Dr. Paul A. Sieving, Director
National Eye Institute
National Institutes of Health
U.S. Department of Health and Human Services
William Beldon, Acting Deputy Assistant Secretary, Budget
On this page:
- Retinal Deseases
- Corneal Diseases
- Glaucoma and Optic Neuropathies
- Strabismus, Amblyopiaand Visual Processing
- Technical Innovations
- Program Initiatives
- NIH Roadmap
Mr. Chairman and Members of the Committee:
I am pleased to present the President’s budget request for the National Eye Institute (NEI) for FY 2005. This budget includes $671.6 million, an increase of $18.8 million over the FY 2004 enacted level of $652.7 million comparable for transfers proposed in the President’s request. As the Director of the NEI, it is my privilege to report on the progress laboratory and clinical scientists are making in combating blindness and visual impairment and about the unique opportunities that exist in the field of vision research.
Retinal diseases are a diverse set of sight-threatening conditions that include age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinitis pigmentosa, Usher’s syndrome, ocular albinism, retinal detachment, uveitis (inflammation), and cancer (choroidal melanoma and retinoblastoma). One of the most tragic retinal diseases, retinopathy of prematurity (ROP), causes severe vision loss in premature, low-birthweight infants. ROP is characterized by excessive growth of abnormal blood vessels in the back of the eye that often hemorrhage and scar the retina. This year, results from an NEI-funded clinical trial, called the Early Treatment of Retinopathy of Prematurity (ETROP), established that early treatment, based on newly developed diagnostic criteria, improves visual outcomes in infants at the greatest risk of developing ROP. The ETROP study also found that these new diagnostic criteria were helpful in select patient subgroups that may not ultimately develop ROP. For these infants, careful observation was found to be the best approach. Results from ETROP will greatly improve visual outcomes for children with ROP.
Age-related macular degeneration (AMD) is a leading cause of blindness in patients over age 60 in the U.S. and is a major health problem in most other developed countries. More than 9 million Americans have some degree of AMD (Archives of Ophthalmology, In Press). Based on the results of an NEI-funded clinical trial, the Age-Related Eye Diseases Study (AREDS), 1.3 million of these people would develop advanced AMD if no treatment were given to reduce their risk. If these people at risk for development of advanced AMD received the supplements (vitamins C, E, beta-carotene, and zinc) used in AREDS, more than 300,000 of them would avoid advanced AMD and any associated vision loss over the next five years. Delaying the advance of a disease in older-age populations is an essential strategy to reduce the burden and incidence of disease.
Uveitis is an autoimmune inflammatory disease of the eye that accounts for up to 10 percent of blindness in the U.S. (Ophthalmology 2004; 111:491-500). In collaboration with researchers at the National Cancer Institute, NEI intramural scientists have reported promising results with the use of a monoclonal antibody (daclizumab) in the long term treatment of patients with uveitis. This new therapy seems to have many fewer side effects than existing immunosuppressive therapies, leading to an improved quality of life. Planning is underway to begin a Phase III study to evaluate the full potential of this therapy.
The cornea is the transparent tissue at the front of the eye. Corneal disease and injuries are the leading cause of visits to eyecare clinicians, and are some of the most painful ocular disorders. In addition, approximately 25 percent of Americans have a refractive error known as myopia or nearsightedness that requires correction to achieve sharp vision; many others are far-sighted or have astigmatism.
NEI intramural scientists found that serum albumin represents up to 13 percent of the total water-soluble protein of the mouse cornea. Humans also have abundant serum albumin in the corneal stroma. Because the serum albumin accumulates in the corneal stroma by diffusion from the blood supply surrounding the cornea, it may provide an improved route of drug delivery to the cornea. Conjugating serum albumin to the drug of choice and injecting the conjugate into the blood stream will not only direct the drug within the cornea, but extend its half-life within this tissue. Future research will evaluate the usefulness of serum albumin as a drug carrier to treat corneal disorders.
NEI intramural scientists recently identified an enzyme called CDK5 that regulates corneal epithelial cell adhesion and migration. Using a model wound healing system, these researchers found that the rate of wound closure was significantly retarded in cells with too much CDK5 and accelerated in cells in which the CDK5 was inactivated. Continuation of this line of research may provide the means to promote rapid healing of corneal tissues that have been damaged by disease or injury.
Cataract, an opacity of the lens of the eye, interferes with vision and is the leading cause of blindness in developing countries. In the U.S., cataract is also a major public health problem. The economic burden of cataract will worsen significantly in coming decades as the American population ages.
