Witness appearing before the House Subcommittee on Labor-HHS-Education Appropriations:
Dr. Paul A. Sieving, Director
National Eye Institute
March 5, 2008
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). The Fiscal Year (FY) 2009 budget of $667,764,000 includes an increase of $648,000 over the FY 2008 appropriation level of $667,116,000. 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.
The loss of sight affects us in fundamental ways, threatening independence, mobility and quality of life. Many eye diseases strike later in life. Thus, as life expectancy has increased, more Americans have become susceptible to vision loss and blindness. One such disease, age-related macular degeneration (AMD), is the leading cause of vision loss. Based on published study data, 8 million Americans are at risk to develop advanced AMD. AMD causes a progressive loss of light-sensing cells in the macula, the center of the retina, making it difficult to read, recognize faces, drive a car, or perform even simple tasks that require hand-eye coordination.
NEI-supported investigators have discovered a second important clue in understanding how a gene variation greatly increases the risk of developing advanced AMD. Previous work implicated the complement factor H (CFH) gene, which functions in the immune system by initiating inflammatory responses to pathogens. Variations in CFH are thought to create chronic, low-level inflammation that damages the macula. This year, NEI investigators clarified a new disease mechanism related to oxidative stress. ARMS2, a gene found on chromosome 10, encodes a protein involved in mitochondrial function. Mitochondria are a cell’s energy storehouses, and they have been implicated in other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Mitochondrial dysfunction associated with aging can result in impaired energy metabolism, increased oxidative stress, and cell death.
Previous studies of eye donor tissue from patients with AMD have found mitochondrial abnormalities, particularly in cells of the macula, the center of the retina where the disease manifests. Based on these findings, NEI-supported investigators proposed a new disease mechanism where the genetically altered function of this mitochondrial protein promotes susceptibility to aging-associated degeneration of the macula, due largely to oxidative damage. Cigarette smoking is a major risk factor for AMD and is known to increase oxidative stress. Smokers with the ARMS2 gene alteration have an even greater risk of developing AMD. ARMS2 and the previously discovered complement factor H gene, which is also adversely influenced by smoking, currently represent the most common susceptibility genes in AMD and have provided important clues to understand AMD and to develop therapies and prevention strategies.
Over the past 15 years, NEI-supported investigators have identified nearly 500 genes with alterations that lead to eye diseases such as glaucoma, cataracts, strabismus, corneal dystrophies and retinal degenerative diseases. Considerable progress has been made in elucidating the molecular mechanisms that cause these diseases. Researchers are now working to develop tailored therapies that address the direct genetic cause of a disease. However, many eye diseases are clinically difficult to distinguish without a molecular diagnosis based on genetic testing. Moreover, genetic testing services are not widely available. As genomic medicine progresses to clinical trials, it becomes necessary to genotype patients with these eye diseases to find suitable clinical trial participants.
Through an innovative program called the National Ophthalmic Disease Genotyping Network (eyeGENE), the NEI is working to enhance the nation’s capacity for genetic testing of eye disease. The eyeGENE program is a network of research laboratories that offer testing for affected individuals coupled to a registry of clinical information that is available to the eye research community through a secure, confidential patient registry. eyeGENE will also create a large data set for investigators to identify additional genetic risk factors and to explore the relationship between a genetic disease (genotype) and its clinical manifestation (phenotype). Programs like eyeGENE will drive genomic medicine and become a necessary fabric for personalized medicine.
The first patients have been enrolled in a landmark clinical trial testing the safety of gene transfer in humans with a form of Leber congenital amaurosis (LCA). Children with LCA are born with severe visual loss. In 1993, NEI intramural scientists discovered a protein called RPE65 that plays a key role in the visual cycle, the set of biochemical interactions that turns light into an electrical signal to initiate vision. Mutations in the RPE65 gene disrupt the visual cycle resulting in severe visual impairment. Fortunately, the cells in the retina remain relatively intact for many years in LCA, providing a window of opportunity to therapeutically intervene.
The proof-of-concept for gene transfer as a treatment for LCA has been thoroughly demonstrated by NEI-supported investigators in a dog breed that naturally harbors RPE65 mutations and in rodent models of the condition. Investigators also conducted rigorous pre-clinical safety studies to gain regulatory approval from the U.S. Food and Drug Administration and from the NIH Recombinant DNA Advisory Committee. The clinical trial includes a dose escalation study, a re-dosing study and evaluation of the treatment in adults and adolescents with the disease. Gene transfer is particularly well-suited to the treatment of retinal degenerative diseases. Nearly 200 single gene defects have been implicated in these diseases. This clinical trial is an important step in treating LCA and in establishing proof-of-concept for gene transfer as a therapy for an entire family of eye diseases.
Retinopathy of prematurity (ROP) is a vascular eye disease of infants born prematurely in which normal blood vessels grow into the retina and cause bleeding and scarring. Infants who progress to a severe form of ROP can become permanently blind. NEI investigators studied the effect of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), derived from fish, and the omega-6 fatty acid, arachidonic acid, on blood vessel growth in a mouse model of oxygen-induced retinopathy. This mouse model shares many characteristics with ROP. The researchers found that increasing omega-3 fatty acids and decreasing the omega-6 fatty acid in the diet reduced abnormal vessel growth and blindness. The omega-6 fatty acid was found to promote the growth of abnormal blood vessels in the retina. Further studies in mice fed diets rich in omega-3 fatty decreased retinopathy by nearly 50 percent. This study suggests the possibility of a preemptive therapeutic approach to ROP and other retinopathies through dietary supplementation. Clinical trials are being considered to evaluate this low-cost and widely available nutrient-based investigative therapy.
Glaucoma is a major public health problem and the leading cause of blindness in African Americans. Published findings suggest that approximately 2.2 million Americans have been diagnosed with glaucoma, and the prevalence of the disease will rise to a projected 3 million by 2020. Glaucoma has traditionally been considered a disease of ocular hypertension in which pressure inside the eye is increased. However, glaucoma can also occur without increased pressure, and increased pressure does not always lead to glaucoma. Glaucoma is more accurately defined as a condition that results in the death of retinal ganglion cells (RGCs), which are highly specialized neuronal cells that process visual information. Thus, glaucoma is now better understood to be a neurodegenerative disease.
Previous studies suggested that a protein called tumor necrosis factor-alpha (TNF-a) may contribute to the eventual loss of RGCs. Elevated levels of the TNF-a protein are found in other neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease and Alzheimer’s disease. The protein is also elevated in microglia cells in the optic nerve of patients with glaucoma. Microglia cells are a type of circulating immune cell unique to the central nervous system. Certain alterations in the TNF-a gene also increase the risk of glaucoma.
To further clarify the role of TNF-a in glaucoma, NEI-supported investigators induced ocular hypertension in mice and found rapid elevation of TNF-a followed by microglial activation, loss of optic nerve oligodendrocytes, and eventual loss of RGCs. Oligodendrocyte cells act like insulation to form the protective myelin sheath for sensitive parts of nerve cells in the central nervous system. Injections of TNF-a in normal mice mimicked this series of events. Deleting the genes that encode TNF-a or its receptor blocked the deleterious effect of ocular hypertension in mice. An antibody to TNF-a had a similar protective effect. Thus, it appears that glaucoma shares some biologic similarities to multiple sclerosis in which TNF-a is thought to play a role in demyelination of nerve cells. This study greatly enhances our understanding of the disease and suggests a new treatment approach by blocking TNF-a activity in the optic nerve. Such drugs are already in use for rheumatoid arthritis and Crohn’s disease.
MEDICINE IN THE FUTURE
Development of an artificial cornea will provide an abundant source of non-immunogenic tissue for transplantation. Cell transplantation has also prevented vision loss in rodent models of retinal disease. It is likely that these efforts will culminate in viable forms of regenerative medicine for eye disease. Genomic medicine will allow us to predict susceptibility to disease and preempt it with a variety of gene-based therapies. Gene transfer will likely become an option to treat many retinal degenerative diseases. Gene-based pharmaceutical therapies will ameliorate the adverse consequences of faulty gene expression. Late-onset diseases like AMD and glaucoma could be prevented or delayed, thereby sharply reducing the impact of these diseases. Research to control blood vessel growth in diabetic retinopathy and AMD will eventually result in therapies that offer near total control of the disease process and prevent severe vision loss. We will have the opportunity to restore ambulatory vision to the blind through high-tech prosthetic devices that produce vision electronically. Such devices will allow those with untreatable conditions to maintain independence and mobility. While there is much work ahead, current research efforts to treat and cure eye disease look very promising.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL EYE INSTITUTE
PAUL A. SIEVING, M.D., Ph.D.
Director, National Eye Institute, National Institutes of Health, 2001
Member, Institute of Medicine of the National Academies
B.A., Valparaiso University (Physics with honors), 1970
M.S., Yale University Graduate School (Physics), 1973
Yale Law School, 1973-1974, leave of absence
M.D., University of Illinois Medical School, 1978
Ph.D., University of Illinois (Biomedical Engineering), 1981
National Board of Medical Examiners, 1978
American Board of Ophthalmology, 1983
Medical License: IL, 1978; CA, 1982; MA, 1984; MI, 1985
Medical Internship and Ophthalmology Residency, University of Illinois Hospital, 1978-1982. Postdoctoral Fellowship in Retinal Physiology, University of California, San Francisco, 1982-1984. Medical Fellowship in Inherited Retinal Degenerations, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 1984-1985. Faculty, Medical School and Rackham Graduate School, University of Michigan, 1985- 2001.
Academic Appointments and Experience:
At the University of Michigan: Assistant Professor of Ophthalmology, 1985-1989. Faculty, Rackham Graduate School Programs in Neuroscience, 1985-2001; Bioengineering Program, 1985-2001. Associate Professor of Ophthalmology, 1989-1994. Founding Director, Center for Retinal and Macular Degenerations, 1990-2001. Founding Director, Ophthalmic Molecular Diagnostics CLIA Laboratory, University of Michigan, 1999-2001. Professor of Ophthalmology and Visual Sciences, 1994-2001. The Paul R. Lichter Professor of Ophthalmic Genetics, 1990-2001. Director, National Eye Institute, NIH, 2001-present.
Association for Research in Vision and Ophthalmology. International Society for Clinical Electrophysiology of Vision. American Academy of Ophthalmology. American Medical Association. American Ophthalmological Society. Society for Neuroscience. American Society of Human Genetics. Bressler Vision Award Committee. Champalimaud Foundation Award Committee, Portugal.
Honors and Awards:
James Scholar Award and Leon F. Moldavsky Physiology Award, University of Illinois Medical School. Fight-for-Sight Research Award. Career Development Award, National Retinitis Pigmentosa Foundation. Olga Keith Wiess Scholar, Research To Prevent Blindness. Distinguished Alumnus Award, Valparaiso University. American Ophthalmological Society. The Foundation Fighting Blindness, Scientific Advisory Board. Senior Scientific Investigator Award, Research to Prevent Blindness. Alcon Award. Doctor of Science (honorary), Valparaiso University, 2003. The Best Doctors in America. Academia Ophthalmologica Internationalis, elected 2004. Pisart Vision Award, 2005, Institute of Medicine of the National Academies, elected 2006.