Statement for the Record
House Subcommittee on Labor-HHS-Education Appropriations
Paul A. Sieving, M.D., Ph.D.
Director, National Eye Institute
On this page:
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) 2013 NEI budget of $693,015,000 includes a decrease of $8,861,000 from the comparable FY 2012 level of $701,876,000. As the director of the NEI, it is my privilege to report on the many research opportunities that exist to reduce the burden of eye disease.
Gene Therapy: In 2008, NEI-supported investigators reported results from a landmark phase I clinical trial of gene therapy in three patients with a blinding, early onset retinal disease, Leber congenital amaurosis (LCA), which is caused by a defect of the RPE65 gene. Treatment, consisting of injecting a viral vector to deliver normal copies of the RPE65 gene, was well tolerated, and there was objective evidence of modest visual improvement in all three study subjects. To date, 15 participants have been treated and all have experienced visual improvements. Recently published clinical trial results find that increasing the dose with a second injection safely expands the area of retina exposed to the treatment (RPE65-AAV). Responsiveness of light-sensitive photoreceptor cells near injection sites increased after treatment. Younger participants, when compared to older participants, did not experience greater visual improvements.
In fact, the two participants with the greatest visual acuity gains were among the oldest in the study. The researchers speculated that the number and health of remaining photoreceptors matter more than patient age, as the rate of photoreceptor loss varies considerably among people with RPE65-deficient LCA. The finding suggests that careful evaluation of photoreceptor cell health is important in determining potential clinical trial participants. Because safety was the primary outcome of this trial, a conservative approach was taken that limited treatment to the eye with poorer vision. In the future, the researchers plan to seek further visual gains by administering three injections of RPE65-AAV and treating the better eye.
A team of NEI investigators restored vision in a canine model of X-linked retinitis pigmentosa (XLRP) using a new gene therapy vector capable of transfecting both rod and cone cells. XLRP is a severe retinal disease that affects both rod and cone photoreceptor cells. Patients with XLRP experience night blindness as children and become blind by middle age. A common form of XLRP results from mutations in the RPGR gene. Treatment restored lost photoreceptor cell structure and repaired photoreceptor cell connections to other retinal neurons that send visual signals to the brain. This study provides a clearer path to clinical trials for XLRP. In addition, gene therapy trials for age-related macular degeneration (AMD), choroideremia, Leber’s hereditary optic neuropathy, Stargardt macular dystrophy (SMD), and Usher syndrome were launched this past year. Clinical trials for juvenile retinoschisis, achromatopsia, and retinitis pigmentosa are also planned. All of these trials were made possible by sustained NEI support to develop and refine gene therapy techniques.
Stem Cell Therapies: In January 2012 Advanced Cell Technologies published preliminary results of the first-ever clinical trials of a product derived from human embryonic stem cells (hESCs). These landmark clinical trials are evaluating hESC-derived retinal pigment epithelium (RPE) cells for the treatment of Stargardt’s macular dystrophy (SMD) and age-related macular degeneration (AMD). In the two treated patients, there were no adverse events and both had modest but objective improvements in vision. The RPE is a highly specialized layer of cells adjoining the retina that support photoreceptor cell function. SMD and AMD are known to result from a diseased RPE.
NEI created the International AMD Genetics Consortium in 2010 to identify the remaining genetic risk variants for AMD. To increase the statistical power needed to identify genes that have small, yet significant contributions to AMD, the consortium is conducting a meta-analysis on 15 Genome Wide Association Studies (GWAS) representing over 8,000 patients with AMD and 50,000 controls. In addition to verifying known genes, the consortium identified 19 new gene variants. The genes identified in these studies function in the immune system, cholesterol transport and metabolism, and formation and maintenance of connective tissue. This study provides a nearly complete picture of genetic heritability for AMD. NEI’s effort to unite the international research community to share GWAS data sets made it possible to solve a common goal in our understanding of this blinding disease.
In 2009, NEI established the NEI Glaucoma Human Genetics Collaboration (NEIGHBOR), a consortium of clinicians and geneticists at 12 institutions throughout the U.S. dedicated to identifying the genetics of glaucoma. NEIGHBOR collected and sequenced 6,000 DNA samples and is the largest genetics study of glaucoma. Thus far, NEIGHBOR investigators identified a risk variant in the gene CDKNB2. This gene is thought to play a role in the development of the optic nerve head, where retinal ganglion cell axons, which degenerate in glaucoma, converge to form the optic nerve. NEI will make GWAS data from NEIGHBOR available to the vision research community for further evaluation in 2012.
In 2011, NEI awarded a grant to support Project Prakash, which combines an extraordinary scientific opportunity with a humanitarian mission. Understanding how the human brain learns to perceive objects remains a fundamental challenge in neuroscience. Project Prakash seeks to treat older children born with congenital cataracts and other eye disorders and then study how their visual function develops.
Visual development normally takes place during infancy before children acquire language and can communicate what they are seeing. By treating older children who can fully communicate, Project Prakash will permit scientists to more directly address the nature of neuroplasticity and visual development. This study will also provide important clinical insights to inform visual rehabilitation. India accounts for nearly 30 percent of the world’s blindness. Many are poor children with treatable congenital eye disorders, but most never receive medical attention because they live in rural areas far from urban medical centers. Tragically, it is estimated that 60 percent of India’s blind children die before reaching adulthood. Project Prakash is a unique opportunity to offer humanitarian medical aid while advancing the field of neuroscience.
Paul A. Sieving, M.D., Ph.D.
Director, National Eye Institute
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. 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.