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Administration requests $15 million funding increase for FY 2004
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WASHINGTON — In early April, National Institutes of Health Director Elias Zerhouni, MD, testified here on behalf of the NIH for support of 50,000 principal investigators at more than 2,000 sites with nearly 80,000 clinical participants for fiscal year 2004.
Dr. Zerhouni invited only 8 of the 27 institute and center directors to accompany him, only to respond to questions from the appropriations subcommittees. While National Eye Institute Director Paul Sieving, MD, was neither invited nor testified, as was previously usual and customary for each director to do so, he requested authorizing legislation under Section 301 of the Public Health Service Act for a 2.4% increase from FY 2003 to FY 2004, for a total request of $648.2 million.
Dr. Zerhouni cited NEI work, saying, “Age-related macular degeneration is a major cause of blindness currently affecting 1.75 million Americans, with advanced degeneration in at least one eye. And more than 7 million individuals are at substantial risk of developing AMD.” He said the number of Americans with AMD will increase to 2.95 million in 2020.
“NIH is engaged in a major research program to understand the predisposing factors, clinical course and prognostic factors of AMD,” Dr. Zerhouni continued. Citing the Age-Related Eye Diseases Study (AREDS), he said, “More remains to be done. We need to spread the word to change practices, continue work to identify the genes that control the risk of this devastating disease and develop more interventions to prevent or delay the onset of blindness.”
Retinal ganglion cell research
Central nervous system (CNS) neurons, unlike peripheral nervous system nerve cells, have limited regenerative capacity after injury or disease. NEI scientists found that axon growth may be due to a factor within the nerve cell itself, rather than in the surrounding environment.
According to Dr. Sieving’s budget request, recent NEI identification of glaucoma genes provides a tool to study the biochemical pathways leading to optic nerve regeneration and also provides insight into designing neuroprotective strategies. The retinal ganglion cells (RGC) encode visual information from these nerve cells to the optic nerve, or to the brain’s rhythm pacemaker, the suprachiasmatic nucleus (SCN). Recently, researchers have shown the presence of melanopsin proteins in a subset of retinal ganglion cells that project into the SCN. These findings indicate that these RGCs entrain the circadian pacemaker.
Additional experiments revealed that the contact among the RGCs stimulated the dendritic growth mode while impairing axonal growth. The implication is that if this signal remains too long after the completion of development, it could suppress axonal growth in the adult. A clearer understanding of the developmental switch from axonal to dendritic growth may be a key factor in CNS regeneration. The challenge for continuing research, believes Dr. Sieving, is “to discover the signals that switch neurons back to the axon growth mode.”
Glaucoma, retinal genetic research
Researchers recently discovered the OPTN gene link to low-tension glaucoma, finding that its four mutations may be risk factors. The protein optineuron in this gene suggests an increased severity of optic nerve damage from glaucoma. This knowledge provides researchers with a tool to study biological pathways leading to optic nerve degeneration and design neuro-protective strategies.
Other scientists are attempting to determine the genes that control the earliest eye development events, one of which is the internal lens. The Pax-6 master gene that controls expression of a number of additional critical genes has led to the discovery of two of the six3 and Grg5 genes. Without these, lens development is stopped and crystalline-synthesizing cells fail to form. According to Dr. Sieving’s testimony, these findings may “ultimately enhance our knowledge of the molecular basis of genetic diseases of the eye and, thereby, open the possibility of future interventions. ”
Additionally, the OA1 gene, which is associated with most genetic cases of ocular albinism, has been identified. This condition limits development of vision in infants and children by altering the eye-brain connections.
A comprehensive genetic analysis of all possible genes in the retina’s photoreceptors is being undertaken to understand their essential role in the visual pathway. Dr. Sieving explained that a mutated photoreceptor gene is present in many newly discovered rod photoreceptor genes. This has led to an understanding of the causes of an abnormal neural cell axon and may help identify retinal disease genes.
Research network to be established
The NEI, in an effort to increase the pace of research in the treatment and prevention of vision loss associated with AMD, is developing a clinical research network of core centers and participating clinics that will help satisfy the need to evaluate new approaches to treating diabetes-induced retinal disorders and investigate other approaches. Researchers will investigate prevention of vision loss and treatment to slow the progression of diabetic macular edema secondary to diabetic retinopathy.
This network will provide a framework for rapid initiation of important studies, pool clinical expertise and carry out multicenter trials as opposed to single-center trials, thus, reducing the number of patients needed at each clinical center. A common treatment protocol will reduce variables that allow valid comparisons among treatments.
A high priority research area is controlling angiogenesis from diabetic retinopathy and retinopathy of prematurity and the neovascularization from glaucoma and AMD. Vascular endothelial growth factor antagonists and PKC inhibitors are among the agents the NEI is investigating as possible new treatments for these eye conditions.
The NEI also is undertaking a major effort to re-invigorate its intramural research program and enhance resources for neurodegenerative and genetic forms of vision loss. Dr. Sieving said, “Ocular genetics research has demonstrated that many common eye diseases have complex and environmental etiologies that must be understood before innovative biological treatments can be designed.”
Genome project completed
A week after the appropriations requests were submitted, Dr. Zerhouni and James Watson, PhD, announced the completion of the 19-year Book of Man genome project that includes between 35,000 and 40,000 genes. The NEI is progressing towards completion of its database to simplify identification of candidate retinal disease genes.
For Your Information:
- Contact the National Eye Institute at 2020 Vision Place, Bethesda, MD 20892-3655; (301) 496-5248. For clinical trial information, see the National Eye Institute home page: www.nei.nih.gov. Also, see neibank.nei.nih.gov/index.shtml for a listing of ocular genes that have been identified, to assist you when taking initial and follow-up family medical and ocular histories.