Choroidal neovascularization (CNV) occurs in both age-related macular degeneration (AMD) and diabeticretinopathy (DR). While anti-VEGF treatment has improved the visual outcome considerably, they are far fromachieving 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 andthe few current approved treatments have limited efficacy. An alternative treatment option, a drug with atherapeutic mechanism different from VEGF suppression and gene augmentation therapy, would be helpful asan adjunct or alternative to existing therapies to suppress CNV and treatment for IRDs. It is well known thatmany retinal degenerations are associated with protein misfolding. Histone deacetylase inhibitors (HDACi) areused in therapy for protein misfolding diseases in cancer. They also attenuate CNV and exhibit neuroprotectionfor IRDs. Butyric acid is a potent, endogenous HDACi. Variations of butyric acid, specifically 4-phenylbutyricacid (4-PBA), have been touted as potential therapeutic interventions in IRDs. However, the clinical translationof butyric acid and its forms is limited due to its relatively short half-life. An effective strategy to overcome thelimitations of ophthalmic therapeutics butyric acid is to synthesize their pro-drugs, a self-assembling butyratenanoparticle (BNP). BNPs are smaller, uniform, and stable at various pH levels and under refrigerated storageconditions. This proposal focuses on evaluating the safety and therapeutic efficacy of BNPs in the preventionof choroidal neovascularization and retinal protection. For Aim 1, we will test the effectiveness of BNP inpreventing 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 efficacyof the proposed therapeutics. Our approach provides an entirely new way of delivering long-lasting pro-drugthat enhances retinal protection irrespective of retinal degeneration.
Public Health Relevance Statement: Project Narrative
Histone deacetylase (HDAC) over expression and protein misfolding is well documented in many retinal
degenerations, whereas, butyric acid is a potent, endogenous HDAC inhibitor. Our proposal will evaluate the
safety and efficacy a novel butyric acid prodrug nanoparticles (BNP). This study will provide a framework for
the development of BNP for the prevention and treatment of choroidal neovascularization and retinal
neurodegenerative diseases.
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