National Eye Institute

National Advisory Eye Council
One Hundred Forty-ninth Meeting
June 14, 2018

The National Advisory Eye Council (NAEC) convened for its one hundred and forty-ninth meeting at 8:30 am on Thursday, June 14, 2018 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 Acting Deputy Director of NEI and Director of Extramural Science Programs. The meeting was closed to the public from 8:30 am until 10:00 am for the reviews of confidentiality and conflict of interest procedures, the Report of the Board of Scientific Counselors and grant and cooperative agreement applications. The meeting was open to the public from 10:00 am until 1:30 pm.

Council Members Present:

Dr. Jose-Manuel Alonso
Dr. Eduardo Alfonso*
Dr. Steven Bassnett
Dr. Thomas Glaser
Dr. Jane Gwiazda
Dr. Dennis Levi
Dr. Carol Mason
Dr. Louis R. Pasquale
Dr. Douglas Rhee
Dr. Sylvia Smith*
Dr. Mary Ann Stepp
Dr. Russell Van Gelder
Dr. Marco Zarbin

*Participated via telephone

NEI Staff Present:

Dr. Houmam Araj
Dr. Neeraj Agarwal
Dr. Sangeeta Bhargava
Dr. Steven Becker
Mr. Gary Berkson
Ms. Cindy Best
Ms. Sylvia Braxton
Ms. Pamela Bobbitt
Ms. Sylvia Braxton
Dr. Brian Brooks
Ms. Monique Clark
Mr. Jay Colbert
Ms. Karen Colbert
Ms. Ashley Dash
Ms. Linda Dingle
Ms. Kathryn DeMott
Ms. Courtney Dodson
Dr. Lesley Earl
Mr. Don Everett
Dr. Martha Flanders
Dr. Shefa Gordon
Dr. Thomas Greenwell
Mr. Dustin Hays
Dr. Brian Hoshaw
Dr. Jeanette Hosseni
Dr. Ellen S. Liberman
Dr. George McKie
Dr. Sheldon Miller
Dr. Lisa Neuhold
Dr. Gale Saunders
Dr. Maryann Redford
Ms. Karen Robinson-Smith
Dr. Anne Schaffner
Dr. David Schneeweis
Dr. Peter Shan
Dr. Paul A. Sheehy
Dr. Grace L. Shen
Dr. Paul A. Sieving
Dr. Michael Steinmetz
Ms. Chantell Stevenson
Mr. Brian Trent
Ms. Melissa Trinchet
Dr. Santa Tumminia
Ms. Veronica Van Wagner
Dr. Cheri Wiggs
Ms. Keturah Williams
Dr. Charles Wright
Dr. Jerome R. Wujek
Ms. Maria Zacharias

Other NIH Staff Present:

Dr. Michael Chaitin, CSR
Dr. Nataliya Gordiyenko, CSR
Dr. Peter Guthrie, CSR
Dr. Kristin Kramer, CSR
Dr. Paek Lee, CSR

Members of the General Public Present at the Open Session:

Mr. James Jorkasky, National Alliance for Eye and Vision Research
Ms. Allison Manson, American Optometric Association (AOA)
Dr. Donald J. Zack, Guerrieri Professor of Genetic Engineering and Molecular Ophthalmology, Wilmer Eye Institute
Mr. Matt Winsor, ARVO

Open Session of the Meeting

10:30 am

Call to Order

Dr. Paul Sheehy

DR. SHEEHY: I would like to go through a couple of housekeeping things, just before we get everybody started and the presentations started.

First, please do remember to sign your conflict-of-interest sheets and give them to Gale Saunders.

Second, again, if you're planning any changes to your travel, please connect with Gale.

And this is our final meeting in 5635 Fishers Lane at the Institute. NIH is leaving this building and we are moving to a more centralized NIH extramural campus about 4 miles to the west of us. It's 6700B Rockledge Drive. So, that is not on a Metro stop. We will have information about transportation and all in our mailings for the October Council meeting.

One of the things I wanted to give Council members an alert to is that at our previous meetings we've talked about an RFA for the Audacious Goals Initiative. It will be reviewed this summer, and we would like to commit this year's fiscal year funds. So, we are going to have a web­ based Council meeting the last week in August, the week of August 20th. I will be sending you out doodle polls to find an hour of availability, and it may be WebEx; it may just be a teleconference. The AGI and another upcoming clinical trial will be addressed. It will be very focused. There will be no open session. It will just be business.

And then, finally, I want to be sure that you all are aware of the upcoming Council dates. The NIH Institute Directors typically have their meeting with Dr. Collins on Thursdays. That conflicts with Dr. Sieving's opportunity to be there. So, we are moving our Council meeting to Fridays. The dates that you might have blocked off in your calendar are going to be different. We are going to start Friday meetings as of October.

Any questions? (No response.)

Thank you very much.

COUNCIL MEMBER: Will it be the same week? We had it on Thursday, but just switch it to Friday? Is that the case?

DR. SHEEHY: Yes.

COUNCIL MEMBER: Okay. Thanks.

DR. SHEEHY: And just to alert you again, now that we're in open session, all our discussions are being webcast. So, please be mindful of the confidentiality of our previous discussions.

Opening Remarks

Dr. Paul Sieving, NEI Director

DR. SIEVING: Yes. Thank you for attending the 149th convening of the National Advisory Eye Council.

I would like to just give you an overview of some events that are happening at the Eye Institute and at NIH.

First, let's start with some big and positive news. Okihide Hikosaka is a scientist in the Laboratory of Sensorimotor Research, LSR, and was awarded the Gruber Foundation Prize, the Gruber Neuroscience Prize for 2018. That is a major recognition. Dr. Hikosaka is working in the basal ganglia. This is a region that has input to saccadic eye movement, very interesting work.

And I would add that the Gruber Prize has a recent record of work in the visual system; this year, Okihide; last year, Josh Sanes, and two years prior to that in 2015, Carla Shatz. That’s very nice.

Our Special Government Employee for the day, Dr. Carol Ann Mason, was elected to the National Academy of Sciences.  She is from Columbia University. We appreciate you being on the Eye Council and also for representing NEI to the BRAIN Multi-Council Working Group. Congratulations, Carol.

We have a new science writer, Lesley Earl, in the Office of Science Communication, Public Liaison, and Education. Dr. Earl has a PhD in cellular and molecular pathology from UCLA, and then, came to the Dental Institute, NIDCR, as a post-doctoral fellow and moved to science writing at the National Cancer Institute, NCI, and now, is with us. Lesley, thank you for some of the notes that I'm looking at right in front of me here.

Let me mention something about the budgets. We have positive news. March 23, which puts it just before ARVO, the FY 2018 budget was passed. NEI received an increase to a total of about $770 million for the current year. You'll hear more about some specifics from Karen Colbert, who is the head of the NEI Budget Office.

But I do want to just add the following: in 2017 -- so, that's a year ago -- we funded 1157 grants, which was up nicely from the 1090 of 2015. But recognize that the grants year by year do not follow in exact lockstep because there is a wave with about a four-year cycle because of the four-year average of our awards.

Keep in mind that it's nice to have 1157 in the year 2017, but that is down 10% from the high-water mark of 2004. So, if you think it is harder to get funded, in fact, you're right.

There are fewer R mechanisms being put out because the monies have not kept pace with inflation.

On the NIH level, the increase was $3 billion, taking NIH to $37 billion, representing an 8.8% increase overall for NIH. So, you can ask why did NEI only receive 5.4%? The principal reason for that is specific earmarks in the omnibus report language for the current year totaling $1.1 billion out of the $3 billion put to NIH. And those monies include $414 million for Alzheimer's, new money this year going into the base. BRAIN received $140 million new money. Antibiotic resistance, influenza, and opioid -- opioid we know is a nationally urgent issue. Opioids received $500 million. So, that totals $1.1 billion, which in large part explains the percent increase difference between NIH and NEI. All worthy causes, but we would like to have opportunity to fund additional investigators.

If you look at the slide there, you see the name "Steve Becker". Steve will be talking in a moment on regenerative medicine activities at NIH. And I would mention, as I did previously, that one of the impetuses for this is new monies to NIH, trans-NIH initiative, and regenerative medicine. That comes through the 21st Century Cures Act. It is small money by the standards of NIH, a four-year total of $30 million. But it is turning out to be important nucleating money that is pulling the Institutes together to figure out how to collaborate and how to move regenerative medicine forward.

So, it has the flavor of the BRAIN Initiative, which is also trans-NIH. And Steve will tell you about that.

Notice up there that, in addition to the Regenerative Medicine Innovation Project, which is NIH level, NEI has two substantial efforts in regenerative medicine, the AGI, going back several years, and, more recently; the retinoid challenge.

Keturah Williams, who is a program analyst at NEI, will tell you about Vision Research opportunities for collaboration with the Department of Defense, DoD, which has a Vision Research Program. But I will leave those details to Keturah.

Later on in the morning, we'll hear from Ellen Liberman, who is the Program Director for glaucoma. And we can congratulate one of our Council members, Lou Pasquale, and others, for a remarkable achievement in accumulating a large number of very carefully defined bases of human glaucoma. And the group Neighborhood recently published a major compendium of genetic factors and variants that are contributing to high intraocular pressure, which is certainly one of the drivers of optic nerve damage as seen in glaucoma.

Getting back to the slide ahead of us, let me just spend a moment on the Audacious Goals Initiative. As Paul Sheehy already mentioned, there is a third initiative that was put out in December 2017 with the application closure in March of 2018. So, that is completed and those applications will be looked at shortly.

That funding opportunity is titled "Translation-Enabling Models to Evaluate Survival and Integration of Regenerated Neurons in the Visual System". The point of this is to move beyond theory and into practice with models that recognizably have elements that mimic human disease and, hence, serve appropriately to develop pre-IND data that can move forward ultimately into human trial. So, I'm pleased to see that third announcement because I believe it turns the corner on the AGI now moving down a pathway toward human intervention.

The amount of monies that will be committed to this -- you've heard this before -- it's on the order of $5 million a year, which is money targeted toward an endpoint, but which is pretty high­-risk kinds of monies to be putting out, a high-risk venture.

We have updated the AGI Steering Committee. I would say that the composition reflects a need to keep AGI broad and based in continuing biology, discovery biology, while recognizing that we have a target that we're aiming for which is to get into human therapy trials.

The original AGI charter described having three to five members, terms of three years which can be renewed. And at this point, we have five Steering Committee members; two continuing, Mark Blumenkranz and Josh Sanes.

Mark is a vitreoretinal surgeon, was Chair of Ophthalmology at Stanford, and is very innovative and has association with early-stage biotech and biopharma; adds a dimension that's needed to the Steering Committee.

The second continuing member is Josh Sanes at Harvard. As you will recall, I invoked his name a moment ago because he received a Gruber Prize in neuroscience last year. He is known

for work in synaptic activity and is part of the Multi-Council Working Group for the BRAIN Initiative. So, immediately, you can see that the AGI has an extension into the BRAIN Initiative.

Three new members. Another Council member doing double duty -- Russ Van Gelder, Chair of Ophthalmology, University of Washington, highly knowledgeable about retinal cellular structure and function in relationship to how this actually works in you and me, in human; also known for melanopsin light responsive cells, translational interest and intent. Russ, thank you for helping on this.

Another new member is Clive Svendsen, a name probably not known to clinical vision people, but likely well known to basic vision people. He is at Cedars-Sinai, Director of the Regenerative Medicine Institute there, and is known for looking at GDNF as a survival factor in treatment of ALS. So, here you have a person who is a discovery biologist and applying at least part of that activity into the translational realm.

And then, the fifth and final is Rachel Wong, who is at the University of Washington, a basic scientist working in retina neuroconnectivity and synaptic function. All of those things are going to be critical as we attempt to put cells from the outside world into the sub-retinal space adjacent to photoreceptors that are in jeopardy from disease and expect that they will connect and wire appropriately.

As I said, it's nice to have a target, but one has to also be cognizant that we don't yet really know how all of this is going to play out, which means we need to continue to incorporate discovery biology in the AGI fabric.

Another AGI activity, or one that's past, at ARVO we had a very interesting evening session. I would thank the group that we have here internal to NEI for organizing that and for Steve Becker in ultimately putting things together.

Three speakers:

Ula Jurkunas at Harvard, who is working on autologous limbal epithelial cells, a transplant for corneal issues.

The second is Susanna Park at UC Davis, who has taken up the challenge of whether bone­ marrow-derived stem cells put into the retina, in fact, have therapeutic potential. That is an urgent issue because, if it's correct, it is very important ultimately therapeutically, but also urgent because of the context of, let's say, scientifically difficult, tenuous trials that are going on, poorly supervised, in some of the southern states by retinal surgeons.

The third, Kapil Bharti, is here at the NEI and is working on deriving human RPE from human fibroblasts taken through the route of IPS cells. And we will be transplanting those in the NIH Clinical Center for the condition of dry AMD. I believe that IND is expected by the end of, I think it is by the end of 2018.

So, that was the evening session at ARVO. I found it delightful, scientifically delightful.

And then, an upcoming event is a workshop, an AGI workshop, that we will convene here at NIH in September on Pathways to Retinal Cell Replacement Therapies. In talking with potential speakers, there was great enthusiasm to share knowledge because there is no single individual who knows enough to put this story together, even at the final stages. So, that will be coming up.

And then, let me conclude by just mentioning that we are in the NEI 50th anniversary year, from 1968 until the present. We are organizing four symposia. Two have already occurred. The first on vision and the brain, held in conjunction with the Society for Neuroscience meeting here in D.C. in December 2017. And that was also an occasion to recognize 50 years of outstanding science by Bob Wurtz and the laboratory that includes Okihide.

And then, that was followed March 22 by vision and immunology. In June, later this month, there will be a symposium on vision rehabilitation, which extends far beyond the mantra "Make it bigger; make it brighter, and you see it easier." We are into neural prostheses at this point in the Vision Rehabilitation Program.

And then, in October, we will conclude with a symposium just looking forward to what is coming down the road for the future of vision research.

So, those are some of the events that are happening at NEI. We have a dynamic and active Institute, and NIH is an interesting and busy place.

Let me entertain three-and-a-half minutes of questions.

COUNCIL MEMBER: Does the October symposium link up to the October Council meeting timewise?

DR. SIEVING: I don't know specifically on that. That is on October 18. I think that's on a Thursday.

Yes, and plane tickets are available.

All right. Good. Thank you. We'll move on.

Update: Cures/ Regenerative Medicine

Dr. Steven Becker

DR. BECKER: Good morning. It's my pleasure to give you updates on our regenerative medicine programs both at NEI and NIH.

And thank you, Dr. Sieving, for teeing it up so nicely. I won't spend too much time going into the details, but, please -- I see some new faces -- if you have any questions, please don't hesitate to ask.

So, the NEI Audacious Goals Initiative, it's our goal to regenerate the neurons and the neural connections of the eye and the visual system. I'm going to give you a brief recap of where we've been and where we hope to go.

The 3-D Retina Organoid Challenge is a prize competition to generate a robust 3-D human retina culture system in order to recapitulate the complexity, organization, and function of the human retina.

And I'll give you an update on what Dr. Sieving mentioned about the Trans-NIH Regenerative Medicine Innovation Project, and its goal is to really accelerate the field by supporting clinical research on adult stem cells in coordination with the FDA.

So, a little bit of background. AGI was launched as a challenge in 2012 for all types of bold ideas to stimulate innovation. In a 2013 development meeting, the actual goal of reconnecting neurons was developed, and we envision it to take 10 to 15 years to realize that goal.

And so, as Dr. Sieving mentioned, we've had a Steering Committee formed to help us plot the trajectory of it. And, as he mentioned, we recently had some new members join. We had a teleconference back in early May. In order to infuse some more expertise on translation and the preclinical development of the 3-D organoids, we had invited some ad hoc participants. And so, those were Dennis Clegg and Val Canto-Soler.

We really are looking, like Dr. Sieving said, to see how we can provide resources and plot into getting to humans. To show you where we've been, we have had a bunch of state-of-the­ science workshops. Starting in 2014, we've appended a meeting to either the Society for Neuroscience Annual Meeting or the ARVO Annual Meeting.

And so, in the boxes, those were our awards that we've issued, and highlighted at the end there is our translation-enabling animal models. So, these are our reports that came out of all those workshops. Please see our latest one in eNeuro, the report about creating a cellular environment for neuro-regeneration.

Dr. Sieving had already mentioned we had an evening session at ARVO that highlighted our current and planned clinical trials involving stem cells. So, I won't go into that, unless there's any questions.

Really what we spent a lot of the time with the Steering Committee talking about is our upcoming workshop that was also referred to by Dr. Sieving. So, our real goals are to learn from a variety of investigators on their journey to form these preclinical IND-enabling studies. We're inviting a bunch of people that have endeavored in the stem cell RPE trials. There's a number that are invited that are taking a neural stem cell route or a retinal progenitor route.

We're going to have a couple of sessions, which I'll outline in a future slide, on what exactly are the considerations or decision points when planning a clinical trial. And we have a whole session pertaining to the manufacturing of these types of cells. And we're also getting industry's perspective in on what the challenges they foresee from their perspective on retinal cell therapy.

And so, the format is going to be a general overview given by a Chair or moderator, and then, mostly discussion-based with some questions that we really want to address during those sessions.

So, here's the sense of what the workshop looks like. It's going to be a day and a half. We're going to really get into the preclinical considerations, especially disease selection, animal models, and the cell delivery. So, we have people focusing on rodents, pigs, non-human primates, and we have experts that can focus on different diseases, retinitis pigmentosa as well as glaucoma and other optic neuropathies.

We're going to invite the FDA to talk to us about the regulatory considerations. This has been a topic that I think you and our Steering Committee have said we really need to engage early with them. And we're looking forward to having them, hopefully, provide some guidance.   There's a new regenerative medicine fast track option that we'll hear back about and some other considerations, depending on if the route is a combination device and cell product, and things like that.

Then, we'll go into, like I said, the decisions that need to be made when developing a clinical trial, and we're going to talk about the safety and efficacy endpoints. And what came up at our AGI Steering Committee is really a big hurdle is the surgical approaches needed for cell therapy, depending on the route of administration and the actual cells and scaffold that are being transplanted. So, we'll get into that.

And we want to wrap up the day trying to synthesize all that information and try to discuss about pathways from getting preclinical to clinical in a variety of diseases and models.

So, the next day, we're going to get into the cell sources and cell manufacturing. We have, I think, everybody that I've listed here, Lonza, Fuji, Cellular Dynamics, New York Stem Cell Foundation, and two manufacturing arms, agencies that are funded by DoD and NIST, BioFabUSA and Nimble have agreed to join and share their experience. So, Lonza has created a GMP-compliant cell source, IPS cell source, and Cellular Dynamics has a pipeline of differentiating them; whereas, BioFabUSA and Nimble are starting cell manufacturing capabilities and capacity that provides kind of tissue engineering more broadly and perhaps can be combined with cell therapies and scaffolding.

And then, the industry perspectives, we're going to invite those small companies and even larger companies that are interested in taking on cell transplantation both for the retina and larger using neural stem cells for different neurodegenerative diseases.

This is to give you an idea of who we hope to participate. We sent out a save-the-date a couple of weeks ago, had a tremendous response, just like Dr. Sieving said. So, we look forward to having really robust discussion.

Just to recap our previous funding opportunities, we set up a consortium that are looking to develop technologies for functional imaging, to enable non-invasive in vivo monitoring of the activity of retinal neurons, and also have a consortium that is using screening approaches to identify unknown regeneration factors. That could be critical for guiding and integrating those neurons that we put into animals and, hopefully, humans.

And then, our last FOA just came out in December and closed in March, and we'll be looking to review them late in the summer. Hopefully, out of that will come some more robust models that can inform how to actually transplant those stem cells and evaluate their integration.

So, every year we have a principal investigators’ meeting for our existing consortia. Upcoming in November is our functional imaging consortium PI meeting, and then, in December our regenerative factors consortium.

And so, it's an opportunity to get some real experts from our external oversight committees to have a dialog with all the Pis to address their barriers and to share the results, so that everybody in the consortium can benefit from everybody's progress. As you can see here, we've picked oversight committee members that focus on varying aspects of the proposals that were received.

Also, we're continuing our seminar series, Neuroregeneration, and we are pleased to confirm our fall lineup consisting of Jeff Goldberg in September and Mike Dyer in December. Those will be webcast, and I can let you guys know, if you're interested.

On to the 3-D Retina Organoid Challenge. Last spring, we had an ideation phase where we just wanted people from all disciplines, and especially bioengineers, to team up with vision scientists to give us their idea of how to create a 3-D culture system that could advance drug development or disease modeling. And so, we got about 13 submissions there. But the overall goal is to create, again, a platform that can be used to better model disease or test drugs.

And so, the winner of the ideation round was awarded in September to Erin Lavik's team, who had proposed a screen printing approach laying down the different retinal neurons to form a complex laminated retina.

And then, in February of this year, we actually asked the community to actually start to generate data that they can present later on in our challenge to show that they were able to generate these in vivo/in vitro model systems. And so, in the fall, we will evaluate the first round of submissions in terms of specific criteria, but I won't go into fine detail now. But I'll get into two things.

We call our participants "solvers" and we call the different corporate entities "sponsors" in our program. Because no money is given upfront, we have really teamed up with different vendors and service providers to enable our participants to acquire materials and services at a discount. And so, we are really appreciative to about more than half a dozen industries and small companies to provide discounts to all our -- I think there's over 50 active members in this challenge right now.

And then, Genentech and Xcell have provided different drug-screening platforms and compound libraries to participants. And they are our Gold Sponsors.

And so, our opportunities to evaluate those data come up October 1st. We've set aside $600,000 for up to six winners to be awarded depending on how many suitable applications are found. And then, depending if we award all that money, we reserve the right to save some of it for the final prize purse of $400,000 to up to three winners.

And so, we have an active listserv of over 120 members participating in the 3-D Retina Organoid email listserv, and we're actively still soliciting small businesses that want to participate and support this endeavor.

So, to get to the NIH Regenerative Medicine Innovation Project, as Dr. Sieving said, it came out of the 21st Century Cures Act, and in addition to long-term funding to the Precision Medicine Initiative, now called "All of Us" or the Cancer Moonshot or the BRAIN Initiative, a small program of regenerative medicine was developed, and NIH is coordinating with FDA to lead this endeavor and 12 Institutes have signed on to participate.

And so, in fiscal year 2017, $2 million was available. Since it came kind of midway through our fiscal year, in order to get that money out, it was issued as competitive revisions or competitive supplements.

But an interesting incorporation of the Act is that it requires the federal funds are matching monetary source with non-federal funds. And so, the idea is that we are going to amplify the money that we have and bring in partners to stimulate the field.

And so, the revision application process was targeted to support those innovative projects that kind of addressed issues that affected the regenerative medicine field widely that were cross­ cutting and could be applied to not just their specific situations. And also, emphasis was given to those products that are relevant to regulatory submissions. So, improved tools, methods, even standards that could improve the evaluation of product manufacturing or safety or effectiveness are also highly desired.

Eight awards were made, and they covered the gamut of different diseases. Because there were such high-quality applications, different NIH Institutes obligated an additional $720,000. And so, the total funding for this FY17 endeavor was $4.7 million.

Here's a list of the actual awardees. As you can see, an eye-related one by Markus Frank for limbal stem cell therapy was chosen. And here's a depiction showing there's about six different areas that were highlighted in these applications.

So, in addition to funding grants, the Regenerative Medicine Program is trying to catalyze through workshops, convening specific meetings that can help the regenerative medicine field move forward. And so, starting out, we wanted to explore the state of the science. So, back in December, we had a nice, comprehensive workshop that looked at clinical development of stem cell transplantation that are listed here, including an ophthalmology session. The basic format of these were presenting clinical case studies as well as manufacturing case studies. So, there was a nice balance between the development and the pipeline needed to support it.

And so, for going forward, the Regenerative Medicine Innovation Project has a couple of principles that we are trying to follow in terms of funding future rounds. We have really embraced that any clinical trials need to be a phased milestone-driven approach, and there will be a pipeline to get to that stage, so pre-IND, which will be investigator-initiated.

We are trying to create a research portfolio that is poised for clinical application. And so, we're trying to support those studies that are going to demonstrate proof of concept for clinical applications for pre-INDs or IDEs.

And we're trying to figure out different ways to develop resources and infrastructure that can support this type of innovation. So, to give you an idea, we have been reaching out to state­ funded stem cell initiatives such as CIRM. We have relationships with different advocacy organizations, all the manufacturing cores funded by the DoD and other federal agencies. And, also, the existing clinical trial networks and small business and industries is something that we have been, I think on a weekly basis, been talking with to try to see how we can support this endeavor.

Back earlier this year, we had Notices of Intent to Publish various clinical trials and pre-IND FOAs. Unfortunately, they're not out yet.  So, I can't go into any more details, but stay tuned. If you want to learn more, please go to the website. It's www.nih.gov/rmi, and that has a recap of the workshop. It has some FAQs about the matching requirements, and we'll have the future funding opportunities up there.

And that's about it. I'm happy to take any questions.

COUNCIL MEMBER: Okay, I have a quick question.

DR. BECKER: Please.

COUNCIL MEMBER: We got into sort of the brainstorming stem cell workshop that you mentioned sort of towards the start. Would there be an advantage to inviting people from overseas to something like that?   I think all of your invitees were all U.S.-based. But I have seen -- and it's not my area at all -- but there have been papers in Nature Biotechnology this year with RPE, stem-cell-derived RPE and for AMO phase 1 trials. I'm just wondering if there is additional information and experience out there, that perhaps if we extended an invitation -- goodness only knows if they would come, but maybe we shouldn't just think nationally, but internationally.

DR. BECKER: Absolutely. Thank you for bringing that up.

We set aside a budget of a couple of thousand dollars to travel, international participants. So far, a couple from Japan we have invited are not able to attend. But I can report that, from the Institute de la Vision, someone working on photoreceptor transplantation, Olivier Goureau, has accepted. So, we are trying to get that expertise. A couple of times there's collaborations with the U.S. investigators, and we're making sure that we have at least that information and knowledge passed along. For sure, it's something that is a challenge, obviously, when we're hosting here instead of anchoring it to ARVO and SFN. And those past workshops have definitely leveraged the availability and attendance of those international people, but it is something that we are trying to do with our limited budget.

COUNCIL MEMBER: You mentioned briefly All of Us. Could you talk a little bit about ocular data that would be collected in All of Us?

DR. BECKER: I can mention --

DR. SIEVING: There is very little at the moment. DR. BECKER: Right.

DR. SIEVING: All of Us is a pay-as-you-go system. So, if we want ocular data collected, NEI needs to buy that service. At the moment, I believe acuities will be collected, and then, medical records. HIPAA, of course, compliant are part of the data that are amassed, and whatever is in there from ocular exams would be part of that. Do you recommend something?

COUNCIL MEMBER: Well, I heard that there was a proposal to get a non-mydriatic fundus photograph, which would be inexpensive and could yield a lot of information across many specialties and would complement very well the UK Biobank approach. Because, with the UK Biobank, they collected IOP using a Reichert tonometer, and that was a really great idea, and it really did take a lot of movement from a lot of people just to get that to happen.

But thank you for complimenting our work, and Dr. Wiggs deserves a compliment, too, on finding all these IOP genes and, then, relating them to glaucoma. But that's how we did it. And so, by using the UK Biobank, it allowed us to really leverage a lot of information.

So, if you had a cup-disc ratio, that would complement the IOP piece, and then, you would find hundreds of cup-disc ratio genes and link them to glaucoma. So, that would be my hope, that something like that complementary could happen.

DR. SIEVING: My perception on this is that we need to have a concerted development of data that matches value in analysis. And we are thinking about putting a group together on that.

We have not done so at the moment. This is to amass data on nominally a million people. It will take a few years for that to happen. It's difficult to imagine how to get a non-mydriatic fundus photograph at multiple, multiple sites. Then, the question would be, so we've got the data; what's the value of this? And that would be in the analytics. And so, we'll pick that up here.

COUNCIL MEMBER: One thing I would say is it doesn't have to be all I million. So, the UK Biobank took 100,000 people and checked their pressure. So, you don't have to have a non-mydriatic camera everywhere. If you got the comparable number of 100,000, of course, that decision support type of analysis would need to be done, but I would guarantee you would get some bang for your buck from that.

DR. BECKER: Yes, the All of Us is just starting workshops on that topic of what to include in the value. That started this past spring and will continue this next year. And we can keep you in the loop.

Thank you.

Consideration of January Meeting Minutes

Dr. Paul Sheehy

DR. SHEEHY: Our next speaker will be Keturah Williams, talking about an exciting new collaboration coming up.

As she comes up, I would like to take as long as it takes, but it shouldn't take long, to ask you if you've looked at the previous meeting's minutes. And does anybody have any comments, amendments, corrections?

Can I get a motion to accept the prior meeting minutes?

COUNCIL MEMBER: So moved.

DR. SHEEHY: Ayes? Nays?

I take that as a great compliment.

Speaking of compliments, before we leave the topic, if any of you are interested in this Challenge competition idea, there is a document on the electronic Council book that looks at Challenge Grants. I can tell you that they've been at NIH for a while, and they are sort of viewed with skepticism. It is kind of like magical thinking that people are all going to put up their own money and go for this.

Our experience has been the structure and process that Steve and Jess Mazerik have put together, this has been the first credible one. Several of my colleagues have approached me, and I sent them to Steve, as the real expert about it. But this is really our Institute has made this a viable and creative and productive funding mechanism and it is due in large part to Steve's and Jess' work. So, I want to give them a shoutout. With that, yes?

NEI/ DoD Collaboration

Dr. Michael Steinmetz
Ms. Keturah Williams

DR. STEINMETZ: Before I introduce Keturah, I would like to give you just a little bit of a background on this new collaboration that we're putting together.

So, the Department of Defense has a very active Vision Research Program that Don Gagliano was fundamental in organizing a decade ago or so. And I've been on the program committee for eight or nine years helping them put together their program announcements and make their funding decisions.

Two things have impressed me about it. One is the quality of science is just really outstanding. It's very applied, very translational kinds of research, things that are missing to some degree in our portfolio. And also, the investigators that apply for that program are not the usual investigators that we see applying for NEI grants. In fact, one of the reasons I'm there is to try to minimize the overlap between the things that they are doing and the things that we do here.

At the very last meeting, we were going through the step trying to triage them and found a very difficult time getting it down to a manageable number of applications. In the end, when the full applications were reviewed, the DoD was only able to fund a small fraction. I think it was between 5 and 6 percent of the applications. There was a tremendous amount of really great science that was relevant to our AGI program and other things that we do that was simply left on the table. So, we entered into some discussions about trying to create a program in which we would be able to collaborate with them and tum some of these DoD applications into NEI grants.

Keturah Williams has been taking the lead for us in helping to put this program together. So, most of you probably don't know Keturah. She's generally sitting in the back. She is a graduate of Carnegie Mellon University with a bachelor's degree in biology and a master's degree in health science policy.

MS. WILLIAMS: Healthcare policy and management.

DR. STEINMETZ: Yes, okay.

And she came here in 2007 as a Grants Management Specialist, and she's been with us since that time, except for a brief affair with Smokey the Bear down at Forest Service, which she recovered from quickly and returned to us. (Laughter.)

And when coming back, she moved from grants management into program and functions here as a Program Analyst.

And most of these numbers that you asked me for, and I spout out and take credit for, it's Keturah who actually puts them together for us.

So, Keturah, if you would tell us a little bit about the program as it stands? And we're hoping to get that instituted in this fiscal year to be able to fund applications next year.

MS. WILLIAMS: Well, good morning. I will be giving you an update on the Vision Research Collaborative (YRC) between the Eye Institute and the Department of Defense.

So, to start to give you an overview of the presentation, I'm going to start by providing some information on the Vision Research Program at the DoD. I will talk about the goals of the collaboration.   I will go over an existing NIH/NSF model here at the NIH. I'll go over our proposed YRC process. And I will end by telling you our current activities and next steps.

To start, the DoD's Vision Research Program was started in 2009 under the Congressionally­ Directed Medical Research Program, which is the research arm of the DoD. The program was started to support military-relevant, peer-reviewed vision research.

And here's a couple of the research projects that have been supported since 2009, which includes corneal healing, retinal and corneal protection, and vision rehabilitation. Not all of the projects are military-relevant. A lot of them also fall under the mission of the NEI.

Like the NIH, the DoD's Vision Research Program has a two-tiered peer-review process.         It starts with an intrinsic technical merit review, and they also have a programmatic review as well. So that all awards are based on scientific merit and programmatic need. As Dr. Steinmetz mentioned, they do have a low success rate, which is why we were interested in this collaboration.

So, with the goals from the project, we, one, hope to provide opportunities for unfunded, high­ quality, high-scoring vision research applications; enhance current NEI program portfolios; expand the scope of research supported by the NEI, and, also, attract investigators, especially new and early-stage investigators who are not usual NIH applicants.

This program is being modeled after a currently active interagency program here at the NIH called the Collaborative Research and Computational Neuroscience Program. This program is between the NIH and the National Science Foundation. It was started in order to promote new collaborations that would integrate computational models and methods with neuroscience.

The program announcements for this program are published by the NSF. All applications come through the NSF, and the applications are reviewed by an NIH-compliant scientific review process. This, again, is a two-tiered review process. After they are reviewed, participating NIH Institutes and Centers select viable proposals to consider for funding here at the NIH.

Based on this program, we put together a proposed process for the Vision Research Collaborative. The Vision Research Collaborative would start with the DoD issuing a normal program announcement. All applications would come in through the DoD. The DoD would review, score, and select applications for funding by the DoD.

The NEI would, then, go in and look at any of the quality high-scoring applications and select any that could enhance or further the NEI mission. Actually, I should say that we would be selecting them to consider for funding. This wouldn't be an automatic funding.

We will, then, contact the Pis of these selected applications and give them the option to reformat and resubmit their applications to the NIH. After they are submitted to the NIH Center for Scientific Review, an SRO from the CSR would prepare a summary statement that includes the abstract from the application, the DoD's review, and, also, a matching NIH score. These applications would, then, come to Council, and we would, then, select a certain number of VRC applications to fund.

Some of our current activities and next steps include our first meeting, which occurred on May 8th, and that included individuals from the Department of Defense. In attendance was the Program Director of the Vision Research Program. We had a grants and contracts officer from the DoD and, also, a policy officer as well. We also had representation from the Center for Scientific Review. We had the SRO that handles the NIH/NSF collaboration. So, that was really helpful. And we also had other leadership from the CSR as well. We also had leadership from the NEI in attendance, too.

Right now, the Vision Research Program is putting together their fiscal year 2019 program announcement. With that, we have had the CSR review the program announcement to make sure that NIH review criteria is included, so that when these applications are reviewed at the DoD, we are certain that they are taking into consideration NIH review criteria. And I also should say that there will be NIH representation at these meetings as well.

We are also putting together a Memorandum of Understanding, as required for this sort of interagency collaborations. After that is signed and approved, we can, hopefully, put forth our funding opportunity announcement. And the funding opportunity announcement will include information for the grantees on how to cut and paste the information from their DoD application into the new NIH application. And we also specify that the content that was reviewed at the DoD has to be the same content that is submitted to the NIH. Budget and scientific content, everything must be the same.

In summary, we hope that this program will enhance the collaboration and communication with the Department of Defense, increase the funding of high-quality DoD VRP applications, expand the scope of research funded by the NEI, attract new and early-stage investigators who are not usual NIH applicants, and, probably most importantly, further the mission of both the VRP and the NEI.

I will take any questions.

COUNCIL MEMBER: I have a question. Could you go back to your flowchart? Right there. So, when the PI has been guided through the reformatting to the NIH application, is it re­ reviewed by another scientific panel?

MS. WILLIAMS: It is not.

COUNCIL MEMBER: It is not?

MS. WILLIAMS: Right.

COUNCIL MEMBER: Okay. How much disparity is there between the DoD format and the NIH format?

MS. WILLIAMS: Well, their general application is somewhat the same. We use the same federal government forms. And actually, we have gone through to match up the DoD's to the NIH's, and it's pretty much the same. They are under different titles.

COUNCIL MEMBER: I see.

MS. WILLIAMS: But we can cut and paste these sections into the NIH. COUNCIL MEMBER: I see.

MS. WILLIAMS: And so, there's not much they need to add. They just have to move it into a different section.

COUNCIL MEMBER: And so, if an individual is invited to do this, the likelihood of their being successful is high?

MS. WILLIAMS: I believe so. Mike?

DR. STEINMENTZ: A hundred percent. (Laughter.)

That is, we won't ask them to do this unless we have decided this is something we would really like to do.

COUNCIL MEMBER: What are the numbers? So, what percentile, percentage, or proportion of grants are funded by the DoD automatically versus those that are remaining, roughly? Or does it work that way? Do the ones that are selected for VRP funding ever come to NIH? I'm confused about the second and third steps.

DR. STEINMETZ: So, the plan would be -- the DoD has a heavy programmatic weighting of -- I'll just say it has to be of real military relevance. So, they are only able to fund 7 percent of the applications that come in there. And so, there will be a lot of very high-scoring applications that will be left on the table, and we will look at those and select the ones from there that are relevant to our mission. So, I expect these to be the top 10 percentile kind of applications.

And their review process is similar to ours. They have study sections. It's probably all the same reviewers, only they are done through a contractor, so they're probably paid more. (Laughter.)

COUNCIL MEMBER: I would like to compliment you guys for going into this process. I think this could be very valuable, and I think it is a really great direction to have gone in. So, I want to congratulate you guys for looking into this and developing this program, because I think it will be very helpful.

COUNCIL MEMBER: I just have one comment. I guess the reformatting from DoD to NIH is necessary for the administrative arm of administering the grants, right? Because, otherwise, it's just a lot of work or some work on the part of the investigators just to get this into that format.

MS. WILLIAMS: Yes, and actually, the program we're modeling this off of, they were paper­ based. So, this is the first time it has been electronic. This has been fun trying to figure out where these -- yes, so it's been fun, but it's an interesting process. But, yes, it is as you say there.

DR. GUTHRIE: I am Scientific Review Officer at the Center for Scientific Review, and I've been involved in the CRCNS process for about 10 years.

It's very straightforward. It's very transparent. I am there to make sure the discussions meet NIH policy requirements, but I rarely have to get involved. I do have to ask them if there are any human subject concerns and things like that that NSF doesn't usually bring up, but, otherwise, it's been very straightforward. The summary statements are trivial to produce.

And the process has expanded to the point where there is now participation from Israeli, German, and French governmental funding agencies. So, it has really expanded well beyond the original NSF/NIH collaboration. And this sounds great; it could go in that direction, too.

COUNCIL MEMBER: That raised another point in my mind about the idea of resubmission. These are single projects? They are done at the end of three to four or five years? And then, you cannot renew them, I assume? Or, if there was a renewal process, how would that occur?

DR. STEINMETZ: These will become regular NIH R01s. And so, they will be open for renewal.

COUNCIL MEMBER: I agree it seems like an excellent opportunity to potentially broaden the portfolio of work coming in. I think the concerns in the extramural community will be the little bit of a black box around NEI selects from remaining VRP applications. Obviously, this is a little different than what happens after study section, and there are some programmatic decisions, I assume, being made as appropriate/not appropriate.

The second issue is going to be whether the DoD study section has the same level of rigor as the standard CSR study sections. Obviously, they'll have a different constituency; they have a different mission. And I could see some concern if it were, whether real, or viewed that there was a difference in the rigor of the review process. It sounds as if there is not particularly. But, again, I think the investigators would expect to see rosters and things of that sort that occur here.

And then, the third is whether there are any economic parameters around this. In other words, if one is looking at the upper 10%, I don't know how many applications there are in this pool, but are we talking about a large number of funded RO1s in the ones, tens, or hundreds going forward, in terms of what the impact would be on the more traditional routes to NEI funding?

DR. STEINMETZ: Well, with the CRCNS program we fund one or two applications per year, and I imagine the same level of involvement here. I assure you the rigor of their review is very high, and CSR has been involved in the beginning to make sure that the review criteria meet all the review criteria at NIH.

COUNCIL MEMBER: And again, you would be overseeing the criteria for programmatic relevance in order to figure out which grants are going to be pulled off this upper 10 percent of the DoD's for consideration by the Council?

DR. STEINMETZ: Yes.

COUNCIL MEMBER: Okay.

DR. STEINMETZ: Any other questions or comments? (No response.) Okay. Thank you, Keturah.

MS. WILLIAMS: Thank you.

DR. SHEEHY: Okay. So, why don't we take a break?

I've been told by the video technical people that there's a fair amount of variation about picking up the audio. So, can you please make a conscious effort to speak closely to the microphone?

The document I referred to about the 3-D Retina Challenge is in the presentations folder of the ECB, and I just realized that I hadn't updated all the slide decks. So, new slide decks are up there and they are available for you.