Age-related cataract formation is believed to result from the complex effects of aging on normal physiological processes. It has long been recognized that lens transparency is a function of a very high concentration of soluble proteins, the crystallins, within the specialized lens fiber cell. In the lens, alpha-crystallin has a dual function: it accumulates in fiber cells in high concentrations to produce the high refractive index needed for transparency, and it functions as a molecular chaperone to protect against clouding of the lens due to protein aggregation. For some time, scientists have attempted to understand how alpha-crystallin can continue to perform its chaperone functions over a range of stress conditions encountered by the lens during a lifetime. New data suggest that under low stress, alpha-crystallin is maintained in a multi-subunit complex. Under conditions of high stress, alpha-crystallin breaks into smaller sub-units that can protect the clarity of the lens from protein aggregation. It has been hypothesized that this chaperone function decreases with age and leaves the lens more vulnerable to stressful conditions. Improving our understanding of this protective role of alpha-crystallin may one day lead to the means to prevent cataract.
GLAUCOMA AND OPTIC NEUROPATHIES
Glaucoma is a group of eye disorders that share a distinct type of optic nerve damage, which can lead to blindness. Elevated intraocular pressure (IOP) is frequently, but not always, associated with glaucoma. Glaucoma is a major public health problem and is a leading cause of blindness in African Americans (Archives of Ophthalmology, In Press).
A hallmark of glaucoma is the death of retinal ganglion cells (RGC) in the retina, which can lead to catastrophic vision loss. Previous NEI studies have found evidence that elevated IOP deprives RGCs of brain-derived neurotrophic factor (BDNF), an endogenous protein that is crucial to RGC survival. Ocular injections of BDNF in rodent models of glaucoma have improved RGC survival. However, due to the relatively short half-life of this protein, the need for frequent ocular injections would not bode well in treating a chronic disease like glaucoma. To overcome this hurdle, NEI-supported researchers recently used gene therapy in rodent models of glaucoma to transfect RGCs with the gene that encodes BDNF, providing a lasting and direct supply of this essential protein. Ongoing NEI-supported laboratory work is evaluating whether gene therapy with BDNF provides long-term benefit and whether gene delivery with other neurotrophic agents, alone or in combination with BDNF, improves RGC survival.
STRABISMUS, AMBLYOPIA AND VISUAL PROCESSING
Developmental disorders such as strabismus (misalignment of the eyes) and amblyopia (commonly known as “lazy eye”) are among the most common eye conditions that affect the vision of children. In addition, more than three million Americans suffer from visual processing disorders not correctable by glasses or contact lenses (Archives of Ophthalmology 1990; 108:286-290).
Patching the stronger eye has been a mainstay of amblyopia therapy. Unfortunately, there is no specific patching regimen that is widely accepted for treating the disease. To address the clinical issue of the optimal number of patching hours for moderate amblyopia, an NEI-supported clinical trial compared daily patching of two hours versus six hours for children with moderate amblyopia. Results from this clinical trial revealed that patching the unaffected eye of children with moderate amblyopia for only two hours daily is as effective as patching the eye for six hours. This finding should improve treatment compliance as patching can be a socially stigmatizing and uncomfortable practice for young children.
The marriage of computer technology and medical science is creating advances in treating even the most intractable diseases. In one such union, specially designed computer chips implanted in the eye may one day make it possible to partially restore visual function to the blind. Ocular neuro-degenerative diseases such as retinitis pigmentosa (RP) and macular degeneration damage and destroy the light-sensitive photoreceptor cells in the retina. The microelectronic retinal prosthesis, a device developed by NEI-supported researchers, mimics the function of photoreceptor nerve cells by turning light into electric signals. In a recently published study, a 74 year-old patient blind with RP was able to see spots of light, detect motion, and recognize simple shapes. Although preliminary, these results are a promising first step in realizing a prosthetic device that can restore ambulatory vision to patients with retinal degenerative diseases, which are a major cause of vision loss in this country.
The rapid progress in areas of gene discovery and bioinformatics has created the need for enhanced cooperation and coordination among groups that provide genetic diagnostic information to the clinician and patient, store and provide DNA specimens to researchers, and maintain data banks of genotype-phenotype information. Such groups are underrepresented in the area of human ocular disease. The purpose of this initiative is to explore the establishment of a national central registry and molecular database of securely coded information from a large number of people with ocular diseases caused by genetic mutations. Information will be provided through a network of cooperating groups who provide genetic and diagnostic services to patients and clinicians. Such a registry and database will be of great value in advancing research for these important diseases.
