National Eye Institute
National Advisory Eye Council
One Hundred Fortieth Fourth Meeting
October 20, 2016
The National Advisory Eye Council (NAEC) convened for its one hundred and forty- fourth meeting at 8:30 am on Thursday, October 20, 2016 at the T-Level Conference Center at 5635 Fishers Lane, Rockville, Maryland, 20852. Paul A. Sieving, MD, PhD, the Director of the National Eye Institute (NEI), presided as Chair of the Council, Paul A. Sheehy, PhD, as Executive Secretary, and Michael A. Steinmetz, PhD, as Director of Extramural Science Programs. The meeting was open to the public from 08:30 am until 2:00 pm when the meeting was closed to the public for a session from 02:00 pm until 04:00 pm for the reviews of confidentiality and conflict of interest procedures, the report of the Board of Scientific Counselors, and grant and cooperative agreement applications.
COUNCIL MEMBERS PRESENT:
Dr. Steven Bassnett
Dr. Laura Frishman
Dr. Thomas Glaser
Dr. Jane Gwiazda
Dr. Dennis Levi
Dr. Stephen McLeod
Dr. Douglas Rhee
Dr. Sylvia Smith
Dr. Monica Vetter
Dr. Jayne Weiss
Dr. Rafael Yuste
NEI STAFF PRESENT:
Ms. Lisa Anderson
Dr. Houmam Araj
Dr. Neeraj Agarwal
Dr. Sangeeta Bhargava
Ms. Pamela Bobbitt
Ms. Sylvia Braxton
Ms. Monique Clark
Mr. Jay Colbert
Ms. Karen Colbert
Dr. Mary Frances Cotch
Ms. Ashley Dash
Ms. Linda Dingle
Ms. Courtney Dodson
Mr. Don Everett
Ms. Diana Fisher
Dr. Martha Flanders
Dr. Shefa Gordon
Dr. Thomas Greenwell
Mr. Dustin Hays
Dr. Brian Hoshaw
Dr. Jeanette Hosseini
Dr. Ellen S. Liberman
Dr. Jessica Mazerik
Dr. Anna Mazzucco
Dr. Sheldon Miller
Dr. Lisa Ann Neuhold
Dr. Gyan Prakash
Dr. Maryann Redford
Ms. Karen Robinson-Smith
Dr. Gale Saunders
Dr. Anne E. Schaffner
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
Mr. Gerod Thigpen
Dr. Santa Tumminia
Ms. Veronica Van Wagner
Dr. Cheri Wiggs
Dr. Jerome R. Wujek
Ms. Maria Zacharias
OTHER NIH STAFF PRESENT:
Dr. Rajeev K Agarwal, ORWH
Dr. Michael Chaitin, CSR
Dr. Nataliya Gordiyenko, CSR
Dr. Paek Lee, CSR
Dr. Bruce Reed, CSR
Dr. Kirk Thompson, CSR
MEMBERS OF THE GENERAL PUBLIC PRESENT AT THE OPEN SESSION:
Dr. James Handa, Wilmer Eye Institute, Johns Hopkins University
Mr. James Jorkasky, National Alliance for Eye and Vision Research (NAEVR)
Dr. Lofti Merabet, Massachusetts Eye & Ear Infirmary, Harvard Medical School
Mr. Matt Windsor, Association for Research in Vision and Ophthalmology
OPEN SESSION OF THE MEETING
CALL TO ORDER AND OPENING REMARKS - Dr. Paul Sieving, NEI Director
Welcomed new Council Members (Drs. Thomas Glaser, Dennis Levi, Louis Pasquale, and Sylvia Smith) and thanked retiring members (Drs. Frishman, Weiss and Yuste).
Two new staff members were introduced: Dr. Jessica Mazerik (Program Manager for the 3D Retinal Organoid Challenge) and Ms. Ashley Dash (Grants Management Specialist).
Dr. Sieving has convened an Age-related Macular Degeneration Pathobiology Working Group that will focus on increasing our understanding key elements of disease initiation and progression. A summary from the Group’s first meeting will be presented later in the open session by Dr. James Handa.
The 3D Retinal Organoid Challenge scientific initiative is following on from the April 2016 meeting. The overall strategy is to make an investment by NEI that will stimulate other government, private and industry organizations develop 3D Retinal Organoids as predictable models of the biology, pathophysiology and drug testing. This effort is being organized by Drs. Mazerik and Becker.