Our plans are to skip lunch. Please come back in 10 minutes.

(Whereupon, the foregoing matter went off the record at 11:17 a.m. and went back on the record at 11:34 a.m.)

DR. SHEEHY: Okay, we have the computers all hooked up now, so we would like to get back to open session. If I can ask you to take your seats?

And so, our next presentation will be from Karen Colbert, who is the Budget Officer for the National Eye Institute.

NEI Budget Update

Ms. Karen Colbert

MS. COLBERT: Good morning.

I will give an update on where we currently stand with the 2018 budget and the outlook for 2019.. But, before I do that, I'll review how we ended 2017. This is the first opportunity to share that final 2017 data. And so, it's important to see where we ended the previous fiscal year because it provides some context for where we are today.

Here you see a history of NEI appropriations since sequestration. In 2017, we saw the continuation of increases to the NIH and NEI budgets. The NEI appropriation saw a $16 million increase over the 2016 appropriation. When you compare the 2017 operating level to the 2016 operating level, we actually had about $24 million more to operate with due to the fact that the reductions in transfers from outside of NIH were not as large in 2017 as they were in 2016.

Here you have a snapshot of the NEI 2017 operating budget by funding mechanism. This snapshot shows the budget distributed across all of our funding mechanisms. As you can see, $622 million of our total budget was spent on extramural research.

This is a different view of the same data from the previous slide. When you look at the percent share of the total budget, 85% of NEI's operating budget went towards extramural research. That 85% share is a trend that has been consistent over time, and, as well, 11% of NEI's budget was directed towards intramural research and 4% spent on research support, which includes salaries and other infrastructure costs.

Here we have a table that compares NIH and NEI competing RPG success rates. One of the measures that we look at over time to see how consistent we are with funding of a number of competing awards is the success rate calculation. And NEI consistently has one of the highest success rates at NIH. In 2017, our success rate was 25 percent. That was just slightly below 2016, but we expected that small decrease because our overall budget increase in 2016 was much larger than it was in 2017, and because we funded more competing RPG awards in 2017, our non-competing commitment base was much higher.

And so, for those who are not familiar with how the success rates are calculated, the formula is very straightforward. It's the total number of competing RPGs funded over the total number of applications that we receive for the year.

Many of you have seen this buying power slide before. The period of the doubling of NIH's budget -- that's the period between 1999 through 2003 -- is a comparison that we still use in the current day. This buying power slide looks at how much our operating funds bought us in the doubling period versus what our funds can buy us today.

And so, BRDPI, which is the Biomedical Research and Development Price Index, is used to measure real annual changes in the prices of goods and services required for research activities. As you can see, buying power relative to the size of our total budget has decreased since the doubling of the NIH budget. And coincidentally, I just actually heard a campaign commercial this morning that talked about the doubling of the NIH budget, so that concept is still very much a part of the current conversation.

Moving on to our current 2018 budget, after much uncertainty at the beginning of the fiscal year, NIH actually received a pretty significant increase of $3 billion for 2018. That amount compares the 2017 final operating allocation to the funding level in the 2018 omnibus bill. In the omnibus bill, NEI received a $41 million bump-up from the 2017 operating level, when you include the general increase of 5.4 percent, which equates to $39.5 million, and the $1.6 million increase for brain research. And we do hope that these trends to increase our budgets will continue into 2019.

I'll talk a little bit about the Cures Act funding. The actual 2018 plan for the Cures authorization was implemented, meaning that Congress actually appropriated the funding levels in the authorization plan. The authorization itself does not guarantee that the funds will be available. Those funds are not available until Congress appropriates them.  And so, however, so far in 2017 and 2018, Congress has appropriated funds according to the plan, and we hope that those trends will continue. As you can see, $496 million was appropriated this year, $100 million towards all of us, $86 million for brain, $300 million for Cancer Moonshot, and $10 million for regenerative medicine.

In addition to the Cures areas in the omnibus bill, there were several other research directives highlighted: Alzheimer's, antibiotic resistance, influenza, $500 million for opioids research. Also highlighted in the bill language was continued support for the Clinical and Translational Science Awards; the Institutional Development Awards, which build research capacities in states that historically have had low levels of NIH funding; the National Children's Study, and the Kids First Program.

While I'm not able to share the full operating plan for 2018 because that information has to be cleared for release outside of NIH, I wanted to share the guiding principles that we have used to implement our funding plan for the year, our operating plan for the year. Our plan is to fund Type 5 non-competing awards at the commitment of record. The increase received this year means that we don't have to implement across-the-board policy reductions. The average cost for competing awards is expected to be slightly above what it was in 2017. The mandate to direct a certain portion of our budget to small business remains intact. The minimum percent share is virtually the same that it was in 2017. For our training awards, the number of slots is expected to remain consistent with 2017, and we plan to implement a 2 percent stipend increase.

At this point, I had planned to talk about the 2019 President's budget because that was the information that we had about 2019 up until this point. However, hot off the presses this morning, the House Labor, HHS, Education Subcommittee is planning to have their markup tomorrow morning. And in advance of that markup, they released their proposal. And for NIH, they have proposed a -- let's see -- $1.2 billion increase, which is 3 percent over 2018, bringing the total budget up to $38.3 billion. And for NEI, they have proposed a 1 percent increase, bringing the budget from $772 million up to $789 million.

We know that the Senate still has to do their work. And so, the Senate will come up with their proposal, and the House and Senate will come together in committee and decide the actual funding levels for NIH and NEI. But, as I said, that's our present information that we know as of today.

So, I'm happy to answer any questions that you may have.

DR. SIEVING: How much of that NIH increase is earmarked?

MS. COLBERT: Quite a bit of it. All of the research funding areas that were earmarked in the '18 omnibus, those as well are earmarked in the '17 budget, and I can read those for you.

DR. SIEVING: Well, that's okay. We'll see the numbers. Thank you.

COUNCIL MEMBER: You mentioned that the -- I forget what the term was -- but sort of the biomedical inflation rate.

MS. COLBERT: Yes.

COUNCIL MEMBER: What is that annually? In keeping with this 5.4% increase or this 3% increase in the budget, what is the inflation rate?

MS. COLBERT: It's in the range of 2.5%.

COUNCIL MEMBER: 2.5?

MS. COLBERT: About 2-and-a-half percent.

COUNCIL MEMBER: And what is the process by which those certain areas like opioids and Alzheimer's become recognized as funding priority areas? Obviously, that's done through legislation.

MS. COLBERT: Sure.

COUNCIL MEMBER: But what is the actual mechanism by which the NIH, then, receives funds on behalf of those research areas?

MS. COLBERT: Sure. There are conversations between our advocacy groups and, of course, Congress. And based on those discussions, they determine which areas they decide to focus on, and then, NIH moves forward with implementing those plans based on the funds that are allocated. And some of them are quite large increases; for example, $500 million for opioids research in 2018. And so, we move forward with the plan as it's been submitted.

DR. STEINMETZ: Just to add to that, it's rare that the money would come to NIH and go to the Director's Office to distribute. Almost always, these special earmarks are given into Institute budgets or divided between a couple of Institute budgets. The money sits in their base, but it's allocated to that particular use, and other Institutes share the money.

COUNCIL MEMBER: And just another point. When you talk about success rates for the grants, if we are lucky to be in the successful column, often our awards are reduced either in time or amount by a certain percentage.

MS. COLBERT: Sure.

COUNCIL MEMBER: I wonder, given the sort of flat funding and the increase in costs, is that average reduction in amount, is that varying? Is it getting bigger over time? Michael, do we keep statistics on that?

DR. STEINMETZ: Yes. So, the current average cost, total cost, on our grants, R0ls and R21s, was $398,687, I think you said, the exact number.

(Laughter.)

COUNCIL MEMBER: But what did we ask for, though?

STEINMETZ: You asked for more than that, I hear.

COUNCIL MEMBER: But is that difference increasing over time?

DR. SHEEHY: No. Especially years when budgets are flat, as it's been, we try to manage to that number in order to keep the success rate up. As Karen mentioned, this year, because we have a 5% increase, our intention is to let that number rise to $410,000, I think, this year.

But we try to keep the number at that level.

MS. COLBERT: Thank you.

DR. SHEEHY: Our next speaker will be Ellen Liberman to talk about the Glaucoma Program.

The Glaucoma Program

Dr. Ellen Liberman

DR. LIBERMAN: And good morning, or close to good afternoon.

I'm going to talk today about the glaucoma and optic neuropathies portfolio. It's pretty much a historical perspective with some of the latest work that we have been supporting.

Before I begin, I want to acknowledge my colleagues at the NEI. I am responsible for most of the basic science portfolio in glaucoma, but Neeraj Agarwal handles the grants in glaucoma that have to do with the Audacious Goals Initiative and many of the genetics grants. Included in this is the Neighborhood Consortium.

If the work involves inflammation, George McKie is the Program Director. And we have a fair number of glaucoma grants in the SBIR portfolio, for which Jerome Wujek is the Program Director. And also, I want to acknowledge my colleagues in the Collaborative Clinical Research Group, especially Don Everett. They've been instrumental in overseeing many of the clinical trials and epidemiological grants that have revealed a lot about glaucoma.

Okay. So, it sits in the portfolio at about 13 percent in 2017. It is a small program, but it's a growing program. And that 13 percent will vary from year to year.  It just so happens in 2017 it came out to 13%. It sits with the Anterior Eye Diseases Group. And so, it is, again, a small and growing program. In dollars, it is about $64 million out of a total of $484 million out of the total NEI extramural grant portfolio, and that translates to 160 grants out of 1,256. This is for fiscal year 2017.

Okay. So, I have been -- I hate to admit this -- but I have been the Glaucoma Program Director since '92. Just to show I don't lack imagination, I did leave the program and I did a number of other things besides it, but in the last few years I've come back to it.

I just want to give you some of my observations, and they're certainly not novel or original. It is a clinical program. So, I work very closely with the Clinical Group on many issues.

The observations and findings in the clinic inform the basic research, and the basic research supports the clinical observations. And the basic research also has provided us with a number

of drugs and diagnostics. So, you can say, well, what's the big deal? It is the NIH mission, is bench-to-bedside. But I want to show you today that the Glaucoma Program has been exceptionally successful in carrying out this mission.

The other observation is it's considered historically an anterior eye disease, but it is a disease involving the whole eye. And so, this is a schematic, and most of you already know this, so just bear with me. In a normal eye, aqueous humor is produced in the ciliary body and it is secreted and circulates through the anterior segment, where it leaves the eye in tissue, filtration-type tissues, the trabecular meshwork and Schlemm's canal. In a normal eye, there is a balance between secretion and the outflow of aqueous humor.

Now there are two functions that aqueous humor has. The first function is that it provides a circulatory system for the front of the eye because the front of the eye is avascular, as most of you know. So, it forms a circulatory system providing nutrients and taking out waste products from the cells in the front of the eye.

It also provides the pressure, the normal pressure, for the eye. The balance between secretion and outflow creates a pressure that maintains the eyeball. So, that's a normal eye.

But in a glaucomatous eye, that aqueous humor is secreted as normal, as it is normally, but it doesn't flow out of the anterior chamber through Schlemm's canal and the trabecular meshwork. There is a blockage. No one knows what that blockage is. In most forms of glaucoma there's no obvious insult, but the insult occurs at that level, at the level of outflow in that filtration tissue system.

So, when outflow doesn't occur normally, you get a buildup of pressure. And the pressure is particularly damaging to the optic nerve head. That area seems to be particularly sensitive to pressure, and the optic nerve head is where the retinal fiber layer axons flow out of the nerve, out of the eye on the way to the brain. So, there's damage at that point.  The retinal nerve fiber layers begin to drop off the retinal ganglion cells start to die in a slow, chronic method.

Okay. So, the portfolio distribution, this is sort of my impressionistic interpretation of the portfolio. There is the front of the eye, as I said, and all the research that goes on in the front of the eye, and then, there's the back of the eye, which is really what the Glaucoma Program has become increasingly interested in.

So, the front of the eye, about 36 percent of our extramural grants in glaucoma deals with the front-of-the-eye problems, where that insult is. It used to deal quite heavily with aqueous humor production. And as you'll see, there are a lot of pharmacological agents that were developed from those studies. But, right now, most of the aqueous humor grants have to do with outflow because the search is for what that area of insult is and to correct it. And there's a lot of pharmacology in the program.

We have a fair investment in genetics. We started with Mendelian genetics, the easy diseases, so to speak, but that really isn't the important type of findings that we want. We want the genetics of the complex disease. So, we have been investing in things like genome wide association studies.

We have a lot of diagnostics being developed. That's about 10 percent of the portfolio. Optical coherence tomography, trying to get better visual fields, psychophysics, understanding progression. We have several studies in diagnostics.

Of course, the back of the eye, which I am not going to touch because we have someone who actually knows something about this. Don Zack is going to come and follow my talk. So, I'm going to leave that all to him. But that is a growing portion of our portfolio. And there's a lot of studies on retinal ganglion cell death and optic neuropathies and regeneration. So, you will be hearing from Don on that.

Okay. So, there are many types of glaucoma. It's not a singular disease. So, 95% of our portfolio is on the adult form of primary open angle glaucoma. That's about 95% of the portfolio. And I'm going to predominantly talk about that form of the disease. And so, I'm just going to use glaucoma and primary open angle glaucoma interchangeably, and just assume that's what I'm talking about unless I say otherwise.

There's also a fair amount of what's called normal tension glaucoma where there is no obvious elevation in pressure, but, yet, you do have damage, and some smaller forms of glaucoma in terms of the prevalence, pigmentary dispersion, exfoliative glaucoma.

One of the small, but important, forms of glaucoma is juvenile open angle glaucoma because that was the beginning of genetics for us. Also, congenital glaucoma where babies are born with very high pressure. So, there are multiple forms. Mostly, we're interested in this form because it is so prevalent.

