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) 2011 budget of $724 million includes an increase of $17 million over the FY 2010 appropriation level of $707 million. 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.
Genomics and Other High Throughput Technologies
In recognition of the 40th anniversary of NEI, Congress designated 2010 through 2020 as the “Decade of Vision,” a resolution that recognizes the potential of eye and vision research to dramatically improve the visual health of the American people. Understanding the genetics of common, complex eye diseases and disorders is fundamental to developing more effective treatments. NEI investigators are capitalizing on the remarkable progress made by the Human Genome Project in part through the recent submission of large, genome-wide association study (GWAS) datasets for age-related macular degeneration (AMD), glaucoma and myopia to the public domain. These datasets, hosted on the NIH database of Genotypes and Phenotypes (dbGaP) website, give the entire vision research community the ability to identify risk genes for eye diseases that affect millions of people.
Glaucoma is a family of diseases characterized by progressive vision loss due to degeneration of the optic nerve. Published studies find it to be a leading cause of blindness among Hispanic and African Americans and the third most prevalent cause of visual impairment and blindness among Caucasian Americans. The most common form of glaucoma, primary open angle glaucoma (POAG), occurs primarily in adults and has a significant genetic predisposition (sibling risk is about ten times that of the general population). Despite the high heritability of POAG, susceptibility has not been linked to a single underlying gene or simple mode of inheritance. GWAS studies are needed to identify common genetic variants that are associated with this genetically complex disease. NEI recently established the NEI Glaucoma Human Genetics Collaboration (NEIGHBOR), a consortium of clinicians and geneticists at 15 institutions throughout the United States dedicated to identifying the genetics of glaucoma. NEIGHBOR will combine data from more than 5000 individuals (2500 glaucoma cases and 2500 controls) to initiate the largest ever GWAS study of glaucoma. NIH also established the Gene-Environment Interactions in Glaucoma study (GLAUGEN)—through the NIH Gene-Environment Initiative (GEI)—to identify the relationship of environmental exposures to gene-trait associations in the disease. These efforts will greatly aid in the understanding of glaucoma and in the ultimate goal of developing more effective treatments for this blinding disease.
As the power of GWAS studies has increased, so also has the amount of data collected. This complexity requires increasing reliance on statistical and computational strategies to evaluate large datasets. As part of its ongoing strategic planning efforts, NEI recently held a scientific workshop on functional genomics that included expertise in vision, genetics, and computation to address these emerging challenges. I created a new senior NEI leadership position, associate director for ophthalmic genetics, to ensure implementation of opportunities in genetics.
eyeGENE is another new and critical genetic resource. eyeGENE is coordinated through NEI and operates as a collaborative partnership of 20 academic research labs across the nation that work to elucidate the genetic basis of eye disease. eyeGENE is creating a centralized repository of DNA patient samples and clinical diagnostic information for use by vision researchers. Patients and their doctors receive genetic information during their participation in eyeGENE. Over the last year, eyeGENE expanded by adding more laboratories and has collected over 1600 patient samples. eyeGENE already improves patient care with personalized medicine while furthering research knowledge.
Translating Basic Science Discoveries into New and Better Treatments
Retinal neurodegenerative diseases such as AMD are the leading cause of irreversible vision loss in older Americans. AMD involves degeneration and destruction of the retinal pigment epithelium (RPE), a thin layer of tissue that supports and nourishes the light-detecting photoreceptor cells in the neural retina. Replacing diseased tissue with a healthy RPE is a possible method to prevent the disease. The recent discovery that pluripotent stem cells can be created from adult, rather than embryonic, tissue provides a new approach to generate donor RPE cells. If proven therapeutically efficacious, these stem cells, known as human induced pluripotent stem cells (iPSC), could provide treatments for a variety of eye diseases while avoiding ethical concerns surrounding human embryonic stem cells. NEI investigators recently reported deriving RPE-like cells from human iPSC cells. These cells demonstrated normal RPE cell functions such as phagocytosis (digestion) of older photoreceptor cell material. The derived RPE cells were next transplanted into the eye of a rodent model of retinal degeneration caused by defective RPE cells. The transplanted cells functioned normally and resulted in long-term preservation of vision in this rodent disease model. These research studies demonstrate the tremendous potential for iPSC in treating certain retinal degenerative diseases and set the stage for examining the behavior of iPSC in a variety of ocular disorders.
