Epigenetic Modifiers to treat Photoreceptor Degenerations

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Abstract: The overall goal of Skyran Biologics is to develop powerful topical therapeutics to combat retinal degenerative diseases. In the course of our studies on epigenetic regulation of retinal development we have defined ways in which histone modifications can lock genes encoding these mechanisms into inactive, condensed chromatin. We found a number of drugs that partially reverse chromatin condensation without any obvious loss of normal cell function. More importantly, these epigenetic modifiers prevent photoreceptor degeneration in models of Retinitis Pigmentosa. In addition to histological and molecular preservation, treatment also reduced loss of visual acuity and contrast sensitivity. Based on our published and preliminary studies, we hypothesize that such drugs can be used to reverse chromatin condensation and allow photoreceptors to respond to and survive disease stresses. This innovative approach to target retina degeneration through changes in chromatin compaction has a strong translational implication as it is mutation independent. From our studies, we selected a lead candidate and now propose two specific aims to address important scientific questions about photoreceptor degeneration. The first is effective delivery of the drug. Epigenetic modifier drugs often show systemic side effects. Topical targeted delivery to the eye will prevent systemic concentrations from reaching a threshold for such effects. Second, although we have data supporting our hypothesis that chromatin decondensation is the key effect of epigenetic modifier drugs, and so should be effective for many photoreceptor degenerations, we have not tested efficacy using different models of both Retinitis Pigmentosa and Age-Related Macular Degeneration (ARMD). In our first Specific Aim we will use our most potent drug, GSK2879552, to test the most effective dosage and frequency of topical treatment that blocks rod degeneration in C57Bl/6rd10 mutant mice. In our Second Aim we will test efficacy of GSK2879552 on two additional models of photoreceptor degeneration, namely the Rho-P23H transgenic mouse, an additional model of Retinitis Pigmentosa, and the Abca4-/-Rdh8-/- double knockout mouse, a model of ARMD. Results of these aims will define the generality of our hypothesis, important mechanisms and treatment of photoreceptor degeneration, as well as help delineate the potential size of the market. The milestones achieved by the successful completion of these aims will position us to propose a set of key Phase II studies using GMP grade material, including systemic toxicity screening, dosing, formulation, and biostability studies that will move us towards an IND filing and human trials.