But all of them have in common the optic neuropathy that underlies glaucoma. That is this loss of ganglion cells. There's dropout within the retinal nerve fiber layer. As a result, you get cupping of the optic disc at the optic nerve head.

So, the risk factors for glaucoma, I'm going to show you some data on this. But the major risk factors are age and race. Family history and elevated intraocular pressure are important. Interestingly, thin corneas turn out to be a major risk factor.

Worldwide, the prevalence of glaucoma is about 2.2% of the population overall, but in African populations it's double. It's cause of blindness worldwide. In 2 million people it causes blindness.   The U.S. statistics pretty much mirror those of the rest of the world. About 2% overall in the U.S. population have glaucoma, but in the African-American population you can see that it's much higher; the prevalence is 4%, again, double what it is overall.

About 120,000 people are blind as a result of glaucoma, and it accounts for about 6% of all blindness in Caucasians. But, again, I really want to emphasize that this is a serious disease, even though we have treatments. In African-Americans it's 19%. That's very, very significant.

And this, also, is just more of the prevalence data. As I said, age is a major risk factor. So, at younger ages, middle age, it's about 0.9%; the prevalence is about 0.9%. African­Americans at that age, the younger ages, it's 2.25%, very significant. Once you hit your senior years, it's 2% overall. The prevalence is 2% overall; African-Americans, 6%. And if you end up being over 80, the prevalence is about 7% overall, almost 10% in African-Americans. So, I'm just sort of trying to emphasize that we have a real significant issue with primary open angle glaucoma.

Okay. So, when I joined, there was a lot of discussion about the role of intraocular pressure, IOP. Is it really important in the etiology of glaucoma? And this was actually an ongoing debate, even though people were treated to lower pressure, and through meds and surgical means, it was by no means certain that this was doing any good. And why was this conundrum cited? Because it turns out that a fairly significant number of people with primary open angle glaucoma actually had normal tension, normal IOPs. About 30% to 40% had around the same as the non-disease subjects.

There's also the converse. Ocular hypertension was found to be fairly common, and that's elevated IOP, but no optic neuropathy. So, this created sort of a controversy. Does treating IOP, lowering pressure, really have any effect?

I want to point out two studies that were supported by NEI, very significant studies, really changed the way we think about glaucoma. So, the first study I want to cite is the Early Manifest Glaucoma Trial. This was very controversial, and it was considered unethical and could not be done in the United States.

So, a group in Sweden took control of this study, and they did a randomized clinical trial that compared the effect of immediately lowering intraocular pressure with no treatment or delayed treatment. As I said, clinicians, even though they had no proof that lowering would be effective, they still were adamantly opposed to this trial.

And it was important because, at the end, based on visual fields and optic nerve progression, results for all patient categories showed considerable beneficial effects of treating to lower IOP. There was a significant delay in progression, and this delay was regardless of age or whether you were in the high or normal tension category. So, it was very important. It sort of laid to rest that controversy about IOP.

And the second trial was the role of intraocular pressure in ocular hypertension subjects. So, this was a randomized trial to determine whether topical hypertensive medication delays or prevents the onset of primary open angle glaucoma. And these subjects which show, actually, no optic neuropathy had very normal cups, et cetera. But should we treat them? So, this was the big question.

Again, a randomized clinical trial that compared the effect of treatment versus no treatment in patients with elevated intraocular pressure, but no other characteristics of glaucoma. And so, again, based on visual field and optic nerve measurements, the treatment with IOP-lowering medication was effective in delaying or preventing the onset of primary open angle glaucoma in these individuals.

Okay. So, that pretty much solidified the idea that treating for pressure is a good thing. We can really save sight by treating individuals with IOP-lowering medications.

So, in terms of medications, I want to show you how successful the NEI has been in developing

just about all the medications we have on the market today. We have a number of drugs that lower IOP that are used extensively and have saved sight.

These are just a few examples, but they're the major examples. The first generation were beta adrenergic blockers. This reduced aqueous humor secretion. So, if you have less secretion, you didn't put a burden on outflow.

We've had a number of NEI-supported investigators whose basic research went into the foundation of developing these drugs, and the best known is Timolol. So, I just want to acknowledge that we had a number of investigators working on that, Tom Mittag, John Polansky, Alvarado, Marty Wax. They were from different institutions, and it was the work that we supported that went into developing this drug that Merck took over.

The other drug that was developed to reduce aqueous humor production is Trusopt, which is a carbonic anhydrase inhibitor. And this was developed by Tom Maren at the University of Florida. When I first started here way back when, one of the first things that happened was that Tom Maren called me and he said, "I understand you're the new Glaucoma Program Director, and I'm retiring, but Merck wants this drug, and I've almost got it to the point where I can tum it over to them. My grant is up. Can you provide a supplement to continue for another year?" And so, we did. We did and do support. We are very committed to supporting drug development that will save sight.

So, these two drugs are both aqueous humor secretion inhibitors. As I told you, the aqueous humor is very important in terms of giving a circulatory system to the front of the eye tissues. Now the question became, what happens to those tissues now that they don't have a source or a robust source of nutrients and a way of secreting waste products? So, there was concern about using these kinds of drugs, and the aim was to get drugs that increased outflow.

The first of this was the prostaglandin analogs, which increased outflow not through the conventional system of trabecular meshwork and Schlemm's canal, but through a different system, uveoscleral outflow. This was developed by the late Carl Camras and Laszio Bito at Columbia.

So, what's interesting about this to me is that there was a number of years ago a real revolt by taxpayers, by public interest groups, that NIH was providing a lot of the work to develop drugs and turning them over to drug companies, and drug companies were gouging patients with these blockbuster drugs.

So, about that time, The New York Times did a full-page expose or investigative report, and what drug did they pick? Latanoprost. So, that made news and died down, but it was sort of interesting that, of all the drugs, that was the one that was picked as a prime example of how NIH, through taxpayer money, funds drugs that go into the drug company and profits.

But Camras and Bito actually took it very far. They did some early very small trials to show its effectiveness. This is, I think, the major drug being used now.

In the last year, we have another drug that came on the market, the Rho kinase inhibitor Rhopressa. This increases conventional outflow. It's not quite sure how it works, but it does

work. In three clinical trials it was shown to be effective. And it was developed at Duke or the foundation part was at Duke by the late Dave Epstein and Vasanth Rao. So, we have been very successful at this, in this arena.

Now I want to tum my attention to genetics because we've had some really good findings, as was already mentioned. The early studies that we invested in were basically Mendelian-type genetics because they were easier, so to speak.

So, the first gene that was identified to be associated with glaucoma is the gene that encodes myocilin, and that was identified by Stone's group as well as Polansky, the late John Polansky at UCSF.    And that gene is responsible for autosomal-dominant juvenile glaucoma. So, it does pay to pay attention to some of these rare forms of glaucoma. It also was found to be responsible for about 2% to 4% of adult glaucoma.

Sarfarazi and colleagues found a second gene for cytochrome b, the CYB1B gene. It is responsible for a percentage of autosomal-recessive congenital glaucoma.

And the same group found optineurin, which is found in an autosomal-dominant form of the disease. It's responsible for about 2% to 3% of normal tension glaucoma.

So, these were the early studies. But I want to move on to what we're doing now because it has gotten very exciting. We've invested a lot of time and money in genetics of glaucoma.

Just this last month, a really blockbuster paper came out in Nature Genetics from the Neighborhood Consortium. That group, along with other investigators did a meta-analysis using GWAS data from 139,555 participants that were derived from three European cohorts. A 112 loci were found with elevated IOP and/or primary open angle glaucoma. So now, the idea is to really sift through all these genes. So far, we've found -- and Dr. Pasquale can probably tell you more about this -- so far, there are genes associated with lipid metabolism, mitochondrial function, or I should say regions with genes known to be associated with lipid metabolism, mitochondrial function, and, interestingly, development, where I found that pretty interesting because it is that outflow system which is blocking. So, it would be nice to know if there are some structural problems with that system that we don't see. Of course, the real challenge now is to find function associated with these regions. As was said, about 133 variants were found that predict with 75 percent accuracy the risk for developing glaucoma.

Now that's in Caucasian populations, but I spent a lot of time sort of talking about how severe the problem is in African and African-American populations. So, what are we doing there? We have two ongoing studies at this point, one from the University of Pennsylvania, headed by Joan O'Brien, looking at primary open angle glaucoma in African-Americans. They're doing GWAS exome-wide association studies and admixture analysis on a cohort of9,000 subjects which includes cases and controls. They are now at the point where results are coming in.

Just to give you some highlights there, the multi-variable risk models showed, which I thought was really interesting, that male gender is associated with risk. That's never been shown before, I don't think. Is that right?

DR. PASQUALE: That's right.

DR. LIBERMAN: Older age, as we would expect, and African ancestry is associated with risk. And there's some crossover with the findings in the Caucasian population, some overlapping SNPs that may have to do with the disease in African-Americans. The question is, is it a different disease? Is it just known to be more severe?

A second study that we actually are not funding but comes from the H3 Africa group out of genome, and we're co-funding this. This study is led by Dr. Ashaye at the University of Nigeria. She's working with some Duke investigators genotyping 120,000 glaucoma cases and controls. That is pretty early in the study. I just wanted to mention it to show that we really do want to put our money into finding what's going on in that cohort or that population.

Okay. So, lastly, I want to just highlight diagnostics because this is another really successful bench-to-bedside area within the glaucoma portfolio. There's always this debate between is it better to have functional tests or structural tests, or what do we get out of each? And so, the gold standard has been functional, the visual fields, but the problem with visual fields, there is a lot of variability. There is a lot of test/retest variability. And it's subjective. It's a subjective test. It depends on the patient to let you know the outcome.

So, there's been over the years a lot of emphasis on developing structural tests, diagnostics, because the feeling is there would be less subjectivity; it would be more objective. And I think, of all the places we've put money, of course, the most successful has been optical coherence tomography. That was developed, again, through an NEI grant by an engineer at MIT, Jim Fujimoto, along with his post-doc, who now is carrying it forward as well -- Jim is also working on it still -- David Huang.

And that was developed in 1991. It's always compared to ultrasound. It images internal tissues, and it has been used to image retinal nerve fiber layer thickness. As far as I know, it is another bench-to-bedside success. So, a lot of ophthalmologists have it in their office and they use it.

At this point, it is pretty much a lot of work has been done, and the whole goal now is slow. So, the goal is to increase speed and resolution to get really to a much deeper level in the inter-retina. It's to increase applications, to look at blood flows with doppler OCT, and it's gotten too sophisticated for me. So, it really is a lot of engineering that goes into this work. I think it has been very successful, and we continue to fund it and we're getting good results.

Just to close with some thoughts on future directions. We've invested pretty heavily in genetic analysis, but, you know, that's just description. We need the biology. We need the phenotype that's associated. And we need to know which of these genes are really going to tum out to be risk factors.

And I think the other big area that really needs a lot more emphasis is the disease in African­ Americans. We need to know more about the genetics and the risk factors and the pathophysiology, considering how severe the disease is. And for diagnostics, we need better endpoints and a measure of progression, so that we can go on with some clinical trials, especially now that we're moving into regeneration.

With that, I'm going to introduce the next speaker. But, first, I'll pause to see if there are any questions about the portfolio. (No response.)

No? Okay.

So, I want to introduce Dr. Don Zack, who is the Guerrieri Professor of Genetic Engineering and Molecular Ophthalmology, and he is the Co-Director for Stem Cells and Ocular Regeneration Medicine at the Wilmer Eye Institute. He received his MD degree and a PhD in molecular immunology from Albert Einstein College of Medicine, and he is currently a full professor at Johns Hopkins.

Scientific Presentation: Frontiers in Glaucoma Research: Neuroprotection and Optic Nerve Regeneration

Dr. Don Zack

DR. ZACK: Great. I want to thank Ellen and Paul and the whole Council for inviting me to speak with you. I've never been to a Council meeting. So, it's interesting to see how the power really gets exerted.

In supposedly an hour, but I'm going to try to make it less than hour because I know we're running late, it's obviously impossible to cover all glaucoma or, even as Ellen said, the back of the eye, but I am going to try to cover some areas that I think are fitting with NEI's mission and future.

Some of you heard me talk last week at the NRL symposium. You may see some overlapping slides. I apologize, but I tried to make it different.

And also, speaking of regenerative medicine, since you've already heard about that this morning, I've spoken to a few colleagues and staff. So, I've tried to include some work from other people in the field, but this certainly is just an occasional survey of highlights. It's not inclusive. There are two major glaucoma experts in the audience, an optic regeneration person, and guidance. So, I look forward to people's comments, but don't look at this as being overly comprehensive.

I just want to mention, trying to be a good boy, I tried to do some homework before coming here. So, I looked up the National Advisory Eye Council last night, the NAEC, and realized you guys have some competition, the National Association of Elevator Contractors.

(Laughter.)

So, if anyone is at the elevator meeting, you're in the wrong place. (Laughter.)

This is actually the first thing that came up on my Google search. Maybe you could get a donation, right?

(Laughter.)

Or maybe NIH lawyers should talk to them. That emblem looks a lot like the Eye Institute, too.

Anyway, more seriously or less seriously, depending on how you look at it, I just want to give our usual disclosure. Some of the stuff I'll be talking about has to do with small molecules that may or may not have some IP at some point. So, Hopkins is managing them.

And I am showing, as I mentioned, some work from some colleagues. I don't know what their disclosures are, so they are what they are.

Okay. So, we're not only talking about the back of the eye, but let's talk about the rest of the central nervous system, which is really important for glaucoma, because although pressure is important, and I used to see glaucoma patients a little bit -- I stopped about 10 years ago -- and we worried about pressure. Now I don't personally worry about pressure much, but it's the connections from the eye to the higher centers in the brain that eventually get damaged. Because, as you know, in glaucoma, the photoreceptors, though they may be affected, are basically there, so the eye sees but it doesn't talk to the brain. So, the brain doesn't see.

