PREPARED STATEMENT OF PAUL SIEVING, M.D., PH.D.
DIRECTOR, NATIONAL EYE INSTITUTE
Mr. Chairman and Members of the Committee: I am pleased to present the President’s Fiscal Year 2017 budget request for the National Eye Institute (NEI) of the National Institutes of Health. Vision science is at the leading edge of neuro-regenerative medicine and discovery science in brain connectivity. I want to share our latest progress and goals in neuroscience, regenerative medicine, gene discovery, and gene therapy.
NEI AUDACIOUS GOALS INITIATIVE
The NEI Audacious Goals Initiative (AGI) is a bold, strategic investment in neuro-regenerative medicine that will enable the restoration of vision through regeneration of the retina – the light-sensitive tissue in the back of the eye. AGI focuses on photoreceptor neurons and retinal ganglion cells. Photoreceptors capture the light necessary for initiating vision, while retinal ganglion cells transmit these light-induced signals to the brain and can degenerate in glaucoma and other optic nerve diseases. Vision scientists have taken the first steps toward achieving the regeneration of these cells by converting stem cells into mature retinal cell types and are integrating these cells into existing retinal circuits. In order for these regenerated neurons to send signals to the brain, they need to grow long connections, called axons, and correctly wire themselves to the appropriate partners in the retina and the brain – a goal that will require new tools and a better understanding of the underlying biological processes.
Last year, NEI awarded the first five AGI projects to develop functional and metabolic imaging technologies that are capable of visualizing a single live cell. For example, adaptive optics (AO) technology has been developed to successfully image a single photoreceptor in patients and track that particular cell in subsequent patient visits. This powerful tool allows clinicians to non-invasively monitor the degeneration of the cell and conversely to image its replacement by healthy stem cells. Prior to this technology, imaging was severely limited by distortions that bent light waves irregularly. In addition to AO, advanced magnetic resonance imaging technology is being developed to assess regeneration of damage to the optic nerve. These five imaging teams were brought together in a collaborative consortium to share data, technology, and early results in order to speed progress toward scientific goals. This consortium also facilitates input and guidance by NEI program staff as well as by an external scientific oversight committee. Importantly, the AGI is a participatory scientific endeavor that actively gathers input from the vision community and the broader neuroscience community in the form of expert workshops and town hall meetings.
NEI is currently reviewing applications from a second AGI funding opportunity to screen cellular and molecular entities critical to the regeneration of neurons, guiding their axons to targets, and making new functional connections. NEI anticipates that once the unknown factors (genes, proteins, signaling molecules, etc.) involved in regenerating retinal ganglion cells and photoreceptors are discovered, the work will advance to specific projects to understand the biological mechanisms through which these factors influence regeneration.
It is noteworthy that AGI has catalyzed the field of neuro-regenerative medicine, with over 20 investigator-initiated projects awarded by NEI in FY 2015. While AGI is independent of the President’s BRAIN Initiative, many vision scientists are BRAIN grantees, and BRAIN research will accelerate AGI efforts to regrow and regulate retinal neurons and their connections in the eye and brain.
TRANSLATIONAL RESEARCH AND CLINICAL TRIALS
Proliferative diabetic retinopathy (PDR) is a serious complication of diabetes, in which vascular endothelial growth factor (VEGF) secreted by the retina triggers the proliferation of abnormal leaky blood vessels. Accompanying vitreous hemorrhage and retinal detachment can lead to permanent vision loss. Since the 1970s, doctors have treated PDR with a laser therapy, but this treatment can damage night and side vision, so researchers have sought improved therapies. Lucentis is one of several drugs that block VEGF and has been shown to be effective in other eye diseases. Diabetic Retinopathy Clinical Research Network (DRCR.net) has 400 retina specialists in over 41 States, one third are university based, and the rest are from community-based practices. A DRCR.net trial found that Lucentis is highly effective in treating PDR, reversing some vision loss without affecting side vision. By comparison, laser treatment merely preserves existing central vision but does not reverse losses. The new research findings demonstrate the first major therapy advance for PDR in nearly 40 years. The network also conducted a study of three anti-VEGF drugs for diabetic macular edema: Lucentis, Eylea and Avastin. After two years, patients with mild vision loss at baseline had similar improvements in visual acuity from all three drugs. However, patients with moderate to severe vision loss at the start of the trial had slightly better improvement with Eylea and Lucentis than the less costly drug, Avastin. From these results, patients and doctors can weigh baseline vision, expected clinical outcomes, and costs when choosing a personalized treatment strategy.
For patients who live in rural or urban underserved communities, telemedicine can be used to remotely screen, monitor and diagnose disease. DRCR.net just launched a new protocol to explore whether telemedicine using a new ultra-wide field imaging technology can allow specialists to remotely identify DR in a patient and to determine what follow up care is indicated. NEI also has supported telemedicine technology development through its Small Business Innovation Research program, e.g., automated retinal scanning technology to detect DR and monitor images at remote clinical sites.
