Evaluating the efficacy of Butyric acid pro-drug nanoparticle in retinal neuroprotection

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Project Summary Choroidal neovascularization (CNV) occurs in both age-related macular degeneration (AMD) and diabetic retinopathy (DR). While anti-VEGF treatment has improved the visual outcome considerably, they are far from achieving a 100% success rate (non-responsiveness between 8 and 50%). Inherited retinal degenerations (IRDs) are a group of heterogeneous, progressive, visually debilitating diseases that can lead to blindness and the few current approved treatments have limited efficacy. An alternative treatment option, a drug with a therapeutic mechanism different from VEGF suppression and gene augmentation therapy, would be helpful as an adjunct or alternative to existing therapies to suppress CNV and treatment for IRDs. It is well known that many retinal degenerations are associated with protein misfolding. Histone deacetylase inhibitors (HDACi) are used in therapy for protein misfolding diseases in cancer. They also attenuate CNV and exhibit neuroprotection for IRDs. Butyric acid is a potent, endogenous HDACi. Variations of butyric acid, specifically 4-phenylbutyric acid (4-PBA), have been touted as potential therapeutic interventions in IRDs. However, the clinical translation of butyric acid and its forms is limited due to its relatively short half-life. An effective strategy to overcome the limitations of ophthalmic therapeutics butyric acid is to synthesize their pro-drugs, a self-assembling butyrate nanoparticle (BNP). BNPs are smaller, uniform, and stable at various pH levels and under refrigerated storage conditions. This proposal focuses on evaluating the safety and therapeutic efficacy of BNPs in the prevention of choroidal neovascularization and retinal protection. For Aim 1, we will test the effectiveness of BNP in preventing choroidal neovascularization (CNV) in a well-characterized laser-induced model of CNV. For Aim 2, we will evaluate the therapeutic efficiency of BNP in a well-characterized genetic model of retinal degeneration. We will perform functional, structural, histological, biochemical, and molecular analyses to evaluate the efficacy of the proposed therapeutics. Our approach provides an entirely new way of delivering long-lasting pro-drug that enhances retinal protection irrespective of retinal degeneration.