What I am going to talk to you today about is sort of two areas. One is sort of neuroprotective strategies, and I'll use some of our work as an example, but there are many labs funded by NEI and elsewhere that have taken this approach, and also, sort of the ultimate, one of the ultimate Audacious Goals is to reconnect the eye to the brain, higher centers of the brain, after there is degeneration of the nerve.

A couple of you have looked at optic discs every day of your lives, and most of them, but, basically -- and this is similar to what Ellen was talking about -- this is a nice, healthy disc where the axons are going over and heading towards the brain. This is what you don't want to see because most of the ganglion cells have died; the axons have died, and you basically have a lack of axons and you have optic nerve pallor.

Some of you -- and I actually did this on myself as a resident, so you know it's not much fun to have a visual field test, but this is really the main clinical functional measure of optic nerve function, where it is basically a video game and you put your head in the bowl. The machine, the computer or Goldmann -- does anybody use Goldmann perimeters at all in glaucoma practice? In glaucoma practice, yes? But that was a manual way of shining lights.

But, basically, you measure a threshold at multiple different points in your visual field, and the black word is here. That means the higher your threshold is, then if it is totally black, you don't see anything. So, that's one of the major -- and this will become relevant, because when we talk about neuroprotection, we can't do something simple like measuring eye pressure, "simple," quote/unquote. But to develop a new IOP-lowering drug, the endpoint that you want to measure, pressure, you can do easily. If you want to measure optic nerve damage and slowing it down, you have to rely on this and other techniques that we'll talk about which are not nearly as easy.

Okay. So, why are we interested in neuroprotection? All current glaucoma therapies at the moment are directed at lowering IOP. This could be eye drops. This could be laser.  This could be surgery. But they're all directed at IOP which, as Ellen very nicely described before, is a risk factor. It's the major risk factor we know about for retinal ganglion cell damage and loss.   But glaucoma does not equal IOP. As Ellen also mentioned, you can have a disjunction between the two.

So, all we can do now is lower IOP. Efforts at lowering IOP are not always successful, although there are many good drugs, again, from work led by the Eye Institute, funded by the Eye Institute. But even when successfully lowered, glaucoma damage can still proceed. So, there is more than IOP.

There's also public health issues which we really talk about today. But there are many people whose IOP is not lowered because they don't have access to medicines; they don't have access to doctors. So, a lot of the blindness that Ellen was mentioning has to do with our failure to deliver care to the people who need it. But, even the people who get the best care -- for example, seeing, again, our two glaucoma experts in the audience -- they don't always succeed in getting the pressure down enough. And sometimes when they get it down enough, damage continues.

So, neuroprotection, therefore, has a possibility of complementing lowering IOP. And I define neuroprotection as something that directly affects the ganglion cells, preserves their function and makes them survive.

Memantine we won't talk about today too much, especially since we're already pretty late. But some of you may know this is really the largest neuroprotective trial that was carried out by Allegan a number of years ago. And it did not meet its endpoints. There was a lot of excitement. Ten years ago, if you went to ARVO and you used the word "neuroprotection," the room was full and you couldn't get in. Then, after memantine failure and multiple failures in the stroke field, neuroprotection became a dirty word, and no VC person wanted to invest. NEI, you know, you were pretty consistent, but I think it got less popular there, too.

But I think, like most things, it was too high at one point; became too low, and now a reasonable approach is neuroprotection is not God, but it's not the devil, either. And I think there are reasonable approaches for neuroprotection, and we'll talk about a few of them.

For traditional drug discovery, as most of you know, one starts with a target. You know, basic research, again, carried out by NIH researchers or our drug company, whatever, identifies a molecular target that's important for the disease of interest, but, then, they set up some kind of screen and they find their primary hits. Then they improve these hits and optimize them, and then, clinical candidates get tested in the clinic.

The problem with this approach in glaucoma -- and this is actually an outdated slide that I borrowed from my friend and colleague Harry Quigley -- is that this is a partial list of all the different molecular targets that somebody has implicated as being important in glaucoma and ganglion cell death. So, if you're going to take a traditional approach, you have to guess, or maybe you can do a little bit better than guessing, but there are too many different targets, I think. There are certainly groups that are working on this. A number of different factors and animal models here that people can modulate.

So, I think this is still a viable pathway forward and worth pursuing, but we've taken sort of different approach which is becoming more popular in drug discovery over the last 20 years or so, so-called phenotype-based assays. In this case, we don't know a priori what pathway we want to target.   We know we want to keep ganglion cells happy. We want to keep them alive. And that's what we assay for, and then, once we get a hit, we have a problem because we don't know the mechanism. With a target derived, you know the mechanism or you think you know the mechanism first, and you look at the molecules. We're looking for molecules, and then, in addition, to go to clinical trials, you often have to do target identification. And I'll quickly go through one example where I think this approach has worked.

We have taken this approach initially in mouse cells, and now in human-stem-cell-derived RPE photoreceptors and ganglion cells. Since today is glaucoma day, I'm only going to talk about the ganglion cells, but pretty much everything I'm telling you, you could kind of use "word replace". You can use the approach for a photoreceptor, AMD. There you want to keep the photoreceptors alive; you want to keep the RPE cells alive. So, if you can set up an in vitro assay that is biologically relevant to your disease of choice, I think you can screen for it.

So, to do this, studying glaucoma, we start with mouse primary retinal ganglion cells. As many of you know, ganglion cells only make up about 1 percent of the cells in the retina. So, to study them, it's nice to be able to purify them. Ben Barres, who was a superstar neuroscientist in a number of areas, including the retina, who many of you know tragically passed away recently, but many years ago he developed the protocol shown here which is a way of purifying the ganglion cells using an antibody against the surface protein called Thy-1 to immuno-purify it.

And then, what we do is we put these 500 to 2,000 of these purified ganglion cells in a multi­ well plate. We started with 96 well plates, then went to 384 and 1096.

And then, we use a high-content screening instrument, which we use one called Cellomics, but there are many out there, which is basically an inverted microscope hooked up, a fluorescent microscope hooked up to a very sophisticated image-analysis system and a robot. So, the system goes through all your plates, counts the number of cells. You can measure live cells, dead cells. You can measure axon, axon length, et cetera, et cetera.

Then, Zhiyong Yang, who was a post-doc in the lab at the time, is now out in San Diego as an ophthalmology resident -- so, he's really getting translational -- but what he did, came into my office very excited with the result up here. He put different drugs in these different wells and looked to see what happened with the ganglion cells.

And when he had set up the medium cell in about 48 or 72 hours, greater than 90 percent of the ganglion cells are dead. So, if you add nothing, you have very few unhappy-looking ganglion cells. However, in this well, hopefully, you can see that there are multiple healthy-looking ganglion cells, neurites, et cetera, et cetera. And this is the result of the image analysis of a dose-response curve. Increasing drug gives you better ganglion cell survival. So, this is sort of just what we're looking for, something that keeps the cells alive, makes the neurites happy, et cetera, et cetera.

This is, instead of looking at 72 hours, this is now looking at two weeks. These cells haven't even been fed for those two weeks. If you look at the top right versus the bottom right, this is all due to that single drug.

Okay. What is that drug? It's up here. We were initially delighted to find that out. It turns out it is a protein kinase inhibitor that is an FDA-approved drug made by Pfizer called Sunitinib or SUTENT.

Now, with Jeff Diamond, who is here at NIH, we did some electrophysiology on these mouse cells after treating them with Sunitinib, and he showed very nice action potential. So, these cells actually not only looked, but behaved like healthy ganglion cells. So, we were reasonably happy. At least the left half of this graph were reasonably happy. Add more and more Sunitinib; you get more and more cell survival, but if you add too much, what happens? The cells die, and that was in the other slide. So, the therapeutic window here, which we have to think about if we're ever going to get to patients, is very narrow. So, you don't want to make somebody worse than they were, and compliance is a major issue in glaucoma anyway. So, trying to get in the sweet spot would be very difficult.

So, working with some chemists and colleagues, Thomas Vojkovsky and Barb Slusher, and Dana Ferris, they made modifications to Sunitinib. This is just one. They made many different modifications. I won't go through the chemistry, except to show you one slide here.  One of these modified molecules still has the neuroprotective activity, but it has much less toxicity.

So, it doesn't kill at the higher doses. So, the therapeutic window is much higher. That made us relatively happy.

Then, we wanted to see, okay, you can save cells in a dish. Well, what about in an animal?

So, this is an optic nerve crush experiment looking at the loss of ganglion cells. This is percent of surviving ganglion cells on the Y-axis. And again, it doesn't get you up to 100 percent, but it gives you several-fold more ganglion cells. And Harry's work has shown in the past that you can actually lose 50 percent of your ganglion cells and still have a totally normal visual field.

So, if one could go from 10 to 30 or 40 percent, that actually clinically would be very significant.

And also in collaboration with Harry's lab, we used a rat laser glaucoma model that he had developed, and just comparing the very left -- I don't know if you guys can see this. I'm colorblind, so I can't see it too well. But, if you look all the way at the left versus the second of left, you see a lot of axonal loss with the glaucoma model. And if you look all the way on the right, Sunitinib again is protecting axons as well as cell bodies in this model.

Okay, so that was part one. We did the screen. We did a phenotypic screen. We got something we thought was interesting. Then, the question is, what is the target?

Derik Welsbie, together with Zhiyong, Cindy Berlinicke, and in collaboration with the NCATS team here at NIH, who are terrific partners to work with, Jim Inglese and Scott Martin -- Scott has left and I think is at Genentech now. But, anyway, we were able to use some of their additional high-throughput screening capability to do another screen, when instead of screening small molecules, we did an sRNA screen because it was a protein kinase inhibitor. So, there was a reasonable guess that it was a kinase that was mediating the neuroprotection.

So, Derik, et al., basically took sRNAs, three sRNAs for all the known kinases in the mouse. We were lucky because there was no guarantee that one kinase would be enough. But they were able to find two separate kinases, either of which gave significant neuroprotection. Three out of three sRNAs were greater than 3 standard deviations to the mean, shown by the arrows.

This shows more dramatically, if you look at the picture, it's not a subtle effect. This is several of the sRNAs versus none. So, you basically get no ganglion cells to many. And today we won't have time to talk about it, but the DLK and Lck, which were the ones that came out first, only two of a number of kinases. But I think, if you do polychemistry, you can actually get better and better survival.

Okay. So, that's an example of neuroprotective screening using sRNAs to map a pathway with DLK and Lck. That work has all been published. So, if anybody is interested, it's out there.

Now what I would like to talk about is sort of the flip side of what we're interested in, but also talking about the Audacious Goals Initiative. It is, can we use stem cell technology to both better study the biology of retinal ganglion cells and drugs as well, but also look towards the possibility of optic nerve regeneration?

Val Sluch, when he was a graduate student in the lab, adapted a method that Robin Alley's group had published for generating photoreceptor cells that was quicker than most of the other protocols out there. And since a number of groups, Connie Cepko and others, in the past have shown the linear development during differentiation, ganglion cells are born before photoreceptors. So, we reasoned that, if this protocol is generating photoreceptors, there should be some ganglion cells in there. And, in fact, there were, if you start looking for ganglion cell markers. The problem is that the number of ganglion cells, when we followed Robin's protocol, was very few. We didn't get enough ganglion cells to really do any biology.

So, what Val did with Vinny Ranganathan and some other members of the lab is generate a reporter line using CRISPR-Cas9 technology, which, for those of you not familiar with it, it's just the newest and greatest genome editing technology. So, what they were able to do is in the BRN3B locus, which is a transcription factor that's important for ganglion cell development, they knocked into that locus the mCherry, which turns the cells red, and, also -- I don't show it here -- but the Thy-1 antigen that we used up here for the mouse cells. We actually put mouse Thy-1 on the human cells. And since the antibody is specific to the mouse cells, we can use it to purify. We can use this to identify and purify human, I'll call them ganglion cells; we realize they are not the same, but they are very similar and we think practically useful. So, these are what some of these beautiful red ganglion cells look like after 30 days in culture and differentiation.

Again with Jeff, we looked at electrophysiology in these human stem cells. The red ganglion cells, they not only look like ganglion cells, but they act like ganglion cells.

This may or may not work. We'll see. They dance like ganglion cells. So, you can see this is time-lapse photography. You can see them putting out their processes. It's almost like a dating process. Some cells they seem to like and make connections; others they pull back from.

So, anyway, we think this is a nice model system. Okay. As I say up here, having a supply of human ganglion cells is nice, but what are we going to do with them? What we would like to do, and what we are trying to do, is what I sort of mentioned earlier, to use in study biology for drug discovery and for transplantation.

Many of you, I'm sure, are familiar with single cell RNA transcriptomics or RNAseq. This is a drop-seq method developed by Evan Macosko and colleagues up in Cambridge. And I won't go through the details, but, basically, it's a way -- you know, most RNAseq, which by itself was a tremendous advance, looks at populations of cells, but ganglion cells are complicated. There are many different subtypes. And in addition to that, when they get injured, since they die over time, cells are probably in different stages of degeneration. So, if you just do typical RNAseq, you get the whole mixture, like taking this whole room and mixing everybody together. We really want to understand cells at the individual level. So, what this method does is gives you limited transcriptomic information of one cell at a time or many cells at a time, but separate cells.

This is some work that Alyssa Kallman and lab has been doing. It's actually using a method that Carl Wayland had developed retinal organoids, and we're not talking about organoids today. But, since we heard about them this morning, I just throw in this quickly.

