Mr. Chairman and Members of the Committee:
I am pleased to present the President’s Budget request for the National Eye Institute (NEI) of the National Institutes of Health (NIH). The fiscal year (FY) 2016 budget proposal is $695,154 million, which is $18.9 million more than the FY 2015 enacted level. As the director of the NEI, it is my privilege to report on the many scientific discoveries and translation of these discoveries to reduce the burden of eye disease.
Vision researchers are developing disease prevention and treatment strategies based on patient variability, genetics and the precise mechanisms of disease. This patient-centric and tailored approach will transform medicine. Over the past few decades, we have discovered hundreds of genes that contribute to inherited eye diseases, more than are known for any other system in the body. For example, in patients with a severe, early onset retinal disease called Leber congenital amaurosis (LCA), NEI scientists discovered a gene mutation in an enzyme that helps processes vitamin A into a form used by the eye’s retina to detect light. Pioneering gene therapy trials in LCA patients successfully inserted a healthy gene, leading to modest visual improvement. Building on this progress, NEI launched a gene therapy trial last year for a blinding disease that affects the optic nerve, which carries visual information from the eyes to the brain. In February, the Sieving lab at NEI launched an ocular gene therapy clinical trial for X-Linked Juvenile Retinoschisis, an early-onset retinal disease that causes the layers of the retina to separate and results in severe vision loss.
NEI is also making progress in identifying the genetic and environmental risks for common, complex diseases like glaucoma. Using genomics tools and the largest cohort of glaucoma patients in the world, investigators in the NEI Glaucoma Human Genetics Collaboration (NEIGHBOR), have focused on the complex interactions of pressure in the eye, anatomy, and ocular nerve damage that lead to blindness. The nine different risk loci (gene areas) which have been identified represent different molecular mechanisms, but only represent part of the genetic picture. To address this knowledge gap, NEIGHBOR is collaborating with the International Glaucoma Genetics Consortium, which will incorporate many more patients, primarily from Asian populations. Furthermore, last year NEI funded two new genetics studies of glaucoma in African Americans, who are at highest risk of the disease.
In degenerative eye diseases, cells such as the neurons in the retina start to die, leading to progressive vision loss. Regenerative medicine is a promising approach to regrow these replacement cells, and in some cases to treat these patients with therapies derived from their own cells. Investigators from the NEI’s intramural regenerative medicine program convert patient-derived stem cells into retinal tissue to study molecular pathways and to develop cell-based therapies. Treating patients with their own cells avoids immune reactions that hinder cell transplantation. As a step closer to realizing human stem cell therapies to restore vision, NEI awarded a contract to Cellular Dynamics International, Inc., to manufacture clinically compatible retinal stem cells for use in human ocular clinical trials.
COMPARATIVE EFFECTIVENESS RESEARCH
Patient participation in health decisions is a key component to precision medicine, and NEI research is providing more therapy options for patients to consider. For example, a recent trial compared the effectiveness of three drugs for diabetic retinopathy (DR), a complication of diabetes and a leading cause of blindness in working age adults. DR leads to growth and leakiness of abnormal blood vessels that damage the retina. In a landmark trial in 2010, NEI-supported investigators established the effectiveness of Lucentis in stopping blood vessel growth, improving vision, and preventing further loss in diabetic retinopathy (DR). Since that trial, however, two additional drugs with similar action, Eylea and Avastin, have also been used for diabetic retinopathy, although their relative effectiveness was unknown. In 2014, investigators participating in NEI’s Diabetic Retinopathy Clinical Research Network concluded that Eylea was superior to Lucentis and Avastin in patients with advanced disease. However, in patients with mild or early onset disease, all three drugs were equivalent. In addition to outcomes based on disease severity, the drugs significantly differ in cost and treatment frequency. Thus the results of this trial provide several options for patients to make informed decisions based on their individual needs.