The Audacious Goals Initiative released a White Paper on the October 2015 Workshop held at the Society for Neuroscience meeting. A complementary Town Hall meeting was held at the 2016 ARVO annual meeting that considered which vision disorders are most amenable to regenerative therapies and what specific issues should be addressed before moving to clinical trials. The AGI will continue with annual Fall and Spring meetings on strategic issues (at SfN and ARVO, respectively).
NEI has convened a meeting to consider the use of stem cells in vision disorders to be held on the NIH campus December 5th. There have recently been highly publicized reports of significant restoration of vision function after transplantation of bone marrow-derived stem cells that have sparked considerable Congressional interest. Given the consequences of either success or failure, these reports need to be confirmed and the underlying mechanisms of either success or failure investigated. The purpose of the meeting is to survey what is known about the biology and potential therapeutic nature of stem cells. The meeting is being organized by Dr. Santa Tumminia.
CONSIDERATION OF JANUARY MINUTES – Dr. Paul Sheehy, Executive Secretary and Director, Division of Extramural Affairs
The Executive Secretary asked for comments and corrections to the June 2016 Council minutes. There were none, and the minutes were unanimously approved.
BUDGET UPDATE – Ms. Karen Colbert, Budget Officer, Office of the Director
Ms. Colbert noted that NIH is under a Continuing Resolution effective through December 9th. Funds are available at 99.5% of the FY15 appropriation for a period corresponding to 19% of FY16. She then reviewed NEI’s appropriation history. The allocation of the NEI appropriation has consistently been about 85% to the extramural program, 11% to the intramural program, and 4% to administration. FY16 had an increase of 50 new Research Project Grants; the impact of the resulting future year commitments on the FY17 success rate is unknown until we have our FY17 appropriation.
Council Discussion: Dr. Sieving noted that NIH has found that the number of unique awardees has remained essentially constant since the doubling the NIH budget while the number of applicants has increased by 33%. As the budget has been essentially flat over the past decade while the cost of research has increased, NEI has adopted a strategy of combining managing the increase in award budget with the number of unique awardees. Thus the number of investigators has decreased by 7%. Dr. Sieving noted that this creates pressures throughout the research enterprise.
Scientific Presentation: The NEI Low Vision and Blindness Rehabilitation Program – Dr. Cheri Wiggs, Program Director, NEI
The Low Vision and Blindness Rehabilitation program directly supports a critical component of the NEI mission: “special problems and requirements of the blind”. The problems and needs of the visually impaired include reduced mobility, difficulty reading (with consequences for employment and education), and compromised instrumental Activities of Daily Living (ADLs) such as cooking. The extent, time course and etiology of visual impairment have important consequences for rehabilitative strategies. The awards in the NEI LVBR program broadly include those directed at restoring ADL functions and those directed at understanding the basic science underlying visual impairment. Efforts to improve ADL functions include both development of technologies and studies of how to improve the visual accessibility of the environment (e.g. due to natural changes in illumination). Studies of the basic science of behavioral adaptations to visual impairment and studies of neural connectivity dynamics accompanying various diseases with visual loss and/or restoration.
Scientific Presentation: Characterizing Neuroplasticity in the Setting of Blindness: The Development of Assistive Technology and Education Strategies – Dr. Lofti Merabet
Dr. Merabet opened by noting that despite significant clinical and scientific advances, blindness and visual impairment continue to be a large public health burden with 1 million blind Americans and another 3.2 million with visual impairment. Moreover, these numbers are expected to double by 2050. However the brain’s inherent capacity to adapt by structural and functional reorganization can be directed to rehabilitation. Dr. Merabet presented some of his laboratory’s work on neuroplasticity and navigation through strategies that operate through learning in the context of play in advanced simulation environments.
