Research in Diseases, Disorders, and Health Conditions
Chronic Diseases and Organ Systems
Age-related Macular Degeneration
Age-related macular degeneration (AMD) gradually destroys sharp, central vision. As the leading cause of irreversible blindness in older Americans, AMD will impose an increasing burden in future years as the baby boomer generation ages. Early disease is characterized by yellow deposits under the retina called drusen. Advanced disease has two forms. ‘Dry’ AMD, also called geographic atrophy (GA), occurs when the retinal pigment epithelium (RPE) and then the photoreceptors in the macula slowly break down, gradually blurring central vision in affected eyes. Exudative, or ‘wet’, AMD is marked by choroidal neovascularization (CNV) in which abnormal blood vessels growing under the retina leak blood and fluid, thereby destroying the structure of the macula and leading to loss of photoreceptors. More than 85 percent of all people with intermediate and advanced AMD combined have dry AMD. However, if only advanced AMD is considered, about two-thirds of patients have wet neovascular AMD. Because almost all vision loss comes from advanced AMD, the wet form leads to significantly more vision loss than the dry form.
AMD affects patients’ ability to read, recognize faces, drive a car, or perform even simple tasks that require hand-eye coordination. It severely restricts mobility, forcing many otherwise healthy seniors to prematurely lose their independence and ultimately to be cared for in costly assisted living facilities. According to 2004 published data on prevalence of AMD, of the nearly 60 million people in the United States age 55 or older in the year 2000, an estimated 7.3 million are at risk of developing advanced, sight-threatening AMD in one or both eyes and 1.75 million citizens currently have AMD. This number is expected to increase to nearly 3 million by the year 2020.241
The landmark Age-Related Eye Disease Study (AREDS) is a longitudinal treatment trial and natural history study established that at-risk AMD patients taking high levels of antioxidants and zinc could reduce progression to advanced disease by 25 percent. Building on these findings, AREDS2 is a multi-center clinical trial examining oral supplementation of macular xanthophylls (lutein and zeaxanthin) and/or long-chain omega-3 fatty acids on the progression to advanced AMD and cataracts. AREDS2 is also evaluating effects of eliminating beta-carotene and/or reducing zinc in the original AREDS formulation on AMD progression. Results from this large, multicenter clinical trial are anticipated in 2013.
The VITamin D and OmegA-3 TriaL , the Low Vision Depression Trial, is an interventional trial to test collaborative care between eye care professionals and low vision occupational therapists to prevent or reduce depression that accompanies AMD.
In May 2011, first-year results from the two-year Comparison of AMD Treatment Trials (CATT) found Avastin, a drug approved to treat some cancers and that is commonly used off-label to treat wet AMD, is virtually identical in improving visual acuity as the Food and Drug Administration-approved drug Lucentis242. The four-armed CER trial also demonstrated excellent results for both drugs when compared between two dosing schedules, either monthly, or on an as needed basis, determined by monitoring signs of fluid in the retina. Both drugs are anti-VEGF243 compounds manufactured by Genentech. Serious adverse events (primarily hospitalizations) occurred at a 24 percent rate for patients receiving Avastin and a 19 percent rate for patients receiving Lucentis. These events were distributed across many different conditions, most of which were not associated with Avastin in cancer clinical trials where the drug was administered at 500 times the dose used for AMD. The number of deaths, heart attacks, and strokes were low and similar for both drugs during the study. The median age of patients in CATT was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations. Importantly, CATT was not powered to determine whether there is a significant difference in adverse event rates between the two drugs.244
Two large AMD GWAS studies (18,000 subjects) identified three new genes associated with AMD; two of these genes (hepatic lipase gene and cholesterylester transfer protein) are involved with high-density lipoprotein cholesterol metabolism, implicating a new biochemical pathway involved in the pathogenesis of AMD. Weaker associations were found with other genes in the cholesterol pathway: ATP-binding cassette transporter and lipoprotein lipase. The studies also identified a new strong association on chromosome 22, near metalloproteinase inhibitor 3 (TIMP3). Mutations in TIMP3 had been known to cause Sorsby’s fundus dystrophy, a rare, inherited early-onset form of macular degeneration.245 246
241 Friedman DS, et al. Arch Ophthalmol. 2004;122(4):564–72. PMID: 15078675.
242 Martin D, et al. NEJM. 2011;364:1897–908. PMID: 21526923.
243 Vascular Endothelial Growth Factor (VEGF) is a signal protein that stimulates the process of forming new blood vessels from endothelial cells and growing new blood vessels from pre-existing vessels.
244 Martin D, et al. Ophthalmology. 2012;119(7):1388–98. PMID: 22555112.
245 Neale BM, et al. PNAS. 2010;107(16):7395–400. PMID: 20385826.
246 Chen W, et al. PNAS. 2010;107(16):7401–6. PMID: 20385819.
In patients with dry AMD or geographic atrophy, researchers discovered that a deficiency of the Dicer1 enzyme in retinal pigment epithelial cells was associated with cell death of these cells. Dry AMD happens when the light-sensitive cells in the macula slowly break down, gradually blurring central vision in the affected eye. In the absence of the Dicer enzyme, cell death was linked to toxic accumulation of double-stranded Alu RNA. Increasing the level of Dicer or interfering with Alu RNA rescued the cell death, suggesting potential therapies for dry AMD.247
Investigators studying choroidal neovascularization, the creation of new blood vessels in parts of the eye, in human patients with wet AMD discovered that the protein CCR3 is expressed in choroidal cells (cells in the layer of the eye that contains connective tissue and lying between the retina and the sclera). Wet AMD happens when abnormal blood vessels behind the retina start to grow under the macula. These new blood vessels can be fragile and leak blood and fluid. The blood and fluid cause the macula to swell and damage occurs rapidly. The damage may also cause scarring of the retina. However, CCR3 is not expressed in disease-free subjects, or from early stage AMD patients who do not yet demonstrate choroidal neovascularization (i.e., patients with dry AMD). Therefore, CCR3 may serve as a biomarker for detecting choroidal neovascularization in patients at early stages of AMD before vision loss occurs. It also may serve as a therapeutic target: drugs that block CCR3 prevented additional vessel growth in tissue removed from AMD patients with choroidal neovascularization, or in animal models.248 NIH is also funding research to understand the genes that control angiogenesis (the growth of new blood vessels from preexisting blood vessels) in AMD, as such work could open up new research and therapeutic opportunities.249 In addition, newly discovered pathways implicated in AMD genetics studies include growth factors, inflammation (Complement Factor H), and cholesterol. NEI with NIDDK is planning a workshop on diagnostic and therapeutic potential CFH pathway in the hope of stimulating new research areas.
247 Kaneko H, et al. Nature. 2011;471(7338):325–30. PMID: 21297615.
248 Takeda A, et al. Nature. 2009;460(7252):225–30. PMID: 19525930.
249 Stefater JA, et al. Nature. 2011;474(7352):511–5. PMID: 21623369