PREPARED STATEMENT OF DR. PAUL SIEVING
DIRECTOR, NATIONAL EYE INSTITUTE
NATIONAL EYE INSTITUTE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Mr. Chairman and Members of the Committee:
I am pleased to present the President’s Fiscal Year 2019 budget request for the National Eye Institute (NEI) of the National Institutes of Health.
FIFTY YEARS OF VISION RESEARCH
It may have been a hot day on August 16, 1968, when President Johnson signed Public Law 489 to create the National Eye Institute, but on March 21, 2018, the biggest blizzard of the season threatened a reception hosted by Congressman Pete Sessions to celebrate NEI’s 50th anniversary. However, snow didn’t deter over 100 vision research stakeholders, National Institutes of Health scientists, patients, and members of Congress from coming out to recognize the vision-saving progress made in the past half century. While my statement usually covers the latest advances, I want to start by reflecting on some of our remarkable research progress, which has advanced clinical vision care.
Over the past 50 years, NEI has funded research of nine Nobel Prize winning scientists, including discovery of the molecular mechanisms by which specialized neurons in the retina detect photons of light entering the eye and initiate biochemical and electrical signals to the brain that convey vision. The key light-detecting protein, rhodopsin, became the first cell membrane-bound protein studied by x-ray crystallography and imaged to reveal the protein structure in three dimensions. This paved the way for the study of other molecules in diseases in and beyond the eye. NEI-funded Nobel laureates also made landmark neuroscience discoveries of how brain circuits form and self-organize in the visual cortex. This has revolutionized treatment for amblyopia, a disorder in which the brain favors visual information coming from one eye over the other. The first use of antiviral chemotherapy was developed for the eye to treat herpes outbreaks on the cornea. In ground-breaking work, NEI scientists discovered the first tumor suppressor gene, retinoblastoma, which transformed all of cancer biology. Conversely, in the past decade, the ocular adaptation of a cancer drug that blocks growth of abnormal blood vessels treats two of the leading causes of blindness: age-related macular degeneration (AMD) and diabetic retinopathy, stopping disease progression, and in many cases, reversing vision loss for medical benefit to thousands of patients.
In its early years, NEI pioneered new methodology for conducting placebo-controlled, multi-center clinical trials, which led to vision-saving laser surgery to treat diabetic retinopathy, AMD, and glaucoma. Large trials identified dietary supplements demonstrated to slow progression to end-stage AMD. Trials compared effectiveness of different therapies for AMD, diabetic retinopathy, and an inflammatory eye condition called uveitis, to inform patients and their doctors of options for personalized treatment. Elevated fluid pressure in the eye, called ocular hypertension, is a precursor for glaucoma, especially in African Americans who have a disproportionate burden of this disease. 1,500 patients participated in the Ocular Hypertension Treatment Study, including 400 African American participants, which led to new treatment guidelines that can reduce incidence in African Americans by 50 percent. A 20-year follow-up study is currently underway to assess the long-term impact. More recently, the first application of genomics methods led NEI scientists to uncover new genetic components for AMD, opening the door to new treatments. Before NEI was established, a major cause of lifelong blindness was retinopathy-of-prematurity (ROP), a disease caused by abnormal development of retinal blood vessels in low birth weight babies born very prematurely. Technology to identify and treat ROP has improved dramatically over the years and a recent NEI trial demonstrated that premature infants can be screened for ROP remotely via telemedicine, expanding access to specialists in rural and underserved communities.
RECENT PROGRESS IN VISION RESEARCH
NEI-supported vision research remains on the forefront of medicine, from regenerative medicine to replace neural tissue lost due to retinal degeneration; to advancing retinal prosthetics, including the Argus II artificial retina which was approved by FDA through the Humanitarian Device Exemption pathway; and pioneering the application of gene therapy to correct blinding disease-causing mutations. One landmark occurred in December 2017, when the FDA approved the first ever gene therapy in the U.S. to correct a retinal degeneration, Leber Congenital Amaurosis, which causes blindness in infants and children. The genetic mutation had earlier been discovered by an NEI scientist in 1993, but researchers had to invent the tools to turn that discovery into a gene therapy. Having set this precedence for all of medicine, the path from gene discovery to clinical trial is now being expedited with vision loss mutations in a dozen genes currently being addressed in pre-clinical and clinical studies.
Also in December, FDA approved two new drugs for glaucoma, the first new medications for this disorder in 18 years. This new class of drugs lowers pressure in the eye through novel targets that are different from existing medications. An ongoing clinical trial is testing a combination therapy of the newer and older drugs used together, which may prove more effective than either drug alone. This research represents the culmination of over 25 years of NEI basic research on molecules that control the contractile machinery of cells, which regulate the flow of fluid out of the eye.
Idiopathic intracranial hypertension (IIH), which primarily affects obese young women, causes the buildup of pressure on the optic nerve, leading to vision loss in nearly 10 percent of patients. The recently completed IIH Treatment Trial of 165 patients showed that for mild vision loss, intervention with acetazolamide plus diet was superior to diet alone for reducing vision loss and improving quality of life. However, neither intervention was effective for patients with moderate to severe vision loss. NEI is funding a new three-arm trial testing different surgical interventions to relieve pressure and protect the optic nerve in 180 IIH patients with more severe vision loss.
SEEING INTO THE FUTURE
The NEI Audacious Goals Initiative (AGI) seeks to restore vision through neuroregeneration in the eye and visual system. This fundamental regenerative medicine approach was initiated in 2013 and is advancing rapidly. NEI has established two collaborative consortia of research teams working on different facets of the challenge: one on functional imaging, and a second for discovery science to identify new regeneration factors by looking in model systems. For example, unlike adult mammals, zebrafish can regenerate their retina after injury, which led NEI researchers to identify a key regeneration factor, present in newborn mice, and through manipulating this factor, they caused new neurons to form in adult mice. Scientists also found that exosomes secreted from stem cells protect a type of retinal cells, the ganglion cells, which are damaged by glaucoma. Exosomes are now being examined for potential therapeutic effect. Exosome-treated rats lost only a third of their retinal ganglion cells following optic nerve injury, compared with 90 percent loss in untreated rats. NEI is now reviewing proposals for a third AGI consortium, to develop animal model systems to facilitate translation of discovery research into the clinic.
NEI just launched new stem cell trials for retinal vein occlusion (RVO)—the second leading retinal vascular cause of vision loss after diabetic retinopathy, and for limbal stem cell deficiency (LSCD). In RVO, the vessels draining blood from retinal tissue become clotted, leading to leaking and bleeding and ultimately starving the neurons of oxygen. The trial will test the safety, feasibility and efficacy of injecting stem cells derived from the patient’s own bone marrow into their eyes. Corneal limbal cells, are responsible for renewing the front layer of the transparent cornea. In thousands of patients with LSCD, loss of these cells causes visual impairment from chronic inflammation, abnormal blood vessel growth, and opaque corneas. The 21st Century Cures Act Regenerative Medicine Program is supporting an NEI project to treat LSCD. Researchers identified a limbal cell marker, ABCB5, which has allowed them to isolate, purify and expand limbal stem cells in the lab in sufficient quantities for transplantation. This summer, NEI scientists are about to launch the first clinical trial using induced pluripotent stem cells-derived retinal tissue to treat the dry form of AMD. Skin cells taken from AMD patients will be manipulated in the lab for about three months, then transplanted back into the same patients, thereby minimizing rejection of foreign tissue that affects many types of transplant therapies.
In 2017, NEI launched a 3D Retina Organoid Challenge Competition (3D-ROC), with the goal of developing functioning “mini-retinas” in a culture dish from human adult stem cells. In September, NEI awarded the $90,000 prize for the Phase I Ideation Stage, to a team that developed the concept of building a retina by screen-printing adult neural progenitor-derived retinal cells in layers that mimic the structure of the human retina. The system is designed to be scalable, efficient, and reproducible, enabling high throughput screening for drug testing. In February 2018, NEI launched Phase II, which soon will award up to $1 million in prizes for developing this work to the critical stage of functional prototypes of human retinas.
In January, NEI announced the launch of a new strategic planning process, under the auspices of the National Eye Advisory Council. The five-year plan will be developed with significant community input, centered around scientific program working groups. It will also align with the NIH Strategic Plan and requirements laid out in the 21st Century Cures Act, including research to address health disparities.
Paul Sieving, M.D., Ph.D.
Director, National Eye Institute
Dr. Sieving is Director of the National Eye Institute, NIH. Previously he was the Paul R. Lichter Professor of Ophthalmic Genetics at the University of Michigan (1985-2001). Dr. Sieving studied nuclear physics at Yale Graduate School (1970-73) and attended Yale Law School (1973-74). He received his MD (1978) and PhD (bioengineering, 1981) degrees from the University of Illinois. After an ophthalmology residency at the University of Illinois Eye and Ear Infirmary under Mort Goldberg (1982-85), he did post-doctoral work in retinal physiology with Roy H. Steinberg at the University of California San Francisco (1982-83) and a clinical fellowship in retinal degenerations with Eliot Berson at Harvard Medical School, Massachusetts Eye and Ear Infirmary (1984-85).
Dr. Sieving is known internationally for clinical and basic studies of genetic retinal neurodegenerations, including retinitis pigmentosa and macular degeneration. As a clinician, he provides ophthalmic care to patients and their families with Mendelian traits that cause photoreceptor dysfunction and neurodegeneration. He is also a tenured Senior Investigator in the NIH Intramural Research Program. His laboratory focuses on the pathophysiology of photoreceptor disease and synapses to the other retinal neurons as well as glial interactions. His studies of pharmacological approaches to slow degeneration in retinal transgenic animal models led to the first human clinical trial of ciliary neurotrophic factor (CNTF) for retinitis pigmentosa, published in PNAS, 2006. He developed a mouse model of X-linked retinoschisis (XLRS) and treated this successfully using gene therapy which restored retinal function. He initiated the first human XLRS gene therapy trial at NIH in 2015 for XLRS (ClinicalTrials.gov # NCT02317887).
Dr. Sieving is an elected member of both the National Academy of Medicine of the National Academies and the German National Academy of Sciences. He previously served as Vice Chair for Clinical Research for the Foundation Fighting Blindness from 1996-2001. He is an award 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 has received many honorary awards including the Research to Prevent Blindness Senior Scientific Investigator Award; the Alcon Research Institute Award; Pisart Vision Award from the New York Lighthouse International for the Blind and most recently, the Pyron Award, which was created by the Retina Research Foundation of Houston to recognize outstanding vision scientists whose work contributes to knowledge about vitreoretinal disease.