Identifying Cytoprotectants for Photoreceptors and RPE Cells to Treat Dry AMD

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Department of Health and Human Services
Award Year:
Phase I
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Small Business Information
ACUCELA INC., 21720 23rd Dr. SE, Bothell, WA, 98021
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(206) 812-1530
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DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the major cause of irreversible loss of vision in the adult population. AMD can be classified into the dry form and the wet form. The dry form involves apoptotic changes in the photoreceptor cells or the retinal pigment epithelium (RPE) cells underlying the central retina (macula). The dry form can progress to the wet form of AMD, which is characterized by the proliferation of abnormal blood vessels under the retina, leading to fluid or blood leakage and to eventual blindness. The dry form represents 90% of AMD cases, and there is currently no treatment for it. Although the underlying causes leading to dry AMD are complex and involve a variety of hereditary and environmental factors, the final death pathway leading to AMD is apoptosis of photoreceptors and RPE cells. We need to identify compounds that inhibit death of photoreceptors or RPE cells so that dry AMD can finally be treated effectively. The use of rodent models has a good track record for evaluating compounds against light-induced stress. However, unlike animal studies that can only test a few compounds at a time, the goal of this SBIR project is to develop specific cell-based assays with minimal false-negatives or - positives using primary bovine retinal cell culture and an immortalized RPE cell line, ARPE-19, to screen large amounts of compounds in 96-well microtiter plates. This will allow us to identify lead small molecules that would counter retinal cell death und er stress conditions that are specific for photoreceptor cells and/or RPE cells. Continuous light exposure and A2E (a RPE lipofuscin generated as a side-product during the visual cycle) accumulation are two major stress factors that can induce oxidative st ress in retinal cells. Neuropotective candidate compounds identified will be developed for the treatment of the dry form of AMD. Specifically, Phase I of this SBIR project consists of the following Specific Aims: 1) Utilize light stress to induce preferent ial photoreceptor cell death in a primary mixed retinal culture system and to identify cytoprotective compounds to counter photoreceptor cell death caused by light stress. 2) Utilize A2E in combination with light stress to induce cell death in a retinal pi gment epithelial cell line, ARPE-19, and to identify cytoprotective compounds against such stress. 3) Determine if neuroprotective compounds identified in Aims 1 and 2 have in vivo activity against light stress using a mouse model. The feasibility of our a pproach will be validated if we can identify novel cytoprotectants for photoreceptors and/or RPE cells as specified in Aims 1 to 3. Phase II of this multi-phase SBIR project will initiate more extensive in vivo studies to confirm the efficacy of the compou nds identified in Phase I. Phase II will also study the mechanisms of the compounds identified for the development of target-based assays to further screen novel compounds. In Phase III we will partner with corporate collaborators who can take these compou nds into and through human clinical trials as an essential step in addressing a huge ( 1 billion+) potential market for new AMD therapeutics. PUBLIC HEALTH RELEVANCE: The goal of this SBIR project is to prove the feasibility of using next-generation, cell- based assays to identify novel cytoprotectants for cells in the retina for treating the dry form of age-related macular degeneration (AMD). Since the final death pathway leading to AMD is the degeneration of photoreceptors or RPE cells in the retina, findi ng compounds that would protect photoreceptors or RPE cells from stress-induced cell death would provide an important new approach to treat dry AMD, an early form of AMD that eventually leads to blindness and there is currently no treatment for it.

* information listed above is at the time of submission.

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