National Eye Institute

National Advisory Eye Council (NAEC)
One Hundred Forty-second Meeting
January 21, 2016

The National Advisory Eye Council (NAEC) convened for its one hundred and forty-second meeting at 8:35 am on Thursday, January 21, 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, Anne E. Schaffner, PhD, as Interim Executive Secretary, and Michael A. Steinmetz, PhD, as Acting Director of Extramural Research.  The meeting was open to the public from 08:35 am until 12:30 pm.  The meeting was closed to the public for a session from 01:30 pm until 04:00 pm for the review of confidentiality and conflict of interest procedures and a review of grant and cooperative agreement applications.

Council Members Present:

Dr. Steven Bassnett
Dr. Laura Frishman
Dr. Jane Gwiazda
Dr. Douglas Rhee
Dr. Monica Vetter
Dr. Jayne Weiss
Dr. Rafael Yuste
Dr. Marco Zarbin

NEI Staff Present:

Dr. Houmam Araj
Dr. Neeraj Agarwal
Mr. Joseph Balintfy
Dr. Steven Becker
Dr. Sangeeta Bhargava
Ms. Pamela Bobbitt
Ms. Sylvia Braxton
Dr. Hemin Chin
Ms. Monique Clark
Mr. Jay Colbert
Ms. Karen Colbert
Mr. William Darby
Ms. Kathryn DeMott
Ms. Linda Dingle
Mr. Donald Everett
Dr. Shefa Gordon
Dr. Thomas Greenwell
Mr. Dustin Hays
Dr. Brian Hoshaw
Dr. Jeanette Hosseini (contractor)
Dr. Ellen S. Liberman
Mr. Chris Nee
Dr. Lisa Ann Neuhold
Mr. William O’Donnell
Dr. Steven Oversby (contractor)
Dr. Gyan Prakash
Dr. Maryann Redford
Ms. Karen Robinson-Smith
Dr. Gale Saunders
Dr. Anne E. Schaffner
Dr. David Schneeweis
Dr. Eleanor Schron
Dr. Belinda Seto
Dr. Grace L. Shen
Dr. Paul A. Sieving
Ms. Karen Robinson Smith
Dr. Michael Steinmetz
Ms. Chantelle Stevenson
Dr. Dan Stimson
Mr. Gerod Thigpen
Mr. Brian Trent
Dr. Santa Tumminia
Dr. Cheri Wiggs
Ms. Keturah Williams
Dr. Jerome R. Wujek
Ms. Maria Zacharias

Other NIH Staff Present:

Dr. Michael Chaitin, CSR
Dr. Samuel Edwards, CSR
Dr. Nataliya Gordiyenko, CSR
Dr. Peter Guthrie, CSR
Dr. Kathy Hudson, NIH OSP
Dr. Paek Lee, CSR
Dr. Larry Tabak, NIH OD
Dr. Kirk Thompson, CSR

Members of the General Public Present at the Open Session:

Dr. Alexander Chubykin, Dept. of Biological Sciences, Purdue University
Dr. Michael Crair, Yale University
Dr. Carol Mason, Columbia University
Ms. Iris Rush, ARVO

Open Session of the Meeting

08:35 am

Call to Order and Opening Remarks

Dr. Paul Sieving, NEI Director

Dr. Schaffner announced that the meeting was being videocast and brought Council members’ attention to folder contents, which included the annual report from the Society for Neuroscience (SfN). Dr. Sieving welcomed Council members. He was pleased to report that Congress had signed a budget into law that included a substantial increase for the NIH of 6.6%. NEI saw a 3.9% increase with an additional 5 million dollars (M) of “pass-through” money for the BRAIN Initiative, bringing the total increase for the institute to 4.6%.  The difference between the NIH and NEI numbers was essentially due to reach-throughs from DHHS on the NIH monies, equivalent to a Dean’s tax. Karen Colbert’s name was mentioned as the new budget officer who would be presenting budget figures. Dr. Sieving talked about 2015 success rates for RPGs across the institutes, which are publicly available at https://report.nih.gov/success_rates/. They ranged from highs of ~30% for NIGMS and 25% for NIDCD, down to 11.5% for NICHD. The NEI put 107M on the street to fund 273 awards out of 1278 applications, giving us a success rate of 21.4%. Larry Tabak, Principal Deputy Director at the NIH presented the 5-year, NIH-wide, Strategic Plan at the October 2015 Council meeting. The plan was congressionally mandated and delivered to Congress in December 2015 after much effort on the part of hundreds of stakeholders and advisors.  It is available on the web at http://www.nih.gov/about-nih/nih-wide-strategic-plan. The plan included statements regarding the nature of scientific discovery and acknowledged the health needs of the American people. Dr. Sieving thanked Drs. Ellen Liberman and Santa Tumminia from the NEI for their service on the Strategic Plan Working Group. 

NIH grant policy changes: Beginning with the January 25, 2016 submission date, reviewers will be asked to consider specific review elements including scientific premise, experimental design, particularly methods to obtain unbiased results, and sex as a biological variable. Training opportunities: Training grant applications mechanisms are highly valued by the NEI. We have both clinical fellowships and postdoctoral opportunities. The NIH has a good summer intern program for high school and college age students.

Dr. Sieving thanked Drs. Carol Mason and Mike Crair for chairing the workshop at the Chicago SfN meeting, the results of which they were presenting at the open session. The SfN annual report highlighted Carol’s science as well as the NEI’s AGI (pgs. 18-19). Dr. Steve Becker will give an AGI update and talk about a town hall planned for the upcoming ARVO meeting, which will engage clinicians in thinking about the nature of disease and suitable targets for regenerative therapies. Dr. Sieving presented “Vision Research, Breakthroughs and Clinical Care,” an overview of NEI vision science, at the Dec. 11, 2015 ACD (Advisory Committee to the Director) meeting. The talk was very well received, and the accomplishments of the vision community were noted by several in the audience. His presentation is available on the NIH video archive. (Paul starts 6:45 into the video.)  

BRAIN Initiative: The BRAIN Initiative came out of President Obama’s State of the Union address in 2014. The initiative was funded in 2014 with 46M and in 2015 with a total of 84M. NEI participated directly with a 1M contribution. Congress increased the NEI base to 5M in 2016. The vision community is benefiting!  About 40% of the funded projects in 2014 went to topics in vision such as neural organization of the retina, and 40% of the vision-related projects were led by NEI grantees. In FY15 a little over 20% of the funds went to vision-related topics. The Initiative will recruit a Director and engage NIH program staff. The Director will be located in the NINDS, and associated program staff will remain in their institutes. The White House focus in 2015 was a Precision Medicine Initiative (PMI) that led to 200M funding that same year. Another 200M for PMI was allocated in 2015. 70M went directly to NCI for their oncology initiatives and the remaining 130M to the NIH to develop a 1 million person cohort who will have full genotypes and medical phenotypes completed. Recruitment and data collection will take some time. Dr. Sieving had earlier engaged Council members on how the NEI could best leverage the PMI either by participating directly in the NIH PMI or through NEI-specific directives. The NIH PMI released 4 RFAs for a Coordinating Center, a network of health care provider organizations, mobile technologies, and a biobank. It will take considerable time to get all of this up and running. In terms of NEI’s plans to engage in Precision Medicine, we currently have active studies in gene discovery for glaucoma, myopia, ocular alignment problems and AMD. Dr. Sieving concluded his remarks with the mention of 3 areas that have had remarkable advances. A January 2016 paper in Nature Gen. by Janey Wiggs et al. reported on 3 glaucoma-related genes – the work of a genetics consortium established 9 years ago. One of the genes was ataxin-2, also associated with spino-cerebellar atrophy and ALS. It causes melting of the macula and is active in optic nerve. This shows an interesting overlap with other neurological conditions, although people with glaucoma have not been shown to be at greater risk for ALS. New genetic variants for AMD were identified. 34 loci with 52 variants are principal in conveying risk for AMD; however, understanding the cell biology will be the challenge. A major advance was discovered for the treatment of proliferative diabetic retinopathy. Treatment with the anti-VEGF compound, Lucentis, was found to be as effective as laser treatment.

Budget Update

Ms. Karen Colbert, Deputy Budget Officer, Financial Management Branch

The 2016 NEI budget appropriation had an increase of 4.6% which included a 5M increase for BRAIN research. After removing pass-through funds, the increase was 3.9%. The outlook is positive compared to the last few years. The NEI will fund noncompeting awards at the committed level. The average cost for competing awards remains flat at 2015 levels, and training grants will receive a 2% stipend increase. A recap of 2015 showed that 85.6% of the budget went to fund extramural research, just under 11% went towards intramural research and the remaining 3.6% went to administrative costs including salaries. The number of competing and noncompeting grants funded over the past few years has been fairly consistent (273 + 770 in 2015). The NEI success rate was 21% compared to an overall NIH success rate of 18%. The NEI has been consistently ahead of NIH success rates. The dip in the NEI success rate from 27% in 2014 was due to an increase in the total number of applications submitted to the NEI. Ms. Colbert shared her contact information and welcomed questions. 

She could not comment on whether the budget increase for 2016 would lead to an increase in our success rate; the NEI operating plan has not been approved by HHS, but it looks hopeful. Dr. Steinmetz explained that the number of RPG’s increased by 25%, which increased the denominator while the numerator remained flat; this accounted for the drop in our 2015 success rate. Council members directed several additional questions to Dr. Steinmetz. One was whether the increase in the number of applications reviewed affected our administrative costs. Dr. Steinmetz responded that it is more costly, and we are tapped for funds that go to CSR to cover these costs. Another question was raised regarding how successful “new” (virtual A2s) applications are in getting funded and if this data could be made available to the extramural community. Dr. Steinmetz said that it was difficult to say because CSR doesn’t examine the new applications to see if the aims have changed, and the data would thus be difficult to track. There are data from the years when A2’s and A3’s were allowed, and success rates did improve with submission up to the A2. The current policy was driven by the extramural community where members found it difficult to change aims and redirect their research. A further question was raised regarding whether the number of grants with modular budgets was going down. Dr. Steinmetz did not know the answer to that question; however, he said that the average cost of NEI grants has been fairly flat over the past 5 years. The final question was what kind of a budget increase would be necessary to maintain buying power to keep up with inflation. Dr. Sieving responded that the budget doubling of 10 years ago has been completely lost through inflation. He mentioned the biomedical research and development price index known as the BRDPI (“bird pie”). The index is updated annually by the Department of Commerce, and estimates the costs of conducting medical research. It has gone up 24.5% over the past 7 years. It takes about a 2-2.5% yearly increase in the budget to keep up with inflation. With a constant budget, our buying power is down about 20%.

Council Operating Procedures

Mr. William Darby, Chief, Grants Management Branch

Every January, Will Darby is tasked with presenting the Council Operating Procedures and what actions are required of Council members with respect to grant applications. Council reviews applications with special considerations, such as vertebrate animal, biohazard, human subject and inclusion concerns, and Phase III clinical trials and foreign applications that are likely to be funded. Council also reviews applications being considered for High Program Relevance (HPR). Special Council Reviews are brought to the attention of the NAEC. The latter is when a PI will receive > 1 million in direct costs from the NIH. Letters of grievance and appeal are brought to Council. The appeals process states that there are only four grounds for an appeal–bias, a specific conflict of interest present during review, lack of expertise, or factual errors that impacted the score. Scientific differences of opinion are not grounds for an appeal. If the criteria for an appeal are not met, then the applicant’s concerns are considered a grievance. If there are grounds for an appeal, then the applicant institution submits the appeal. Council has two options—they vote to agree with the appeal, in which case the original application with no changes is sent back for re-review—or deny the appeal and concur with the original review group.  Some changes are handled independently by staff without requiring Council approval such as appointing a new PI, moving a grant from one institution to another, awarding supplements to existing grants for equipment, etc. and handling termination procedures. Council members should never personally discuss pending applications or issues with someone in the extramural community. Such communications put the member in conflict with the application should it come before Council. If a Council member is contacted by an investigator, there is a standard response letter in the Council Operating procedures on the ECB (Electronic Council Book) they can send to the investigator. The Council member should also contact the Director and/or the Executive Secretary any time such contact occurs. All pending issues need to be considered by all Council members. A vote was taken to approve the Council Operating Procedures for 2016. Council unanimously voted in favor.  A copy of the 2016 Procedures as well as Guide Notices regarding Special Council Review and Appeals have been uploaded to the ECB.

Scientific Presentation

Drs. Carol Mason and Michael Crair, Co-Chairs of the AGI Workshop on Reconnecting Neurons at the October, 2015 Society for Neuroscience Meeting in Chicago. 

Dr. Mason began by stating the problem that retinal ganglion cell neurons (RGCs) generally fail to regenerate after retinal or optic nerve damage. The emphasis of the workshop was to discuss ways in which axons can regrow, and the cellular and molecular attributes that allow them to regrow. The presentation was divided into 2 parts; Dr. Mason addressed the cellular and molecular aspects and Dr. Crair addressed target engagement. As background for the workshop, the state-of-the-art on axon guidance and target engagement was reviewed. There were about 20 investigators on the panel including those in the area of spinal cord regeneration, and 60 outside participants. The Journal of Neuroscience agreed to publish a white paper on the workshop. 

Dr. Mason presented results and challenges in rodent models of axon regeneration from eye to brain and across the optic chiasm. There is a consortium of guidance cues at the midline that involve attractants (e.g., VEGF), repellants, and permissive molecules for both ipsilateral and contralateral fibers. A major question is how axons are organized at the nexus. There is evidence that ipsilateral and contralateral fibers are distinctly organized and only partially overlapping with the topography of the optic tract, but the cues for this organization are unknown. Glial cells, including macrophages, polydendrocytes and microglia have both deleterious (myelin) and positive effects on axon regrowth. In development these cells are important for passage through the midline. Blocking the myelin proteins have not been generally useful in permitting regrowth. Macrophages make oncomodulin, a substance that increases signaling. A suppressor of signaling in astrocytes, SOCS3, if repressed, can enhance regeneration in the optic nerve (Benowitz and He). In retinal ganglion cell neurons (RGC). mTOR, which is blocked by PTEN, must be upregulated to allow axon regrowth. If suppressors of neurite outgrowth like PTEN and KLF4 are blocked, then optic nerve regeneration is enhanced (Goldberg and He). He et al. have found that specific kinases that causes microtubule elongation, also promotes RGC survival and induce growth cones, both of which are required for axon regeneration in the optic nerve. Dr. Mason reviewed the state of RGC stem cell biology. An article by Sanes and Masland described about 50 unique classes of RGC’s based on their morphology and function, which is ultimately based on differential gene expression. Knowledge of the transcription factors (TFs) regulating differentiation of RGC subtypes and controlling contralateral versus ipsilateral fibers coming from these subtypes will be an important in directing RGC differentiation from stem cells. Work from several labs indicates that the SoxC family of TFs are important for contralateral fibers, while control of ipsilateral fibers is quite distinct and involves FOXD1 and EphB1. Timing of neurogenesis and when cells are born also determines their identity and ultimate target. Some advances have been made in creating RGCs. The Goureau lab in Paris has been successful in generating RPE cells and retinal-like neurons from human IpSCs in vitro. No successful transplantation or axonal regrowth from these cells has yet been achieved. The He lab has also made the discovery that some RGC subtypes are better able to regenerate after optic nerve crush. aRGCs account for nearly all of the regeneration after blocking PTEN. These cells selectively express osteopontin and have receptors for other growth factors. This is promising. Dr. Mason went on to describe four major challenges to progress in the field of regeneration. First, axons must get past the optic chiasm. Second, better models than optic crush are needed to mimic human trauma. Third, it must be determined how much recapitulation of the developmental program is necessary. Fourth, the generation of RGCs from stem cells and their successful transplantation must be achieved. 