I want to mention that this is done with Jeff Wang, who is an engineer at Hopkins, who has really been terrific. And he is the one in his lab, his student Anu built the drop-seq that this data came from.

But this is looking at a retinal organoid that's about 100-odd-days old with drop-seq, showing that you can cluster all the different cell types in the retina. But today, since we're really concentrating on ganglion cells, we didn't use those organoids because the organoids, No. 1, have very few ganglion cells. And two, the ganglion cells don't survive very well in the organoids. So, we used the protocol that Val developed that I showed you earlier, which is the 2-dimensional method with ganglion cells.

So, this is some work that Jie Cheng, who is a research associate in the lab, did of using drop-seq on purified retinal ganglion cells, so you can get a number of different clusters. I'm sure many of you know of Josh Sanes' beautiful work with bipolar cells, and now he's doing non-human primates. So, we're working with Josh and, hopefully, going to compare some of the human RGC subsets with the other non-human primates.

This shows different patterns of genes that seem to reflect the different subsets. This shows the same data in a different way. If you look at the seven different subsets that we've identified beforehand, you find even some of the well-known ganglion cell genes, some of them are expressed in all the subsets, and some of them -- ISL2 is an example, isletl, you know, even Thy-1. Thy-1 is in a particular subset to ganglion cells and not others at higher levels.

Okay. So, that's one thing. So, we think the ganglion cells can be used to study biology, and using CRISPR-Cas9, we can downregulate or upregulate genes to study a number of things that were not possible before.

Then, in terms of getting more towards transplantation, we have been working with Hai-quan Mao, who is another engineer at Hopkins who is very interested in surface polymers and

molecules. You may have noticed that the pictures I showed before, the axons grow in all directions, and they go one way, and then, turn left and right. There's no directionality with those neurites.

But Hai-quan's lab, with Kellin and Russ, they're able to electrospin scaffolds and fibers that are linear. So, you can't see it here, but there are tiny fibers going left to right or right to left.

They don't have directionality, but they're all horizontal.

As a result, you can see that the neurites grow pretty straight. And again, this is time-lapsed, so you can see they're growing in the direction you want them to grow. And this shows, you know, they could grow pretty fast. So, this is a 10-day culture, the axons and these human stem-cell-derived ganglion cells can grow 5 millimeters. So, it's not an optic nerve yet, but it's getting there.

And then, I also mentioned drug discovery. All the early work, as I said, was done with mouse ganglion cells.   But, okay, now we've got human ganglion cells. So, we tested our same favorite molecule, Sunitinib, with a dose-response curve. And again, with human cells, just like mouse cells, one can show cell- survival-promoting activity. So, that suggested the system might be usable got a larger screen, which, hopefully, would be more relevant and, also, obviously, would not require animal. This requires the expense of some culture medium, which requires a lot of support. It's expensive.

Okay. So, let's go back to, okay, let's say we've got ganglion cells and let's say something is wrong with the nerve. So, getting back to the higher centers of the brain, and our neuroscience collaborators, I want to share with you some work from a number of people who have been making important strides in the field. And again, I apologize for not including everybody's work, because there's really a lot of people working in this area.

So, as was mentioned earlier, the Audacious Goals, really restoration of usable vision in humans, so the regeneration of neurons and retinal connections of the eye and the visual system. Optic nerve regeneration is one of those goals. And let's start with endogenous ganglion cells. So, these are ganglion cells that are still there, but their axons are injured. So, they don't have good connections. So, we need to worry about in this case endogenous RGCs and axonal regeneration.

This is a slide and some data from Zhigang He's lab that I would like to share with you. He has actually started this work probably 10 years ago, but it is really getting more and more advanced. He has shown that certain suppressors of axonal regeneration, if you inhibit them -- and PTEN is one of those -- you can increase axonal survival and axonal outgrowth.

So, this is an example here. This is optic nerve crush in the optic nerve and in the control, and you're labeling the axons and the ganglion cells. In the controls they all stop, and if you wait a week, two weeks, or three weeks, nothing happens. They may eventually die, but they don't grow past the crush site.

But in his PTEN knockout animal, you can see it's clearly not normal, and that's going to be a theme here. I don't think anybody yet can totally regenerate an optic nerve, but I think a number of groups are really working together to make great strides to get a small, but real percentage of the ganglion cells to regenerate past the crush site and, with some sensitive, functional studies in mice, maybe even restore some function.

So, this is PTEN knockout. They are also knocking out genes in humans. So, it's becoming more doable. It might not be the easiest thing to do, but, again, that may change in the next few years.

So, people have also looked at molecules that are involved in the PTEN pathway, and Osteopontin is a molecule that Zhigang's lab has also studied in collaboration with Josh Sanes.

What you can see here again is that these molecules increase axonal extension beyond the injury site.   And if you quantify it, this is the number of axons, and they're small numbers. And going to the right is distance from the crush site. The further you get, it gets lower, but the combination of molecules does give you a clearly significant increase.

These slides I got from Larry Benowitz. Larry has also been looking at things that promote survival of extension of ganglion cells and zinc. He and his collaborates found that shortly after axonal injury there is a big increase in zinc content in the inner plexiform layer and axon sites which eventually synapse and lead to damage to ganglion cells.

Based on these studies, they have hypothesized that this zinc here is important. So, in order to test as well as develop a treatment, Larry and his group have explored zinc chelators.

And I think you will all agree that this is a pretty impressive result. Again, an optic nerve crush injury, but the difference is -- and it's PTEN versus TPEN; everybody makes jokes it's the same letters, but this one is the chelator, TPEN.  And if you put the two together, you get quite a bit of axonal growth beyond the injury.

And this is another picture from Zhigang's lab. What you can see is that the axonal growth -- this is now labeling the eye and seeing where it goes -- some of those axons go beyond the chiasm.

Another one of Larry's slides.  This is just giving a summary, and not an inclusive summary, but a summary of some of the factors, transcription factors. Jeff Goldberg's lab has looked at KLF9, which seems to be important. There are molecules; there are growth factors. A whole variety of different molecules have been identified that promote. And Carol has obviously done a very beautiful lab with the chiasm and how axons cross. So, I think that the scientific basic science pieces are getting to be there and, with hope, we'll get there.

How am I doing timewise? I'll talk fast in my New York --

So, the last part of this, and then, a few slides on translational stuff, is, okay, we talked about endogenous; what about exogenous RGCs? If a patient has already lost the RGCs, what can you do? You could put in a chip and connect it to the visual cortex, and there are people working on that. But we're taking the more traditional approach of thinking that we want to stick with the eye.

Does the National Eye Institute cover it if it goes to the cortex and it's not an eye? Is that still in your -- you may have to change the name.

This is some beautiful work from Jeff Goldberg's lab not with human cells, but mouse cells, where they cut mouse retinal ganglion cells, inject it into the eye, and was able to show that they got pretty good integration of these transplanted ganglion cells. And they were able to get some targeting to the superior colliculus and the suggestion of some function.

Another totally independent group, but it's always nice in science, obviously, when different people replicate each other, Peter Barabas' lab up at Scapens, who used to work with Michael Young, and now he's got his own group there, working with Josh Sanes, they've been looking at the mouse ganglion cell subsets and also have been transplanting them.

I think one nice addition to his study is that, as some of you know, in the retinal regeneration field when people have tried to transplant photoreceptors, if you do a wild-type eye or a normal eye versus an injured eye, it often can change the ability of the eye to get in, and secondary scarring can create problems.

So, what Peter showed and his group is actually in a mouse model of glaucoma, microbeads or using NMDA to kill ganglion cells, they actually get increased integration of the cells in the glaucoma model. So, if you had to pick it, that would be great. But it looks like the disease is not preventing the transplant.

We're really not transplanting people. It's hard to see here, but investigators have tried to take some human ganglion cells and injected them into a mouse eye. Most of them just died and did not integrate, but in a couple of -- this is not a typical picture.  This is the best picture. But in some mice we were able to get human ganglion cells to live in the immunosuppressed mice.

And Tom Johnson, who actually used to work with Slav Tomarev at NEI, and is now a resident, about to be chief resident and faculty member at Wilmer, he has taken some of these human ganglion cells and treated mouse explants with them and is able to get these cells to integrate into the ganglion cell layer and has some very nice processes.

All right. For the last couple of minutes, we get to the hard part, you know. We like translation. We heard about translation. We all agree that basic science is important. The Eye Institute continues to fund that highly.

Once we've got this part, how do we translate to the clinic? In glaucoma, neuroprotection is tough. Unlike some diseases where there's a rapid effect, glaucoma is slow and chronic. It's got a variable clinical course. The outcome measures have significant variability. As I mentioned before, we can't measure eye pressure. So, what are we going to measure? Are we going to measure visual fields, some other measure of function, some imaging method? There are now ways to look at apoptosis of ganglion cells in vivo. But it's not obvious.

The other thing which Ellen sort of referred to with the ethical issues of having a no treatment group, you know, in 2018, there's no way that one would ever consider not treating patients. So, if you're going to add a neuroprotective agent, you have to add that on top of the best treatment. So, it's not easy.

And also, unlike VEGF inhibitors where patients love to get that needle in the eye because they see better, in glaucoma the best thing we're going to do really is stabilize vision. It's unlikely with a neuroprotective agent; transplantation could improve it. But neuroprotection will probably stabilize but not improve.

Also, it's a generally an asymptomatic, non-life-threatening disease, except for obviously losing vision is a symptom. So, maybe that's not the right word. Unlike cancer, where patients will take something that makes them pretty sick to stay alive, I think glaucoma patients probably will -- you know, it's hard enough to get patients to take their drops every day. I think something that makes them sick will be difficult. So, neuroprotective will have to be very safe. Memantine we already talked about, which increased interest in the field.

We need to encourage academic/industry interactions. We have to, as was talked about earlier today, interact with the FDA, find the money to fund it. And then, in terms of actually developing a clinical trial -- maybe we won't go through all of this today, but, you know, there are many issues of what kind of patients you do, what group do you select, how do you follow them, et cetera, et cetera.

And lastly, I would like to just end with some slides Jeff Goldberg sent me, because this is an actual clinical trial, neuroprotection, that's underway. So, maybe a year from now we'll say it's been solved.

Many of you know about the Neurotech implant. It's also got interesting histories of some of the people in this room. But the CNTF, which is basically a little cartridge with an RPE-like cell line that secretes CNTF is implanted. It didn't work particularly well in certain other retinal degenerative diseases, but Jeff has been running a trial now with these in glaucoma.

So, they're taking patients. They first had a single-center trial to look at safety and related issues. And now, the patients are randomized to give sham surgery on the implant. They've already enrolled 44 of 66 patients at the institution shown here. It's listed in clinical trials. And I think within the next year we'll know if this Neurotech CNTF formulation is able to promote survival of ganglion cells.

In conclusion, we all agree about the goals of the Audacious Goals. Neuroprotection and optic nerve regeneration are still challenging goals. But, given the recent and continuing research advances in the field, I think there is great hope that our shared dream will, hopefully soon, become a reality.

And I just want to thank my colleagues and friends for providing slides and, of course, the NEI for funding, and the people in the lab who have done a lot of the work that I talked about. I tried to mention their names during it.

So, thanks very much. (Applause.)

Done at one o'clock.

(Laughter.)

COUNCIL MEMBER: Don, I have a question.

DR. ZACK: Sure.

COUNCIL MEMBER: That was an excellent presentation, really exciting work.

How long a window do you have when you begin -- you said something earlier. You said you lose these cells, and then, you're trying to regenerate things. If the axons are gone, how much time do you think you have in regenerating?

DR. ZACK: It's a good question. I would bounce it off your colleague Carol. I think it's not super-short, but I don't really know. I mean, I think if you do optic crush, the ganglion cells -- one thing which I alluded to, but I didn't talk a lot about, different subsets get injured differentially. So, some cells probably die quicker than others. But if you do a pretty strong, even a transection, even if 80 or 90 percent of the cells die, those 10% or 20% that are left, and we don't understand why, they will stay there for weeks and months.

COUNCIL MEMBER: Oh, okay.

DR. ZACK: So, I think, but can't give you hard data, that the window is not that short.

COUNCIL MEMBER: And my second question, you talked about these human ganglion cells. What was the age of isolation of those retinal ganglion cells?

DR. ZACK: Well, it's an ES cell line, Hl, H7, H9, iPS. And the differentiation protocol, using the reporter, it turns on at about day 25 in culture. And we are trying to understand whether is a one-month ganglion cell different than a two-month versus a three-month. And the single-cell studies I think will answer that eventually, but we don't know. But most of these studies were probably 45 days, something like that.

COUNCIL MEMBER: Okay. Thanks.

Dr. MASON: To answer a question raised just now about cell, I think it's cell-type-specific. And in some of Josh Sanes' work, your work, and Zhigang's work, running very vast differences in generation of injured retinal --

DR. ZACK: And then, the harder question is humans, too. COUNCIL MEMBER: And humans, yes. We don't know anything.

My question is a technical one. On the nanofibers, looking at the axons growing on that, are the nanofibers on something else, like a scaffold?

DR. ZACK: No. They're electrospun on a plastic surface.

COUNCIL MEMBER: On a plastic surface? So, how could that be translated into putting strut --

DR. ZACK: Yes. I think it will be difficult to -- you know, neurosurgeons do amazing things, so we could ask them. But the way we're looking at it now is I think it would be tough to do that in vivo, but one could make the nerve in vitro on a surface and, then, transplant some piece of that, but it's not clear.   I think the other thing which would be helpful is attractive molecules, which I think might be a better way to do it, yes.

COUNCIL MEMBER: Don, a fantastic talk. I mean, it's really extremely exciting work.

I have two questions on the translational front. One is, when do you think intervention should happen clinically? You have lots of people with eye pressure of 25. Do they all get neuroprotection or do you wait until someone has lost a little field? What's the target audience for a drug?