Video Games and the use of virtual reality (VR) therein are used in a variety of behavioral and physical therapies. The scientific basis of their use is that elements in these games are coupled to specific neurotransmitter systems associated with rewards (dopamine), novelty and graded goals (serotonergic and noradrenergic), and attention (cholinergic) that are in turn coupled to neuroplastic capacities. In some games, particularly “first person shooter” games, success depends on players developing a robust spatial cognitive map of the environment and its features (such as structures, rewards, perils). Versions of these games exist for the blind which the VR is used to generate an environment that is revealed to players through audio cues. Children who play such games develop very accurate mental maps of the environment. Dr. Merabet has developed a rehabilitative software package (Activity-based Environment Simulator) based on a real structure (a building at the Carrol Center), trained the children using VR game-based experiences and then tested their navigation skills in the actual environments. Learning to navigate the structure can be either directed (i.e. under the supervision of an instructor) or not (i.e. as an individual playing a game). Subsequent tests of proficiency showed the approach was effective (85% of subjects developed mental maps of the environment) and that the gaming mode led to more robust mental maps applicable to “real world tasks” (e.g. ability to develop accurate alternate routes). fMRI studies show similar cortical activation patterns in sighted and blind subjects. Future work will extend this software to multiple buildings, including navigation of the external environment and to expand the sensory modalities (e.g. tactile input). Other projects include 1) developing more abstract maps (e.g. of a subway system) and 2) moving the technology to other platforms (e.g. smart phones).
Over the past 20 years it has become increasingly recognized that education strategies that are successful for ocular blind children are significantly more difficult for cortical/cerebral blind children. The leading cause of Cortical Visual Impairment is prenatal hypoxia/ischemia and, given the improved ability to save premature infants, this is leading to an increase in cortical/cerebral blind children. A major challenge is that hypoxia/ischemia leads to a more diffuse injury leading to more subtle visual impairment that is not evident by standard structural imaging. However imaging of white matter tracts show altered connectivity of cortical visual processing streams.
Dr. Merabet concluded by noting the parallel upswings in public interest and knowledge in rehabilitation and the scientific/technical foundations for new and improved strategies.
Council Discussion: In response to questions from Council, Dr. Merabet noted cortical/cerebral blind children do not respond as well as ocular blind children to VR-based rehabilitation strategies and that this is what prompted them to establish that the same neuronal pathways were not available. However, through technologies to identify those pathways that are patent in CVI individuals, we may be able to adapt our strategies to build on residual or alternative learning/neuroplasticity capacity.
In response to a question about the challenge of assimilating large maps through auditory cues, Dr. Merabet suggested that the introduction of other sensory modalities may make the task more tractable or that some sensory modalities may be more appropriate for specific tasks (e.g. haptic for linear maps).
Update: Toward an Era of Trust and Transparency in NIH Clinical Trials – Dr. Maryann Redford
Over the course of the past decade a number of internal and external groups have studied clinical trials as supported by NIH. In 2015 NIH formed a Clinical Trials Task Force; it built upon the work of subsequent groups and developed an overall package intended to enhance 1) application and award processes, 2) the ability to review applications for trials, 3) trial oversight, transparency, and efficiency, 4) sharing of clinical trial results. Specific elements of the package include: 1) use of a single IRB for multicenter studies; 2) a requirement for Good Clinical Practice (GCP) training for grantees and NIH staff; 2) Funding Opportunity Announcements specific for clinical trials that will specify required information and include clinical trial – specific review criteria; 3) direct applications to review panels with appropriate statistical and trials methodology expertise; and 4) specific Terms of Award that specify responsibilities including trial registration and results reporting in clinicaltrials.gov . Policies and resources are currently in development to support further recommendations from the Working Groups. While NIH recognizes that these changes will be very disruptive and that reality is vastly more complicated than can be addressed by a one-size-fits-all solution, our responsibility as stewards of the public trust creates an imperative for the highest standards of Clinical Trial practice and management.
Council Discussion: Council discussion centered on the unknowns regarding data sharing, GCP training, cost burden of these changes, and timing of these changes.
Update: Loan Repayment Program – Dr. Neeraj Agarwal
The purpose of the Loan Repayment Program is to attract and retain health professionals to a career in research by paying their educational debt. NEI supports activities within the program that support investigators doing patient-oriented clinical research or research on pediatric disorders. The program has a high success rate, 88% for NEI applications and 59% for NIH overall.
Report of the National Academy of Medicine: “Public Health Approaches to Reduce Vision Impairment and Promote Eye Health” – Dr. Mary Frances Cotch
This was an 18 month study sponsored by a partnership of ten professional, private, and governmental sponsors, including NEI/NIH. The charge to the group was to “Examine the core principles and public health strategies to reduce vision impairment and promote eye health in the U.S.” The committee first assessed the scope of vision impairment/loss in the U.S. noting that the majority of Americans over age forty have some degree of vision impairment and that visual impairment and loss have annual costs on the order of $140 billion. The impact of vision loss is correspondingly large including: Quality of Life; increased risk of physical, cognitive, sensory, and mental/psychological disorders; and interactions with other conditions.
