Witness appearing before the Senate Subcommittee on Labor-HHS-Education Appropriations:
Dr. Paul A. Sieving, Director
National Eye Institute
May 21, 2009
On this page:
- Ophthalmic Genetics
- Translational Medicine
- Visual Neuroscience
- Clinical Trials and Diagnostics
- Medicine of the Future
- Cancer Research Portfolio
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) 2010 budget of $695,789,000 includes an increase of $7,309,000 over the FY 2009 appropriation level of $688,480,000.
OPHTHALMIC GENETICS
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 in the US. 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. Based on published study data, 8 million older Americans are at risk to develop advanced AMD.
Advanced AMD can take two distinct forms, either geographic atrophy or wet AMD. In geographic atrophy, large areas of the retina atrophy and die. In wet AMD, abnormal blood vessels grow into the retina, leaking blood and serum that damages the retina. Previous studies have found several gene variants, which regulate inflammation, are associated with the “wet” type of AMD. These variants are thought to lead to chronic, overactive inflammatory responses that damage retinal tissue and eventually lead to AMD. Most recently, the first gene associated exclusively with the geographic atrophy, namely the Toll-like receptor 3 (TLR3) gene, was published. The Toll-like receptor 3 (TLR3) gene encodes a viral sensor which activates immune responses. When TLR3 activates in response to certain viruses, it induces cell death in the retina thus causing geographic atrophy. Alternatively, in humans, it appears that low activity of TLR3 confers protection against geographic atrophy, most likely by sparing the death of retinal cells. This is the first evidence that viral infection may contribute to the development of geographic atrophy. Ongoing work includes screening for viruses in affected individuals as well as developing methods to decrease TLR3 activity in the retina.
Glaucoma is a group of eye disorders that share a distinct type of optic nerve damage, which can lead to blindness. Elevated intraocular pressure is frequently, but not always, associated with glaucoma. Published study data find that approximately 2.2 million Americans have glaucoma and a similar number are unaware that they have developed the disease. Like AMD, Glaucoma is a genetically complex disease likely involving many changes in many genes. NEI is committed to exploiting the latest genetic technologies in finding the genes that contribute to this common disorder. To this end, NEI initiated funding for genome wide association studies, a powerful approach that enables investigators to scan the entire human genome to detect multiple, subtle gene variants that increase the risk of developing this complex, blinding disease. Knowledge of the genetic basis of glaucoma is crucial to developing personalized therapies that target specific genes in order to prevent vision loss.
Each genetic discovery has made it possible to study the implicated gene’s function in health and disease. NEI investigators have made considerable progress in understanding the molecular mechanisms of genetic eye disorders and are developing rational therapies that address the molecular cause of the disease. The first success in this translational research effort are the reports of positive results from recent phase I clinical trials of gene transfer in a form of Leber congenital amaurosis (LCA), a severe, early onset retinal disease. In the effort to accelerate progress NEI established eyeGENE, a research program that offers genetic testing to patients through a national network of vision research laboratories in exchange for participation in a secure, confidential patient registry and DNA repository. DNA samples and corresponding diagnostic and clinical information are made available to the vision research community to recruit patients for clinical trials and to conduct genetic and molecular studies. eyeGENE represents a new paradigm to personalize medical care in the practice of ophthalmology. Knowledge of an individual’s genomic profile will enable patients to make informed decisions about presymptomatic, preventive treatments or highly targeted molecular therapeutics.
TRANSLATIONAL MEDICINE
Neovascularization refers to the growth of new blood vessels. In some diseases, such as diabetic retinopathy and AMD, neovascularization is mistakenly activated and becomes a major pathologic consequence of the disease. Neovascularization can cause severe and irreversible vision loss due to abnormal vessel growth and consequent fluid leakage into the retina. Previous studies have established vascular endothelial growth factor (VEGF) spurs neovascularization and several therapies have been developed to prevent the abnormal activation of the VEGF protein. A recent NIH-supported study reports on the discovery of a protein, Roundabout4 (Robo4), that stabilizes the existing vasculature and prevents neovascularization by inhibiting VEGF activity. Robo4 maintains vascular integrity by inhibiting VEGF-induced cell migration, vessel formation and permeability. Vascular eye diseases are the most common cause of vision loss in the United States. This study suggests a new and promising therapeutic avenue to control neovascularization by regulating Robo4 activity.