Clinician scientists will play a major role in translating laboratory findings into safe and effective therapies. However, the vision research community has raised concerns about the future of clinician scientists. Declining clinical revenues are making it increasingly difficult for clinicians to find time away from the examination room to get the training they need. However, many of the investigational therapies now being contemplated will be translated by the next generation of clinician scientists. We need to make sure that current clinician scientists have a capable next generation to pass the torch to.
In addition to its existing extramural training and career development grant programs, the NEI is working to increase the ranks of the clinician scientist through a new intramural clinician scientist training program at the NEI. The Clinician Scientist Development Program is designed for board eligible/certified clinicians who seek to develop an independent research program that integrates the field of vision research with the clinical study of patients with ocular disease or disorders.
The NEI recently published its forward looking National Plan for Eye and Vision Research. The NEI’s ongoing planning process involves the assessment of important areas of progress in eye and vision research and the development of new goals and objectives that address outstanding needs and opportunities for additional progress.
The National Plan can be accessed through the NEI website at http://www.nei.nih.gov/strategicplanning.
The NIH Roadmap provides a framework for the priorities the NIH as a whole must address in order to optimize its entire research portfolio. The NEI is committed to the initiatives of the Roadmap and is working to meet its goals. I would like to highlight NEI’s involvement in two Roadmap Initiatives: “Nanomedicine” and “Re-Engineering the Clinical Research Enterprise.”
The NEI and the National Human Genome Research Institute are heading an NIH committee charged with implementing the Nanomedicine Roadmap Initiative. Nanotechnology originated in the fields of engineering and physics and refers to the research and development of materials and devices at the atomic, molecular or macromolecular levels. Nanomedicine integrates nanotechnology with biomolecular processes. The long-term goal of the Nanomedicine Roadmap Initiative is the development of therapeutic nanotechnology interventions for medical diagnosis and the treatment of disease. To meet these goals we are establishing a process to solicit ideas and concepts germane to the development of Nanomedicine Development Centers. Nanomedicine Development Centers will be designed to achieve an understanding of biological systems at the nanomolecular level.
Over the past decade NEI-supported laboratory research has given rise to an unprecedented number of promising, pre-clinical therapies for eye disease. NEI’s continued success depends on building the clinical infrastructure for translational medicine. Consonant with the NIH Roadmap initiative “Re-engineering the Clinical Research Enterprise” the NEI is creating cooperative clinical research groups that will enhance and expand clinical trial infrastructure. Over the last year, the NEI implemented the Diabetic Retinopathy Clinical Research Network. More than 70 clinical centers with the capability to participate in the clinical trials network have been identified. This network joins the highly effective Pediatric Eye Disease Investigator Group as models for future clinical networks the NEI plans to build.
Mr. Chairman that concludes my prepared statement. I would be pleased to respond to any questions you or other members of the committee may have.
Department Of Health And Human Services
National Institutes Of Health
National Eye Institute
PAUL A. SIEVING, M.D., Ph.D.
Director, National Eye Institute, NIH, 2001-Present
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 (Retinal Physiology), University of California, San Francisco, 1982-1984. Medical Fellowship (Inherited Retinal Degenerations), Harvard Medical School / Massachusetts Eye and Ear Infirmary, 1984-1985.
At the University of Michigan: Assistant Professor of Ophthalmology, 1985-1989. Faculty, Rackham Graduate School Programs in Neuroscience, 1985-2001; Bioengineering, 1985-2001. Associate Professor of Ophthalmology, 1989-1994. Founding Director, Center for Retinal and Macular Degenerations, 1990-2001. Founding Director, Ocular 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.
Honors and Awards:
James Scholar Award and Leon F. Moldavsky Physiology Award, University of Illinois Medical School. Fight-for-Sight 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. The Best Doctors in America.
Association for Research in Vision and Ophthalmology. International Society for Clinical Electrophysiology of Vision. American Academy of Ophthalmology. American Ophthalmological Society. Society for Neuroscience. American Society of Human Genetics. National Board of Visitors, Christ College, Valparaiso University.
Department of Health and Human Services
Office of Budget
William R. Beldon
Mr. Beldon is currently serving as Acting Deputy Assistant Secretary for Budget, HHS. He has been a Division Director in the Budget Office for 16 years, most recently as Director of the Division of Discretionary Programs. Mr. Beldon started in federal service as an auditor in the Health, Education and Welfare Financial Management Intern program. Over the course of 30 years in the Budget Office, Mr. Beldon has held Program Analyst, Branch Chief and Division Director positions. Mr. Beldon received a Bachelor’s Degree in History and Political Science from Marshall University and attended the University of Pittsburgh where he studied Public Administration. He resides in Fort Washington, Maryland.