Technical advances and opportunities include live imaging, and discovery of genes (in C. elegans) that control guidance and regeneration. Live imaging has revealed axon regrowth over time, and interestingly, the regenerating axons fasciculate with extant, uninjured axons. Glycerophospholipids, released by glia, are a new class of molecules that appear to regulate targeting of regenerating spinal cord axons. 

Gaps in our knowledge include an understanding of what conditions are required for remyelination. Regenerating axons are unmyelinated and exhibit poor conductivity, but treatment with the voltage-gated potassium channel blocker 4-AP and other factors enhances conduction and results in better visual acuity in a mouse model where the optic tract has been cut. We need to know more about the role of inflammation in regeneration, and neuroprotection is also a necessary prerequisite for RGC survival and regeneration of axons. Basic researchers also need to engage clinicians to determine what patients and what diseases are the easiest to target.  We need a model for optic neuritis, a condition that affects many people. There is also evidence from spinal cord that injured axons undergo mitochondrial alterations in the early disease stage, and perhaps targeting those changes in the optic nerve might make it possible to save axons.     

Dr. Michael Crair gave the second part of the presentation, focusing on aspects of central targeting, synaptogenesis and circuit formation. Dr. Crair cited the complexity of both central targets and different RGC subtypes in forming connections, and synaptogenesis as a dynamic and highly regulated process that is also tightly linked to overall circuit development. Barriers to progress outlined at the workshop included the limitations of the optic nerve crush model, and that developmental studies of synaptogenesis will ultimately need to be extended into the adult context. Additional questions included formation of new RGC connections to the “wrong targets”, and how many neurons are needed to restore visual function. Techniques to visualize and measure the function of regenerating axons, synapses and circuits are critical, and the BRAIN Initiative was cited as a potential resource. Basic research into regenerative lower organisms (e.g. amphibians), the potentially opposing regulation between regeneration and synaptogenesis pathways, optogenetics, and standardized optic nerve injury models are other areas for additional investigation. 

Final thoughts from the workshop included the idea that incremental regeneration could result in significant visual function improvement, and the promise of stem cell therapies and combinatorial approaches (e.g. partial RGC regeneration combined with an implant or methods to induce cortical plasticity) were also cited. In order for these advances to be translated into humans, viral gene therapy techniques need to be optimized for use in primates. Visual training therapy and a greater understanding of adult plasticity also need further attention. Increased engagement with the clinical community is also key, including consideration of what disease(s) are best suited for an initial study. 

The workshop concluded with asking the participants their estimate of how long functional recovery in humans will take. As far as simple restoration (i.e. detection of light), it was generally agreed that this can be done in mice very soon, and in humans in 5-10 years. Substantial RGC recovery in mice was thought to be feasible in 5 years, and in humans in 10-15 years, perhaps through a combined approach using a biological intervention (to achieve short distance axon growth) plus an engineering device to encourage growth to the geniculate. Photoreceptors were also acknowledged as a more attainable target, as they don’t require long distance axon regeneration. RGC cell protection in combination with methods to promote central plasticity was also proposed as another approach which may be more feasible, as would partial injury or disease models, such as optic neuritis, where prevention of degeneration in combination with enhanced regeneration and plasticity may be more easily achieved.