RNA interference is a new approach that has been touted as having great potential for treating many diseases. This method harnesses a naturally occurring process that cells employ to control gene expression. By designing a small, interfering RNA sequence (siRNA), it is thought investigators can target and silence specific genes with specific siRNAs. Vision researchers have developed siRNA sequences to prevent the expression of VEGF in AMD and diabetic retinopathy that have been demonstrated to prevent neovascularization in animal models. However, a recent NEI-supported study suggests that siRNA may not always target the intended gene to initiate RNA interference. This study provides an important cautionary note to the entire field of siRNA that systemic administration of this treatment may have unintended consequences and side effects.
VISUAL NEUROSCIENCE
Although the function of astrocytes, a cell type found in the brain and central nervous system, is not entirely understood, they have long been thought to maintain normal neuronal function. More recent evidence suggests that astrocytes may have some function in neural signaling and processing. Recently, NEI investigators found key evidence that astrocytes also act as a critical intermediary between neurons and local blood flow. In this study, inhibition of astrocyte activity decreased local blood flow. This finding explains why imaging devices, like functional MRI, detect blood flow changes that correspond to neuronal activity. Pathologic changes in astrocytes are implicated in Parkinson’s, Alzheimer’s, and other neurodegenerative diseases. The specific effect of astrocyte activity on the hemodynamic response provides a basis for the interpretation of functional MRI, adding qualitatively to the clinical and research utility of this powerful imaging tool across the broad spectrum of neurologic disease.
CLINICAL TRIALS AND DIAGNOSTICS
Cataracts (clouding of the ocular lens) remain the primary cause of blindness in the world today. Researchers at NEI and NASA collaborated to develop a Dynamic Light Scattering device which allows clinicians to detect and quantify the amount of unbound alpha crystallin proteins in an intact eye. With this device, it is now possible to safely and reproducibly measure the extent of lens damage and cataract formation caused by oxidative stress to a patient’s eye (and perhaps the body) by measuring alpha crystallin reserves. This provides clinicians with the ability to monitor lens health, and may allow preventive or therapeutic actions that delay or eliminate cataract formation and blindness.
Each year approximately 33,000 Americans undergo corneal transplants to replace diseased corneas, the normally transparent tissue that protects the eye and helps focus light on the retina. Corneal transplants are among the most common and successful transplantation procedures in medicine but sufficient donor is not available. Eye banks, the primary source of donor tissue, refrain from harvesting tissue from donors over age 65 because of uncertainty about the integrity of older corneas. However, the recently published Cornea Donor Study (CDS) found that corneal transplants using tissue from older donors, ages 66 to 75, have similar success rates as tissue from younger donors, ages 12 to 65. Based on these findings, the study authors recommend that the age limit for donor tissue should be expanded to 75. The CDS study gives eye banks, transplant surgeons and patients confidence in the use of older donor tissue. This finding should help eye banks keep pace with the demand for corneal tissue.
MEDICINE OF THE FUTURE
Development of an artificial cornea will provide an abundant source of non-immunogenic tissue for transplantation. Cell transplantation has 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. We will have the opportunity to restore ambulatory vision to the blind through new prosthetic devices that reproduce 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 are very promising.
CANCER RESEARCH PORTFOLIO
NEI funds basic research on cell biology, development and the regulation of blood vessel growth where findings could have relevance to our understanding and treatment of cancer. NEI also supports a phase III clinical trial on the treatment of retinoblastoma, a cancerous, blinding and potentially fatal eye disease. Consistent with the FY 2010 NIH priority to expand cancer research funding, NEI will increase its FY 2010 commitment to this portion of the portfolio by 4.4 percent.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL EYE INSTITUTE
BIOGRAPHICAL SKETCH
PAUL A. SIEVING, M.D., Ph.D.
Director, National Eye Institute, National Institutes of Health, 2001
Member, Institute of Medicine of the National Academies
Education:
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
Licensure:
National Board of Medical Examiners, 1978
American Board of Ophthalmology, 1983
Medical License: IL, 1978; CA, 1982; MA, 1984; MI, 1985
Professional Experience:
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.
Professional Organizations:
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.