integration. Survival is optimal when cells are delivered to transition zones, where diseased retinal tissue transitions into relatively healthy tissue. These current RPE replacement studies are informing efforts aimed at replacing neural retinal cells; photoreceptors and ganglion cells.
- While there was some support for using non-eye cells (e.g. bone marrow cells) for their trophic paracrine support, there was greater enthusiasm for the tissue replacement approach.
- It is important to establish best practices and optimal criteria to thoroughly characterize relatively differentiated cells in vitro to ensure authenticity prior to transplantation into humans;
- Animal models are best useful to study 1) efficacy and function, 2) long term survival, and 3) head to head comparison of candidates in models;
- Important considerations include determining the potential for tumorigenicity, and studying efficacy and long term cell survival.
Autologous vs. Allogeneic
- Immune rejection of transplanted cells is complicated and not well understood;
- Autologous cells from the patient have the advantage of fewer concerns about immune rejection, but the time and expense necessary to develop iPSCs from autologous sources are much greater;
- Autologous iPSC-RPE therapy is nearing IND filing and clinical application;
- Allogeneic approaches were also considered and an “off-the-shelf” strategy based on HLA characterization that would allow a single donor to serve as cell sources for many patients.
Stem Cell Trial Requirements
- Depending on the disease and stage, the cell therapy strategy might be different, thus, identify a target disease and stage for treatment;
- Develop a robust and controlled manufacturing process to determine batch to batch variability and clinical product purity;
- Develop release criteria to authenticate cell identity and define the mechanism of action of the cell therapy product – ensure that the cell meets its “critical quality attributes.” Examples: cell authentication, potency assays, potential mechanism of action;
- Design toxicity and tumorigenicity studies of the clinical product to be used in patients using the clinical dose (human equivalent in an animal). These procedures must be GLP-qualified;
- Develop animal models to test efficacy and determine in vivo mechanism of action of the cell therapy product. Efficacy endpoints in animal models should reflect the cell therapy product’s mechanism of action;
- Develop minimally invasive procedures to deliver the cell therapy products in the eye to minimize the possibility of adverse events;
- Designed clinical protocol including exclusion/inclusion criteria for patient selection. Various patient cohorts were considered.
Unregulated Stem Cell Clinics
- There has been a proliferation of stem cell clinics that offer unapproved and non-monitored stem cell therapies with reports of disastrous outcomes, in some cases enucleation of the eye;
- Some of these clinics list their services on ClinicalTrials.gov, fostering the misperception that they are rigorous clinical trials with approval from the FDA or having NIH sponsorship;
- Representatives of professional societies have taken strong stances on the issue of “stem cell tourism”;
- It is important to increase public understanding of the hazards and current limitations of stem cell therapies. Steps include educational roles for professional societies and clarifying that registration on ClinicalTrials.gov does not denote FDA or NIH approval.
Possible Roles for NEI
- Continue to support rigorous clinical trials that elucidate critical next steps leading to therapy;
- Partner with other NIH Institutes to support basic research to address stem cell toxicity/tumorigenicity and the optimal delivery devices and routes of stem cell and derived therapies;
- Along with the vision community, develop novel endpoints to assess treatment response that take into consideration daily function and quality of life in addition to visual acuity;
- Establish reference datasets to facilitate the authentication of cell types;
- Continue outreach efforts with professional organizations regarding their ongoing monitoring of unapproved stem cell ocular applications.
Council members encouraged NEI support of studies of the mechanism(s) of action of transplanted cells. Council members also encouraged NEI to look at lessons learned from other success stories, e.g. RPE65 gene therapy.
The 3D Retina Organoid Challenge
Dr. Jessica Mazerik
The initiative developed through interactions with Congressman Pete Sessions, who has an interest in advancing therapies for retina diseases. This led to a meeting organized by NEI in April 2016 to review the state of the science and identify goals for a prize competition. Our goal is to develop a physiologically relevant 3-D retina organoid prototype that can be used to advance understanding of retina biology, diseases, and therapies. The challenge has two categories: disease modeling and drug discovery.