Several questions and considerations were raised in a discussion that followed the presentation. One was whether high resolution adaptive optics could image the different types of RGCs. Dr. Mason responded that this is doubtful; a marker, like a reporter would be necessary to see details of cellular morphology. A Council member commented that in glaucoma, neuroprotection strategies appear to inhibit regeneration, a point that Dr. Mason said was also raised at the workshop, but there was no definitive information on that topic. Olfactory ensheathing cells appear to promote ganglion cell survival, and given the complexity of the mammalian system and the myriad factors involved, perhaps organ or cell culture systems could be used for transplantation. Dr. Crair responded that we could learn from other model system like amphibians where ganglion cells can regenerate, and mammalian organ systems like the hippocampus, where there is considerable regeneration of cells in the adult. Interactions with the neuroscience community in general will be helpful. An interesting comment from a Council member was that it might be more important to know if something works rather than how it works! There was interest in why optic neuritis, an inflammatory condition that is also a sequela of multiple sclerosis (MS), was mentioned as a target disease. Dr. Mason said there is loss of RGCs and axonal connections, a phenomenon that is shared with glaucoma. Another Council member commented that there have been two recent breakthroughs in the MS field with successful remyelination in MS patients using stem cells, and the generation of a monoclonal antibody that has aided in recovery from optic neuritis. Engaging clinicians, especially neurologists, will be advantageous to any discussion of regeneration in the visual system.  Panelists and participants of the workshop considered it enjoyable and informative, likely due to the format that included only brief presentations by the Co-Chairs and a set of questions provided for the panelists before the workshop by the NEI AGI Committee that helped direct the discussion.

Lens and Cataract Portfolio Analysis

Dr. Houmam Araj, NEI Program Officer

Dr. Houmam Araj has been directing the NEI Lens and Cataract Program since 2006. Based on a request by Dr. Sieving for an update on the Program to Council, Dr. Araj gave an overview of lens and Cataract research in general, and funded lens and cataract projects in particular. The Lens and Cataract program, in FY 2015, accounted for 7% of the NEI extramural budget and the same fraction of total grants. Following introductory comments on the scope of the Program – Dr. Araj proceeded to describe three main themes that serve to summarize lens and cataract research: Lens development; Homeostatic dysregulation and cataract formation; and Oxidative damage and cataractogenesis. In order to illustrate some of these broad areas of research, Dr. Araj presented some success stories from the field. The first story, which has been unfolding over the past century, beginning with the classic experiments of Hans Spemann, involved the process of lens induction and its central role in lens and eye formation. Pax6 is a master regulatory gene in the pathway from presumptive lens ectoderm to formation of the lens placode. Current research in lens induction and development continues to reveal the role of TFs and signaling pathways controlling differentiation. A second success story, which has unfolded over the past year, involved the potential linkage between the cholesterol biosynthesis pathway and cataract formation. One group of investigators (Makley et al.) created a knock-in mouse model of human cataract followed by high throughput drug screening and discovered that compound 29, related to lanosterol, was able to partially restore transparency both in vitro and in vivo. A second group (Zhao et al.) cloned the gene for a mutant aA-crystallin, which they expressed in human lens progenitor cells. When cells were exposed to lanosterol, protein aggregates were completely dispersed. In a canine model, 3X daily, topical treatment with lanosterol was able to significantly reduce lens opacity. Interestingly, lanosterol is a precursor of cholesterol, which raised concerns about the use of statin drugs for cholesterol management. However, to date a consistent relationship between statin therapy and the development of cataracts has not been established. Another intriguing point is whether a compound like lanosterol, that resolves a protein aggregation in the lens could also have a beneficial effect in other diseases that involve protein aggregation or misfolding, such as Alzheimer’s and Parkinson’s, etc. Dr. Araj next highlighted the unique opportunities presented by the lens as a model system as well as the clinical significance of cataract, secondary cataract (PCO), and presbyopia. The beauty of the lens system is its simplicity with only 2 cell types, a high protein concentration and the virtual absence of organelles. There is also a complexity in the myriad post-translational modification and truncation of lens proteins. In terms of its clinical significance, cataracts are responsible for 35% of the world’s visual impairment and over half (51%) of the world’s cases of blindness. Dr. Araj also alluded to the potential linkage between lens research and the NEI Audacious Goals Initiative (AGI), especially the role of lens molecules in axon guidance and regeneration, in addition to linkages between lens investigations and other areas of research within NEI and NIH. Finally, Dr. Araj discussed some of the complexities and challenges facing the lens and cataract field and then opened the floor for feedback from Council members. Feedback was positive especially on the inclusion of the AGI angle into lens research interests. A Council member pointed out that although the AGI focuses on the retina, the AGI RFAs do overlap with the interests of the lens community, and where appropriate this could be brought to the attention of lens researchers. There was also the observation that 2/3 of NEI grants are not retinal, and Council should appreciate the “totality” of the eye and avoid a silo approach. A Council member requested future portfolio presentations and specifically mentioned the cornea program.