Using patient-specific induced pluripotent stem cells (iPSCs), NEI researchers are developing the first personalized therapy for the “dry” form of AMD. The retinal pigment epithelium (RPE) is a single layer of cells that carry out the critical function of nourishing and supporting the adjacent photoreceptor cells. In dry AMD, RPE cells start to die, leading to photoreceptor cell loss and visual impairment. The NEI intramural research team has developed a clinical-grade manufacturing process to derive iPSCs from AMD patients and convert them into RPE tissue. The RPE tissue is delivered using a biodegradable scaffold that helps integrate and maintain proper orientation of the tissue in the back of the eye. The entire RPE tissue manufacturing process takes only 142 days after a blood draw from an AMD patient. Patient-derived tissue has the distinct advantage over donor tissue as it is less likely to be rejected by the immune system. In preclinical work to prepare for a human trial, the NEI team demonstrated that transplanted tissue integrates in the retina and restores lost function in a pig model of retinal degeneration. Success in the pig model, along with production of clinical grade iPSC has paved the way toward filing an application for Investigational New Drug (IND) with FDA in 2017.
iPSC technology is a potentially powerful research tool that enables scientists to transfer their knowledge of known disease pathways in particular cells and organs to shed light on the impact of these same disease mutations in entirely different cell types of other organs. For example, iPSCs derived from a heart disease patient have a mutation in the gene STAT3. This mutation impairs blood vessel growth, and immune and wound-healing responses. The STAT3 gene has also been suggested to play a role in RPE immune responses and in molecular signaling that may lead to AMD-like symptoms in patients. The NEI team is now testing RPE tissue derived from this patient’s cells to understand the role of STAT3 in AMD.
Cataracts are a clouding of the lens caused by misfolding and aggregation of lens crystallin proteins, and can result from many causes including side-effects of drugs like steroids, or surgery, or most commonly from aging. Cataracts occur in over half the population over age 70 and are a major cause of vision loss in older adults. Researchers identified a class of molecules that bind to crystallins, reverse their aggregation and restore lens transparency in mouse models of cataract. These agents could be delivered via eye drops, potentially eliminating the need for costly surgical cataract removal.
GENETICS AND GENE THERAPY
In the largest-ever Genome Wide Association Study (GWAS) for AMD, NEI investigators were part of an international team that studied more than 12 million gene variants from more than 43,000 participants with and without AMD. The group identified 52 associated common and rare gene variants associated with AMD. The success of this study, particularly for rare variants, was predicated on the extremely large sample size of participants and bringing together an interdisciplinary team of clinicians, geneticists, and bioinformatics experts to analyze “big data.”
Glaucoma is the second leading cause of blindness globally. It is a group of conditions that damage the optic nerve and have a genetic predisposition. A consortium called the NEI Glaucoma Human Genetics Collaboration Heritable Overall Operation Database (NEIGHBORHOOD) recently identified three new genes that contribute to the most common form of glaucoma, increasing the total number of such genes to 15. One new gene is an enzyme that protects cells from oxidative stress. Another gene had previously been implicated in a rare form of severe early onset glaucoma. Despite the high heritability of glaucoma, identifying glaucoma genes has been a challenge and the biological mechanisms are poorly understood. To address the mechanistic challenge, NEIGHBORHOOD researchers integrated eight independent GWAS, involving over 37,000 glaucoma patients and controls to better understand genes and phenotypes.
A pioneering technology called optogenetics introduces light-sensing proteins into cells that are not otherwise light sensitive. In retinitis pigmentosa (RP), the light-sensitive photoreceptor neurons have died, however many other neurons in the retina are preserved. NEI investigators have established proof-of-principle with optogenetics gene therapy in blind mice. By delivering light-sensing proteins directly to retinal bipolar cells, they effectively bypass the dead photoreceptor neurons upstream and can elicit a visual response. This exciting work is being translated into a clinical trial. There are many gene mutations that cause RP, yet optogenetics is not treating a single mutation; a single therapy that restores visual responses could have widespread application.
A major scientific breakthrough in the past few years was the development of a gene editing tool called CRISPR/Cas9, in which specific DNA mutations can be changed in specific cells. As a research tool, this system allows researchers to introduce molecular changes in cell cultures or animal models to study the function of individual proteins. The tool also has fundamentally important implications for clinical therapy in adult tissues. NEI is funding research that is correcting genetic mutations in stem cells created from patients with genetic mutations for RP, Usher syndrome, and Best disease. In the future, these corrected stem cells could be used as a cell therapy. NEI also is funding research using CRISPR/Cas9 for a wide variety of other ocular disorders affected by specific gene mutations such as a form of glaucoma and Fuchs’ corneal dystrophy.
RETINA ORGANOID CHALLENGE COMPETITION
NEI is preparing to launch a $1.5 million challenge competition to catalyze therapies for retinal diseases by developing retina organoids. Organoids are 3D, self-assembling, mini-organs grown in a dish from human stem cells. They can be used for disease modeling, drug development, and therapeutic transplantation. On April 4, 2016, NEI held a technical planning meeting of industry and academic experts to review progress in organoid engineering of the retina and other organs, and to help design challenge parameters. The Congress requested a retina disease challenge in NEI’s FY 2016 Appropriations Report. This competition dovetails with the AGI and will accelerate retinal therapies since the human tissue-based models will aid in developing and testing regenerative therapies for retinal neurons.
The audacious goal to regrow new neurons in the retina and restore vision builds on a foundation of audacious science that is described here. In the near terms, we will advance the understanding of mechanisms that underlie eye disease. The mechanistic knowledge will propel the drive for clinical applications that help fulfill the promise of gene and cell therapies that benefit patients.