NEI staff are currently occupied with outreach and marketing. This entails presentations at professional meetings, advertising in scientific journals, and notifying other agencies. The target audience includes academics, industry non-profits and small businesses. While some may be challenge “solvers”, other interested parties may be willing to provide other means of support such as partial funding, in-kind validation, discounted reagents, etc. As further part of the outreach effort, NEI has created a discussion forum to bring together potential collaborators to foster solvers’ interactions and collaborations.
The Challenge will go forward in two phases, each with specific endpoints. Either Phase may award multiple winners and the prize for that phase will be split accordingly. The winner(s) of Phase I will deliver concrete, tangible concept proposals. The winner(s) of Phase II is expected to deliver publication quality data, possibly to include an “abstract” style video that gives an overview of the prototype and highlights unique/important features. It is not necessary to participate in Phase I to participate in Phase II.
Early Spring 2017
Early Fall 2017
- February 28, 2017: Information webinar for groups interested in supporting challenge solvers
- March 29, 2017: Challenge launch webinar
- Will coincide with posting of the federal register notice, where challenge details and deliverables will be documented
The Open Session adjourned at 12:00 PM.
These minutes were submitted for the approval of the Council; all corrections or notations were incorporated. We hereby certify that, to the best of our knowledge, the foregoing minutes and attachment(s) are accurate and complete.
Paul A. Sheehy, Ph.D.
National Advisory Eye Council
National Eye Institute
Paul A. Sieving, M.D., Ph.D.
Chairman, National Advisory Eye Council
Director, National Eye Institute
Attachment A: National Advisory Eye Council - January 2017
Eduardo Alfonso, M.D.*
Kathleen and Stanley J. Glaser Chair in Ophthalmology
Director of the Bascom Palmer Eye Institute
University of Miami Miller School of Medicine
Miami, FL 33136-1134
Steven Bassnett, Ph.D. (2019)
Professor of Ophthalmology and Visual Sciences
Washington University School of Medicine
St. Louis, MO 63117
Thomas M. Glaser, M.D., Ph.D. (2019)
Department of Cell Biology and Human Anatomy
University of California, Davis
School of Medicine
Davis, CA 95616
Jane Gwiazda, Ph.D. (2019)
Professor of Vision Science
New England College of Optometry
Boston, MA 02115
Dennis M. Levi, O.D., Ph.D. (2019)
Professor of Optometry and Vision Science
University of California, Berkeley
Berkeley, CA 94720-2020
Carol Ann Mason, Ph.D.*
Professor of Pathology and Cell Biology, Neuroscience, and Ophthalmic Science
Columbia University College of Physicians and Surgeons
New York, NY 10032
Stephen D. McLeod, M.D. (2018)
Professor and Chair
Department of Ophthalmology
University of California, San Francisco
San Francisco, CA 94143
Louis R. Pasquale, M.D. (2019)
Director of Mass. Eye & Ear Glaucoma Service
and Ophthalmology Telemedicine
Massachusetts Eye and Ear Infirmary
Boston, MA 02114
Douglas Rhee, M.D. (2019)
Professor and Chair, Department of Ophthalmology and Visual Sciences
Case Western Reserve University Hospitals
Cleveland, OH 44106
Sylvia B. Smith, Ph.D., FARVO (2019)
Professor and Chair
Department of Cellular Biology/Anatomy
Medical College of Georgia
Augusta, Georgia 30912
Russell Van Gelder, M.D., Ph.D.*
Professor and Chair
Department of Ophthalmology
Director, UW Medicine Eye Institute
University of Washington
Seattle, WA 98104-2499
Monica L. Vetter, Ph.D. (2018)
Professor and Chair
Department of Neurobiology & Anatomy
University of Utah
Salt Lake City, Utah 84132
Jayne S. Weiss, M.D. (2016)
Professor and Chair
Department of Ophthalmology
Louisiana State University
Health Sciences Center
New Orleans, LA 70112
Rafael Yuste, M.D., Ph.D. (2017)
Department of Biological Sciences
New York, NY 10017