AGI Update

Dr. Steven Becker, AGI Liaison, Office of the Director, NEI

Dr. Becker started his presentation with the NEI AGI timeline and mentioned the three successful workshops to date: “Optic Nerve Regeneration” at the November 2014 SfN meeting, “Photoreceptor Regeneration” at the May 2015 ARVO meeting and “Reconnecting Neurons in the Visual System” at the October 2015 SfN meeting. A fourth workshop is in the planning stages for the upcoming ARVO meeting in Seattle. The focus will be “Retinal Ganglion Cell Replacement.” Muller glia and other cells will be examined as potential sources for RGC replacement and how migration and integration of these cells can be utilized. Dr. Monica Vetter from Utah and Dr. Peter Hitchcock from Michigan will act as co-Chairs. There are a number of confirmed participants for the RGC workshop. January 1, 2016 was the submission deadline of the most recent RFA entitled, Discovery-based Science to Identify Factors Influencing Neural Regeneration in the Visual System (U01), which seeks the identification of new, neural regeneration factors. So far there have been 20 letters of intent submitted. Dr. Becker also mentioned the AGI Town Hall planned at ARVO to engage physicians and the vision community in a discussion of what ocular diseases and disease states are potential targets for neuro-regenerative medicine. An NEI AGI online discussion forum will be launched to afford the vision community an opportunity to comment on past workshops and provide insight on regenerative therapies. The NEI is also planning for a workshop at the November 2016 SfN meeting in San Diego, “Creating a Cellular Environment for Neuro-regeneration. The focus will be the interactions of photoreceptor and ganglion cells with other cells and the extracellular environment that are necessary for regeneration. It will be patterned after previous workshops to include a discussion of gaps in knowledge, barriers to progress and promising strategies for future research. The AGI seminar series on neuro-regenerative medicine was kicked off with a talk by Josh Sanes from Harvard U on November 2, Assembly of Feature Detecting Circuits in the Retina. Future talks scheduled for 2016 include Dennis Clegg from UC Santa Barbara who will talk on stem cell therapy for ocular disease and John Flanagan from Harvard who will speak about molecular cues for axon guidance and regeneration. The NEI AGI web site is being constantly updated, and Steve encouraged the audience to take a look. The 2016 SfN workshop was put forward to Council members for concept clearance, and they endorsed the proposal. 

