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

项目摘要 脉络膜新生血管(CNV)发生在老年性黄斑变性(AMD)和糖尿病患者中 视网膜病变(DR)。虽然抗血管内皮生长因子治疗显著改善了视力结果，但它们远没有 达到100%的成功率(无响应率在8%到50%之间)。遗传性视网膜变性 (IRDS)是一组异质性、进行性、视觉衰弱的疾病，可导致失明和 目前批准的为数不多的治疗方法疗效有限。另一种治疗选择，一种具有 与抑制血管内皮生长因子和基因增强治疗不同的治疗机制将有助于 抑制CNV和治疗红斑狼疮的现有疗法的辅助或替代疗法。众所周知， 许多视网膜变性与蛋白质的错误折叠有关。组蛋白脱乙酰酶抑制物(HDACi)是 用于治疗癌症中的蛋白质错误折叠疾病。它们还可以减弱CNV，并表现出神经保护作用 对于红斑狼疮。丁酸是一种强有力的内源性HDACi。丁酸的变化，特别是4-苯基丁酸 酸(4-PBA)，已被吹捧为IRDS的潜在治疗干预措施。然而，临床翻译 丁酸及其形式的含量因其相对较短的半衰期而受到限制。一种有效的战略来克服 眼科治疗药物丁酸的局限性是合成其前体药物，一种自组装丁酸 纳米颗粒(BNP)。BNPS较小，均匀，在不同的pH水平和冷藏条件下都是稳定的 条件。本建议侧重于评价BNPS在预防高血压中的安全性和治疗效果。 脉络膜新生血管和视网膜保护。对于目标1，我们将测试BNP在 在具有良好特征的激光诱导的脉络膜新生血管模型中预防脉络膜新生血管(CNV)。对于目标2， 我们将评估BNP在视网膜变性遗传模型中的治疗效率。 我们将进行功能、结构、组织学、生化和分子分析来评估疗效 建议的治疗方法。我们的方法提供了一种全新的方式来提供长效亲药物 这增强了对视网膜的保护，而不管视网膜是否退化。

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.