And the second is, what do you think the FDA will take for an endpoint? Is it going to be a field loss?     Is it going to be an OTC thickness measurement? Where do you sense that's going? Because that really defines what the task at hand is going to be for translating this to clinical use.

DR. ZACK: I mean, both great questions, which I have limited answers for, but will start with the when to treat. I mean, Ellen talked about the ocular hypertension treatment study, which actually was the one and only glaucoma clinical trial that I was involved with. So, it was fun to watch it.

And I think, Ellen, you mentioned very well the results, but we left out one part of that. Even though the number of people who develop glaucomatous optic nerve damage get cut in half by treatment, which is great, you're still treating 80 or 90 percent of patients who are not going to develop damage.

So, it's the same issue here, I think. Do you treat a large group to benefit a few? Or do you wait for more severe disease and treat the people who really need it? And I think the real answer is going to become efficacy/toxicity balance. If the drug was totally safe and cheap, then I would do it early. If it is like Sunitinib and has significant systemic toxicity, then you wait for somebody who has failed.

One joke about neuroprotection; it's very hard to prove it works. But, once you start on patients who are tolerating it, you can't prove it's not working.

But I think if there was a safe slow release or some kind of formulation that you could use, I would do it relatively early.

Sorry, the second question? Yes, sorry. So, Wiley Chambers is the one to talk to about that. I've never discussed it with him, but what I've heard from a lot of colleagues is, as of right now, 2018, visual field testing is the only thing that the FDA will consider approving, consider using for approval. There have been lots of very smart people who have talked to the FDA and tried to convince them OCT, other kinds of imaging methods.

And again, I don't know if this is true, but I have heard quoted that, when we can show a .9 correlation coefficient between OCT and visual fields, then -- and I think it's only a matter of

time (a) when the imaging gets better and (b) when the FDA modifies its approaches. But I think just doing fields, we're almost never going to get there. But I think new methods are going to help that.

COUNCIL MEMBER: That was an amazing presentation. I learned a huge amount. I'm not a glaucoma person at all.

My question is, why are the traditional glaucoma medications not considered neuroprotective? Because do they not protect?

DR. ZACK: I think that's a semantic question. Yes, I mean, the whole goal, we're helping patients with a neuroprotector because we want to protect the nerve. When I, and I think other people who are neuroprotective people, we're talking about something that directly affects the ganglion cell and its process and its response to injury, as opposed to getting rid of the injury, because lowering eye pressure, you're basically getting rid of what's injuring -- well, I shouldn't say "what's injuring" -- what's a risk factor for the injury of the ganglion cells.

COUNCIL MEMBER: So, I guess I'm thinking about, how do we weigh the differences between optimizing treatments, like making the current drugs -- patients more compliant and take those drugs better, make them less irritating to the ocular surface, reduce cost, increase availability, versus these others in terms of public health outcomes? It seems to me there's a lot more we could do with drug treatment and availability and compliance.

DR. ZACK: I mean, it's complicated. I think they're both important. If resources were sufficient, I think both approaches are parallel. The public health point of view, my daughter is graduate, or she's graduating, a graduate in public health. So, public health is very close to our heart. I mean, we have major problems of public health, I guess. I don't want to say too many political things live, but maybe I should.

But we've tried to improve care and delivery. As you may know, there are eye drop bottles which have counters in it. There are people who have developed apps for the phone that remind people when to take drops. So, there's a lot of room for improvement, but it's not a lack of effort. And in terms of pressure lowering, there are new devices coming out all the time. But I would say, on that curve of getting as far as you're going to get from IOP lowering, we're pretty far along the way and we're at the flatter end. And there's still room for improvement, but I don't think it's going to change dramatically. I mean, there are enough patients out there that certainly would help; whereas, I think neuroprotection -- again, I'm biased because I think it's interesting -- but I think neuroprotection would really complement it. And again, there are the whole subset of patients whose glaucomatous loss is not related to pressure.

Ironically, related to that maybe -- I'll let everybody go enjoy the day after this -- but I think the first trial, and you guys can correct me if I'm wrong, the -first trial that showed that lowering eye pressure -- I mean, doctors knew it for years -- was the normal pressure glaucoma trial, because it was considered unethical to treat, at least in the U.S., patients -- when people had low eye pressure, we didn't think, or some people didn't know that eye pressure was involved. So, if your pressure is normal to begin with, they tried to lower the eye pressure more. And actually, if you have a normal pressure and lower it more, you actually have less damage. You may have damage from the treatment, but --

COUNCIL MEMBER: I may be able to provide some insight. To your question of the public health compliance, lower costs, so with sustained release, new surgeries, industry is really taking up the mantle to try to take that to the next level. But a lot of those companies were funded or started with NIH/NEI SBIR grants. So, I think NEI gets to take credit for that effort, too.

Don, great presentation. I 1,000% agree that this would be very complementary and a welcome addition to the Glaucoma Armamentarium. But I think, with intraocular pressure, the next phase of development and discovery is going to be in disease-modifying treatment. So, right now, all of our IOP-lowering treatments are palliative. They attack other things than what's actually causing the pressure elevation. The next stage that we're just getting to is starting to attack what is actually going wrong. So, rho kinase inhibitors may or may not be, probably are the first wave to come for that.

DR. ZACK: Thanks, Doug.

Since you mentioned rho kinase inhibitors, I might mention that the front-of-the-eye and the back-of-the-eye groups can talk to each other because rho kinase inhibitors are also probably neuroprotective. So, that may be one that does front and back.

COUNCIL MEMBER: Yes, very exciting talk. Thank you.

Can you elaborate a little bit more on the cartridges in the clinical trial at the end of your talk? Why do you need these cartridges instead of intraocular injections or drops? I suppose that, I mean, recently slow or sustained release. I mean, this is the reason. How often would you have to -- that's another thing that works -- how often would you have to use --

DR. ZACK: I'm sorry, you're talking about Neurotech? COUNCIL MEMBER: Yes. Yes.

DR. ZACK: There are a whole number of companies that are doing different kinds of slow release, either formulations or drugs. Neurotech -- I mean, Paul can answer this better than

I -- but it's a year -- how long? -- or even longer. I mean this is actually cells in the cartridge. So, that is secreting, they're synthesizing, making the CNTF. I think it's potentially for years, right? What was the --

DR. SIEVING: The latest that I heard this week was 10 years.

DR. ZACK: And this is not a small molecule. This is obviously a protein. So, I think it's different whether you're talking about small molecule delivery or large molecule. If you want a small molecule, VEGF is an example where industry is really spending a lot of money and a lot of effort to get a slow release formulation. And hopefully, we could apply the same technology to glaucoma. But I think for small molecules -- and I'm no expert on this -- I think we're talking about a month to two or three. Whereas, if it's a protein that's secreted, if the cells stay alive, it could be treatment once and you're done.

COUNCIL MEMBER: Excellent talk, Don. Thank you very much.

I just wanted to address Russ' question about who to treat. Obviously, I don't think we can treat everyone. It would probably be prohibitively expensive. I think what we want to identify are the fast progressors, the people who are at increased risk for blindness. And we don't know who those people are right now, but we're doing research using genetics to see if we can predict which of these open angle glaucoma patients are the rapid progressors. And I think those would be the people that we would want to target. Presumably, many of them would come from African-derived populations because they're going blind more with a higher burden than Caucasian counterparts.

COUNCIL MEMBER: So, Lou, I appreciate that. The perverse thing, of course, though, is that if you identify that population and you target the drug development to that population, you wind up with a drug that is only usable in that population. And that creates a Catch-22, obviously.

The other point which is kind of buried in the OHTS trial -- I was at Wash U when Mike Kass was running that. So, we were very familiar with it. It is that if you actually look at the Kaplan-Meier curves for pressure-lowering, they're separated by about a year in the first five years. That is, yes, there is a clear reduction in the incidence of glaucoma that occurs when you lower pressure, but if you follow the two curves, they're basically parallel with a split of about 12 to 18 months between them, which means that if 5 percent develop glaucoma of ocular hypertensives at four years, at five and a half years in the treated group you get the same number of people developing disease. So, we basically have about a year and a half of benefit for development of glaucoma. This doesn't apply to people with glaucoma.

COUNCIL MEMBER: Yes. No, but what you say is absolutely correct. But one of the things that -- and Don kind of actually answered it. So, I'm going to take the words out of your mouth, Don. It is that one of the pitfalls of that argument is that you don't know if you lowered it enough. Because in the OHTS trial it was lowered by a very modest 20%. Now it took a lot to get that 20 percent; with the normal tension study, 30%. The EMGT study, which was roundly criticized for the exact same thing, which said that you only delayed it a little bit, it's a very modest pressure reduction. Now again, these are post-hoc analyses, but you do get some indication from the NEI-funded trial, that if you really lower the pressure by about 40%, the curve is essentially flat.

So, I think a legitimate argument could be made using the clinical trials data that, if you lower the pressure enough, there's a majority, if not a lot, or almost all patients will actually have an effective cure.

DR. ZACK: I just want to mention, related to Russ' comment, I skipped over this because of time reasons, but I think you're exactly right, that when you select patients, some people say for neuroprotection you want to select your rapid progressors or you want to select angle closure plate patients because they can get bad damage very quickly. But, even if you get a positive effect, then does it extend to your general population? So, where do you want to start and how do you want to go? Clinical trials design, as many of you know much better than I, is a very complicated business and there are a lot of implications of how you do it.

All right. Thank you for your attention and for your great questions. (Applause.)

DR. SIEVING: Thank you, Don. That was a good adjunct to the portfolio analysis. Thank you.

DR. ZACK: Thank you.

DR. SIEVING: Big opportunities ahead for glaucoma.

DR. ZACK: The pressure's on, right?

(Laughter.)

DR. SIEVING: Moving well and quickly.

DR. SHEEHY: So, unless anybody has some things they really want to bring up, I see a lot of people looking whichever way toward the door.

(Laughter.)

But this is an opportunity to bring things up.

Neuroscience Forum

Dr. Louis Pasquale

DR. PASQUALE: So, Mike asked me to talk just very briefly about the Neuroscience Forum that I attended last week where they were looking at apps and mobile technology and how they can help neurological diseases.

I was really impressed by the fact that people are making great headway in using these devices, you know, smartphones and social media, to gain insights into neurological disease and neuropsychiatric diseases.

So, one study was interesting. It was looking at -- they got IRB approval to do this. They looked at women who had had childbirth and was looking at the social media feed and was able to predict which women were going to go on to postpartum depression, which can be very serious.

Other people were looking at manic depression and trying to predict when people would go into manic phase, because that's when it's hard to treat manic depressions, and they don't want treatment then.  But, then, they would go crash into depression, and that's when they're in serious trouble.

My take-home from that was that the cell phone, et cetera, is great for neuropsychiatric disease,

but I think we would need more in ophthalmology. If we wanted to use technology to digitally phenotype eye disease, I think that the smartphone is not going to be as helpful as opposed to something like a Google glass that would be detecting your eye movements and perhaps changes in your eye movements with eye disorders, chronic, complex disease, or what have you.

And so, I guess if we see proposals coming down the pike from maybe small business to use sort of like smart eyeglass technology for ocular disease detection, those should be given some consideration.

Cultivating Mid-Stage Investigators

DR. SMITH: I have a question. A number of Council meetings ago, we talked about cultivating that kind of mid-stage investigator. You remember that? And that was very exciting, I think, to realize. I just wanted to get an update.

DR. STEINMETZ: So, yes, in fact, the NIH OD has taken this up, and they present us with statistics every round about mid-career investigators who are in danger oflosing their grants. And we were 99 percent. I mean, we had just unbelievably good at that. So, the goal is to try to provide bridge funding or to reach for grants for mid-career investigators who have no other source of funding and would close their grants. And we were the best of all the NIH Institutes.

DR. SHEEHY: And incidentally, we're at like 140% of our targets for ESIs.

Closing Comments

DR. SHEEHY: Okay. Hearing no hot potatoes thrown at us, I'll thank you for all your efforts. Please remember we've changed the date, October 12th.

Adjourn

(Whereupon, at 1:20 p.m., the meeting was adjourned.)

Attachment A: National Advisory Eye Council June 2018

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
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
Jose-Manuel Alonso, M.D., Ph.D.
Professor
The State University of New York College of Optometry
New York, NY 10036
Louis R. Pasquale, M.D.
Director of Mass. Eye & Ear Glaucoma Service and Ophthalmology Telemedicine
Massachusetts Eye and Ear Infirmary
Boston, MA 02114
Steven Bassnett, Ph.D.
Professor of Ophthalmology and Visual Sciences
Washington University School of Medicine St. Louis, MO 63117
Douglas Rhee, M.D.
Professor and Chair, Department of Ophthalmology and Visual Sciences
Case Western Reserve University Hospitals
Cleveland, OH 44106
Thomas M. Glaser, M.D., Ph.D.
Department of Cell Biology and Human Anatomy
University of California, Davis School of Medicine
Davis, CA 95616
Sylvia B. Smith, Ph.D., FARVO
Professor and Chair
Department of Cellular Biology/ Anatomy Medical College of Georgia
Augusta, Georgia 30912
Jane Gwiazda, Ph.D.
Professor of Vision Science
New England College of Optometry
Boston, MA 02115
Mary Ann Stepp, Ph.D.
Professor
Departments of Anatomy and Regenerative Biology, and Ophthalmology
George Washington University Medical Center
Washington, DC 20037
Dennis M. Levi, O.D., Ph.D.
Professor of Optometry and Vision Science
University of California, Berkeley
Berkeley, CA 94720-2020
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

Ex Officio

Marco A. Zarbin, M.D., Ph.D.
Professor and Chair Department of Ophthalmology
UMDNJ-New Jersey Medical School Newark, NJ 07103

 

DoD Representative position is vacant

Last updated: February 19, 2020