High Priority Area: Molecular Therapies for Eye Disease

Dr. Steven Becker and Dr. Houmam Araj

Drs. Becker and Araj provided Council with an update on a Funding Opportunity Announcement (FOA) published in 2013, PA-13-283, that solicited R01 applications for a high priority area, Molecular Therapies for Eye Disease. The FOA encouraged approaches that utilized 1) control, modification or delivery of genetic material, or 2) the use of small molecules or optogenetics to treat eye disease. Dr. Becker described the background and rationale behind the FOA and provided Council with some data. Over the past 2 years, 58 applications have been submitted under the FOA, and 13 have been funded, which is an overall success rate of about 30%. There are no set-aside funds for these, and they are reviewed in regular CSR study sections. He presented information on the funded investigators and the disease focus. Approaches run the gamut from stem cells to optogenetics to encapsulated cell therapies. Applications were in program areas of retina, cornea and glaucoma. Dr. Becker highlighted the work of three groups. Martin Katz at the University of Missouri-Columbia will develop a drug delivery system in a dog model of late-infantile neuronal ceroid lipofuscinosis (LINCL). This condition is caused by a mutation in the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1) that results in brain atrophy, retinal degeneration and blindness. The Katz group will employ two strategies, a cell-based delivery system and gene therapy to achieve continuous delivery of TPP1 to the vitreous. A second project from Lbachir Ben Mohamed from UC Irvine will develop T-cell based immunotherapeutic strategies to prevent reactivation of herpes simplex virus type 1 (HSV-1) and prevent corneal blindness due to latent HSV-1 infection. Demetrios Vavvas from MEEI is investigating a form of cell death, necroptosis, involved in RGC death in glaucoma. This work will examine the enzyme pathways involved in necroptosis and develop neuroprotective strategies by inhibiting the pathway(s) in animal models of glaucoma. These projects fit nicely into the NIH’s current emphasis on precision medicine. 

General Council Discussion

Dr. Bassnett was the NAEC representative to the NIH BD2K initiative. He shared the results of a teleconference in which he participated. The initiative was established to consider ways to store, mine and train for the myriad data coming out of electronic medical records and other biomedical data. Eleven Centers of Excellence were identified in 2013. The open session of the meeting included updates on BD2K, results of an all-hands meeting, presentation of concepts for possible 2017 funding and the QUBBD Initiative, which seeks to partner NIH biomedical investigators with quantitative investigators in NSF division of mathematical sciences to form teams to tackle the problems presented by big data. There was discussion of training (T32s) and diversity initiatives to partner with under resourced organizations. There was also a discussion of the review of social media and crowd-sourcing applications to help (https://www.heartbd2k.org). This is similar to the online game, Foldit, that engaged the public to help decipher the 3-D structure of proteins.

Infrastructure development is the current emphasis of BD2K, and these efforts will, in the future, also coalesce with precision medicine.

A Council member raised a community concern regarding the burden of information required for the T32 institutional training mechanism. Dr. Neeraj Agarwal, the NEI training officer, responded that with the May 25, 2016 receipt date there will be new, user-friendly and fewer tables required for T32s and T35s. A Guide Notice was published with information on the new tables, NOT-OD-16-007. Dr. Agarwal also mentioned that any forthcoming announcements about administrative supplements for incorporating BD2K training would be sent out to all current NEI T32 investigators. Dr. Bassnett said that NEI did not appear to be represented in terms of BD2K initiatives, either in Centers or training, and asked how we might better leverage the opportunities. Dr. Steinmetz commented that the current announcements are for data technology—writing code etc., areas that are not the strength of the vision community.  The point was raised that there are basic researchers looking at synapse control and regeneration, and they might benefit from concepts that already exist in computer design. A symposium at ARVO might be advantageous to bring those knowledgeable with network design, diodes, and circuitry, etc. to share their knowledge. Dr. Steinmetz mentioned that things are actually moving in the opposite direction, and it’s the human brain that has faster and better parallel processing “algorithms” that are of interest to computational people. There was mention of CRCNS (Collaborative Research in Computational Neurosciences) a joint NIH and NSF program designed to bring together multidisciplinary expertise in a wide variety of areas including electrophysiology, gaming, economic theory, machine learning etc., and the program has been very successful.  Dr. Cheri Wiggs is the NEI liaison to CRCNS. The NEI funds one or two grants every year out of this program and targets younger investigators and people who are new to vision research.

This concluded the Open Session of the meeting.  The Open Session adjourned at 12:30 PM.

Certification

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.

Anne E Schaffner, Ph.D.                                                                             
Interim Executive Secretary
National Advisory Eye Council
National Eye Institute

Paul A. Sieving, M.D., Ph.D.                                                                                   
Chairman, National Advisory Eye Council
Director, National Eye Institute

Last updated: May 28, 2020