Witness appearing before the
Senate Subcommittee on Labor-HHS-Education Appropriations
Paul A. Sieving, M.D., Ph.D., Director
National Eye Institute
May 11, 2011
On this page:
- TECHNOLOGIES TO ACCELERATE DISCOVERY
- TRANSLATIONAL SCIENCES AND THERAPEUTICS DEVELOPMENT
- ENHANCEMENT OF EVIDENCE-BASE FOR HEALTH CARE DECISIONS
- NEW INVESTIGATORS, NEW IDEAS
- BIOGRAPHICAL SKETCH
Mr. Chairman and Members of the Committee:
I am pleased to present the President’s budget request for the National Eye Institute (NEI). The Fiscal Year (FY) 2012 budget of $ 719,059,000 includes an increase of $18,832,000 over the FY 2011 appropriation level of $700,227,000. 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.
TECHNOLOGIES TO ACCELERATE DISCOVERY
The causes of common diseases are complex in that there are potentially many different environmental factors and genetic variants that can contribute to disease. New technologies such as genome-wide association studies (GWAS) allow investigators to scan the genomes of patients to identify genetic risk variants for common diseases. Individually, each of these variants may only contribute to a small percentage of cases, so GWAS require many subjects to identify low frequency risk variants. In the largest GWAS study in vision research to date, NEI investigators recently sequenced DNA from over 18,000 patients and control subjects and identified three new genes associated with age-related macular degeneration (AMD), the most common cause of vision loss in older Americans. Two of these genes are involved with high-density lipoprotein cholesterol metabolism, implicating a new biochemical pathway involved in the pathogenesis of AMD. These findings will allow researchers to better understand the disease mechanisms underlying AMD and develop therapies that address the root cause of vision loss. Glaucoma is another heritable blinding disease where the genetic underpinnings are poorly understood. The NEI Glaucoma Human Genetics Collaboration, a consortium of clinicians and geneticists at 12 institutions throughout the U.S. dedicated to identifying the genetic factors associated with glaucoma is conducting a large-scale GWAS that involves scanning 5,000 DNA samples. The consortium is using state-of-the-science technology to sequence the exome, the full complement of protein coding regions in the human genome, in a subset of patients. The data from these DNA samples are expected to be available to the vision research community in 2011.
TRANSLATIONAL SCIENCES AND THERAPEUTICS DEVELOPMENT
Positive results of ongoing, pioneering clinical trials of gene therapy for Leber congenital amaurosis, a severe, early onset retinal disease, have encouraged applications of this approach to many other eye diseases. In the past year, NEI investigators demonstrated proof-of-concept of gene therapy using animal models of AMD, achromatopsia, Leber’s hereditary optic neuropathy, retinitis pigmentosa, and red-green color blindness. Previous work with animal models established the utility of gene therapy in juvenile retinoschisis, optic neuritis, and Stargardt disease. These studies now allow investigators to conduct the pre-clinical work necessary to pursue regulatory approval for clinical trials. In addition, novel gene delivery systems, such as the use of nanoparticles, have shown promise in animal models. Such vectors will be helpful in expanding the reach of gene therapy to target a variety of ocular tissues such as retinal ganglion cells and the light-sensitive photoreceptor cells.
ENHANCEMENT OF EVIDENCE-BASE FOR HEALTH CARE DECISIONS
For treating the blinding (“wet”) form of advanced AMD, monthly ocular injections of a drug, Lucentis, was approved in 2007 by the FDA. This was the first effective treatment that not only stopped progression of the disease, but also improved vision for many patients. Lucentis blocks formation of new, but abnormal blood vessels that leak fluid into the central part of the retina that is responsible for keen vision. It was developed from another inhibitor of blood vessels, Avastin, which since its approval in 2004, has been used to block new vessels that form to nourish growth of some cancers. Even before final FDA approval of Lucentis, ophthalmologists began using Avastin “off-label” for treating AMD, and today, most AMD patients receive Avastin. Given the lack of data regarding the effectiveness of Avastin for AMD treatment, in 2007, the NEI had an obligation to patients and clinicians to compare the two drugs and to evaluate whether the drugs could be used less frequently as needed - called PRN - rather than monthly as originally approved for Lucentis. Visual acuity improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. When each drug was given PRN, there also was no difference between drugs. For PRN dosing, patients required four to five fewer injections per year compared to monthly treatment and still had substantial gains in vision.
Lucentis was also studied in a comparative effectiveness trial for diabetic macular edema (DME), a common sight-threatening complication of diabetes in which fluid from leaky blood vessels causes the retina to swell. For the past 25 years, DME has been treated with a laser to destroy abnormal blood vessels. Although laser therapy slows disease progression, the effects are temporary, and repeated treatments can damage healthy retinal tissue and impair vision. In recent years, ophthalmologists have been supplementing laser treatment with ocular injections of either Lucentis, a drug that prevents blood vessel growth, or triamcinolone, a corticosteroid to reduce inflammatory complications. An ongoing clinical trial comparing the safety and efficacy of these two drugs is being conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net), a public-private partnership funded by NEI, the Type 1 Diabetes Funding Program, and industry collaborators. After one year, Lucentis + laser treatment was superior in both safety and efficacy compared to triamcinolone + laser or to laser alone. This landmark clinical trial identified the first new safe and effective treatment regimen for DME in more than two decades. In addition, the study demonstrated that intravitreal triamcinolone, which had been used in 60 percent of patients with DME, had significant side effects (cataract and glaucoma) and was not better than laser alone. These results are already being used by community ophthalmologists to greatly improve the vision and quality of life for people living with diabetes.
Treatment of cataracts in infants is challenging for pediatric ophthalmologists and parents. Replacing the opaque lens with an artificial lens is critical to prevent permanent loss of vision in the eye. After removing the cataract, contact lenses have been the preferred method to overcome the loss of the natural lens. However, it is difficult and stressful for parents to insert a contact lens into an infant’s eye. Removing the cataract and surgically implanting a transparent intraocular lens (IOL) in adults is common but had not been fully characterized in infants. An NEI-supported clinical trial found no difference in visual acuity with contact lenses compared to IOLs one year after cataract removal. However, IOLs caused significant numbers of surgical complications. Based on these results, the use of contact lenses is considered the safest effective treatment for infants with cataract.
NEW INVESTIGATORS, NEW IDEAS
The increasingly quantitative nature of the biomedical sciences and the explosive growth of genomic, transcriptomic, proteomic, metabolomic, neurophysiological and clinical data require that investigators work at the interface of biology and computational sciences. The NEI is committed to developing the next generation of vision researchers and has expanded its institutional training grant program with a program in ocular statistical genetics at several universities. This program will partner researchers with expertise in mathematics, modeling, and computation, fields that are not usually affiliated with ocular research, with researchers in all areas of vision science to provide state-of–the-art training for a new breed of researchers.
Paul A. Sieving, M.D., Ph.D.
Director, National Eye Institute
National Institutes of Health
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.