The committee issued nine recommendations including declaring a goal to reduce the burden of vision impairment, creating a public/private partnership to increase public awareness, creating an eye/vision public health surveillance system, developing a research agenda, developing evidence-based practice guidelines, expanding professional education programs, aligning public health and clinical practice objectives, building state and local public health capacity, and developing partnerships of communities and health departments to promote eye and vision health.
A follow-up meeting of the committee and the sponsors will be held in March 2017.
Council Discussion: Which parts of these recommendations will be assigned to NIH will likely be determined at the level of the Department of Health and Human Services. Given that we are currently under a Continuing Resolution and looking at a transition of Presidential Administrations, it is unlikely that any new activities will be started prior to the next Council meeting.
Update: Age-Related Macular Degeneration Pathobiology National Advisory Eye Council Working Group – Dr. James Handa
AMD is the leading cause of blindness in the US and developed nations with an underappreciated impact on patients’ quality of life. Significant progress has been made in treating some forms but treatments for other forms are still needed. AMD is a complex disorder with multiple biological pathways affected by factors including aging, environment and race/ethnicity. The charge to the working group was to 1) consider biological causes and disease mechanisms of AMD disease; and 2) develop hypotheses for clinical study, including clinical trials founded on high impact preclinical evidence. The group’s discussions were framed by a set of six questions that considered future high value genetic studies, approaches to profile functional AMD phenotypes, biomarker validation and therapeutic targets, therapeutic strategies to slow progression, animal and in vitro disease models, and national resource needs.
The Working Group generally agreed that the identification of major new loci is unlikely and that genetics at present has limited use as predictive tool for risk or progression. Future studies should look to understand the relationship between genetic associations and impact on specific gene expression and protein function, and connect these changes to pathogenesis.
Working Group members recognized the opportunity for “omics” to characterize functional phenotypes of AMD as well as to illuminate the multiple pathways associated with AMD. Similarly, there is a need to identify and validate biomarkers and therapeutic targets. Despite discussion of several options no clear consensus arose on priorities.
The Working Group noted that systematic analysis of existing longitudinal data that have state of the art imaging modalities could determine reproducible, robust, imaging biomarkers. Additional longitudinal cohort studies could be designed to consider early disease or prevention and conversion from intermediate disease to either GA or NV AMD. Important factors to consider in the design of such studies include tissue(s) to be studied, current availability of patient populations and how to recruit new cohorts, and comprehensive characterization.
The Working Group agreed that the focus on developing animal and in vitro models should be on mimicking components of AMD pathogenesis that can be used for experimental manipulation and that there has been recent progress. Models are necessarily reductionist and we must be mindful of the complexities that are lost. Furthermore, since this is an age-related disease there are cost and time considerations.
The value of Biobanks that provides high quality, well characterized tissue was widely acknowledged as were the difficulties in logistics and high cost. No consensus emerged on where this should be prioritized. However there may be opportunities to develop appropriate national resources within existing programs with Biobanks (e.g. NIH Precision Medicine Initiative Cohort Program, Million Veteran Program). However standardization of tissue collection and clinical phenotyping are key.
In summary, Working Group members agreed that this meeting was an important and promising beginning. The nest discussion will focus on areas for special research emphasis, the future of AMD clinical studies, community resources, and novel funding mechanisms that encourage collaboration.
Council Discussion: Dr. Sieving reminded Council members that the purpose of this initiative is not to develop Funding Opportunity Announcements but rather serve as a think tank and high level resource for Council. Dr. Rhee noted that the Cleveland Clinic is developing a Biobank (with support from EverSight) that will be available to the public and acknowledged the value of standardized Standard Operating Procedures. Dr. Bassnett noted that given the cost of studying late onset diseases, access to NIA’s colonies of aged mice should be investigated.
GENERAL COUNCIL DISCUSSION:
The Council discussed the BRAIN initiative and Dr. Yuste noted that President Obama highlighted it as one of the important science accomplishments of his administration.
Council members endorsed the idea of having topic-based working groups to act as a think tank and provide advice on the state-of-the-art in certain areas of interest to Council. Given that NEI has historically not had topic-based FOAs, the present intent is not to use this group to identify or develop FOAs. Council members discussed how to capture and communicate the deliberations of the Working Group in a way that did not become restrictive or prescriptive.
The Open Session adjourned at 2:30 PM