I want to end by updating you on NEI’s exciting Audacious Goals Initiative (AGI), which focuses on regenerating neurons and reestablishing their neural connections in the eye and visual system. The ambitious goal of restoring vision to millions of patients has energized the vision community and is attracting the attention of researchers in the larger neuroscience and regenerative medicine disciplines. Several grants will soon be awarded from the first funding opportunity which sought innovative technologies to enable imaging retina, first in living animals and ultimately in patients. Such technologies will permit the understanding and assessment of clinically applicable regenerative therapies. To achieve our goals, NEI, in consultation with the vision community and the AGI Steering Committee, is organizing a series of workshops to assess the state of the regenerative medicine in the visual system. This past November, the first such meeting of experts addressed the scientific challenges of optic nerve regeneration. This coming year, workshops will tackle photoreceptor and retinal ganglion cell regeneration. The AGI has enabled the formation of pioneering multidisciplinary teams creating a vibrant and collaborative community that will drive this initiative towards translational success.
In many ways, the NEI AGI complements the President’s BRAIN Initiative, which seeks to understand the neural connections and circuits that underlie brain function. Just as the visual system represents a large portion of the brain, 14 of 59 initial BRAIN projects focus on the retina or visual cortex. One NEI grantee, who is now working on a BRAIN grant, is comprehensively classifying neurons based on the genes they express. Another innovative grant is using molecular tools in animals to manipulate specific neurons in the retina and visual cortex using light focused through a specialized microscope. As NEI director, I am humbled by contributions of the vision research community.
Dr. Sieving became director of the National Eye Institute, NIH, in 2001. He came from the University of Michigan Medical School, where he was the Paul R. Lichter Professor of Ophthalmic Genetics and the founding Director of the Center for Retinal and Macular Degeneration in the Department of Ophthalmology and Visual Sciences.
After undergraduate work in history and physics at Valparaiso University, Dr. Sieving studied nuclear physics at Yale Graduate School in 1970-73 under D. Allan Bromley and attended Yale Law School from 1973-74. He received his M.D. from the University of Illinois College of Medicine in 1978 and a Ph.D. in bioengineering from the University of Illinois Graduate College in 1981. Dr. Sieving completed an ophthalmology residency at the University of Illinois Eye and Ear Infirmary in Chicago. After post-doctoral study of retinal physiology with Roy H. Steinberg in 1982-83 at the University of California, San Francisco, he did a clinical fellowship in genetic retinal degenerations with Eliot Berson in 1984-85 at Harvard Medical School, Massachusetts Eye and Ear Infirmary.
Dr. Sieving is known internationally for studies of human progressive blinding genetic retinal neurodegenerations, including retinitis pigmentosa, and rodent models of these conditions. His laboratory study of pharmacological approaches to slowing degeneration in transgenic animal models led to the first human clinical trial of ciliary neurotrophic factor (CNTF) for retinitis pigmentosa, published in Proceedings of the National Academy of Sciences, 2006. He also developed a mouse model of X-linked retinoschisis and successfully treated this using gene therapy which restored retinal function. In 2015 Dr. Sieving’s lab launched a gene therapy clinical trial to evaluate safety and efficacy in humans. He maintains a clinical practice at NEI for patients with these and other genetic retinal diseases, including Stargardt juvenile macular degeneration.
Dr. Sieving served as Vice Chair for Clinical Research for the Foundation Fighting Blindness from 1996-2001. He is on the Bressler Vision Award committee and is a jury member for the €1 million annual ‘Vision Award’ of the Champalimaud Foundation, Portugal. He was elected to membership in the American Ophthalmological Society in 1993 and the Academia Ophthalmologica Internationalis in 2005. He received an honorary Doctor of Science from Valparaiso University in 2003 and has been named among the ‘Best Doctors in America’ multiple years. He has received numerous awards, including the Research to Prevent Blindness Senior Scientific Investigator Award, 1998; the Alcon Research Institute Award, 2000; and the Pisart Vision Award from the New York Lighthouse International for the Blind in 2005. Dr. Sieving was elected to the Institute of Medicine of the National Academy of Sciences in 2006.