Results of gene therapy in adult patients with Leber congenital amaurosis (LCA), a severe and early onset retinal disease, indicate that the treatment is safe with evidence of lasting visual improvement. Further studies will evaluate gene transfer in younger patients with healthier retinas, which may prove to be more efficacious. These encouraging findings are considered “proof-of-concept” that will accelerate work on additional gene-based therapies for the broad spectrum of retinal diseases.
In a unique interagency collaboration, NEI and NASA scientists developed a new diagnostic technology that pre-symptomatically identifies those at risk for cataract development. The device uses a technology called dynamic light scattering to measure the amount of alpha crystallin protein in the lens. Alpha crystallin retards cataract development. Humans are born with a fixed amount of alpha crystallin, and cataract formation begins when the supply of alpha crystallin is exhausted. This new clinical tool allows clinicians to monitor lens health and study therapeutic interventions that may delay or eliminate the onset of cataract formation and blindness.
Using Science to Enable Health Care Reform
To reduce unnecessary health care spending, it is important to determine which therapies are most effective in real world clinical settings. To this end, NEI is conducting a number of comparative effectiveness clinical trials. Laser treatment is a standard of care for diabetic eye disease where abnormal blood vessel growth damages the retina. Although effective, laser treatment does damage peripheral vision and repeated treatments are often needed. Recent clinical evidence suggests that various drugs may confer a better and safer outcome. The Diabetic Retinopathy Clinical Research Network (DRCR.net), a consortium of over 600 clinicians from academic and community-based practices, is conducting clinical trials to compare the safety and efficacy of drug therapies as an alternative to laser treatment for diabetic macular edema and proliferative diabetic retinopathy. Diabetic eye disease is among the most common causes of vision loss and blindness in the United States.
The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) is a multi-center study evaluating the relative efficacy of two similar drugs. Lucentis was approved by the FDA in 2006 for treatment of AMD. Retinal specialists frequently use a far less costly alternative, Avastin, off-label and have evidence that it is a safe and effective alternative to Lucentis. Medicare and supplemental policies already cover the cost of both drugs and related patient care. However, the cost differential is anticipated to reach $2-3 billion per year under current conditions. CATT is the only controlled, well-designed comparison of the two drugs. Results from the CATT study are expected in FY 2011.
Focusing on Global Health
The World Health Organization estimates that a potentially blinding infectious disease, trachoma, affects 8 million people, making it a leading cause of blindness in the developing world. Repeated infection causes scarring of the transparent cornea, leading to irreversible blindness. Intervention programs with the oral antibiotic azithromycin have been successful in eradicating the disease in areas with moderate levels of trachoma. However, in severely affected communities, infection returns rapidly after treatment. In a recent NEI-supported clinical trial, investigators observed eradication of trachoma in severely affected communities in Ethiopia after a multi-dose treatment course. They also found that azithromycin led to a sharp reduction in childhood mortality, likely through concomitant treatment of respiratory infections, gastrointestinal diseases, malaria and other endemic diseases. These results provide strong rationale for intervention in areas severely affected by trachoma. These international efforts augment the bilateral U.S.-India Accord for Collaborative Vision research signed in 2005.
Reinvigorating the Biomedical Research Community
The increasingly quantitative nature of the biomedical sciences and the explosive growth of genomic, proteomic, metabolomic, 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 by expanding its institutional training grant program with a new program in ocular statistical genetics. This program will partner researchers with expertise in mathematics, modeling and computation—fields that are not usually affiliated with ocular research—with investigators in all areas of vision science to provide state-of-the art training. This program also parallels the establishment of the NEI intramural research program in Computational Medicine and Biology. The NEI will first leverage existing computational resources at NIH and then design a collaborative program that interfaces with the larger NIH-wide effort. Computational Medicine and Biology will provide the NEI with increased ability to meld biological information to clinical care, based on rapidly evolving knowledge of the genetic basis of disease, including gene expression, protein structure, protein-protein interaction and biological networks.
PAUL A. SIEVING, M.D., Ph.D.
Director, National Eye Institute, National Institutes of Health, 2001-Present
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: