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

评估丁酸前药纳米颗粒在视网膜神经保护中的功效

基本信息

批准号：
10602346
负责人：
Manas R Biswal
金额：
$ 29.68万
依托单位：
NUTRIFORWARD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602346
关键词：
Acids Actins Age Age related macular degeneration Angiography Animals Apoptosis Apoptotic Attenuated Biochemical Biological Biological Assay Biological Availability Blindness Blood Vessels Bruch&apos s basal membrane structure Burn injury Butyrates Butyric Acids Canis familiaris Carrying Capacities Cell Nucleus Cell Proliferation Cells Choroid Choroidal Neovascularization Collagen Type IV Cone Creativeness Cyclic GMP Development Diabetic Retinopathy Disease Dose Endothelial Cells Enzyme-Linked Immunosorbent Assay Exhibits Extracellular Matrix Extravasation Eye Fibrosis Funding Fundus Genetic Models Goals Half-Life Harvest Health Histologic Histone Deacetylase Histone Deacetylase Inhibitor Histones In Situ Nick-End Labeling Inflammation Inherited Injury Inner Nuclear Layer Isolectin Japan Laser injury Lasers Licensing Malignant Neoplasms Mass Fragmentography Measures Medical Modeling Molecular Analysis Mus Nature Nerve Degeneration Neurodegenerative Disorders Normal saline Opsin Optical Coherence Tomography Oryctolagus cuniculus Outcome Paraffin Penetration Pharmaceutical Preparations Phase Phenotype Photoreceptors Point Mutation Prevention Prodrugs Property Proteomics Refrigeration Reporting Retina Retinal Degeneration Retinitis Pigmentosa Rights Rod Safety Sampling Shapes Site Smooth Muscle Stains Sus scrofa System Testing Therapeutic Therapeutic Intervention Thick Tissues Toxic effect Treatment Efficacy Universities Variant Vascular Diseases Vascular Endothelial Growth Factors Vascularization Visual alternative treatment autosome bevacizumab clinical translation comparison control effective therapy effectiveness testing efficacy evaluation efficacy study experimental study gene augmentation therapy histological studies imaging system immunogenicity improved inherited retinal degeneration mouse model nanoparticle neuroprotection non-histone protein novel overexpression phosphoric diester hydrolase polypeptide postnatal prevent protein misfolding receptor response retinal imaging self assembly success transcriptome whole genome

项目摘要

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.

项目概要脉络膜新生血管（CNV）发生在年龄相关性黄斑变性（AMD）和糖尿病患者中视网膜病变（DR）。虽然抗 VEGF 治疗显着改善了视力结果，但还远远不够。达到 100% 的成功率（无反应率在 8% 到 50% 之间）。遗传性视网膜变性 (IRD) 是一组异质性、进行性、视力衰弱的疾病，可导致失明和目前批准的少数治疗方法疗效有限。另一种治疗选择是使用具有以下作用的药物：与 VEGF 抑制和基因增强疗法不同的治疗机制将有所帮助，因为现有抑制 CNV 疗法和 IRD 治疗的辅助或替代疗法。众所周知，许多视网膜变性与蛋白质错误折叠有关。组蛋白脱乙酰酶抑制剂 (HDACi) 是用于治疗癌症中的蛋白质错误折叠疾病。它们还能减弱 CNV 并表现出神经保护作用对于税务局。丁酸是一种有效的内源性 HDACi。丁酸的变体，特别是 4-苯基丁酸酸（4-PBA）被认为是 IRD 的潜在治疗干预措施。然而，临床转化由于其半衰期相对较短，丁酸及其形式的应用受到限制。克服困难的有效策略眼科治疗的局限性丁酸是合成其前药，一种自组装丁酸盐纳米颗粒（BNP）。 BNP 更小、均匀且在各种 pH 水平和冷藏条件下稳定状况。该提案重点评估 BNP 在预防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 在以下方面的有效性：在特征明确的激光诱导 CNV 模型中预防脉络膜新生血管 (CNV)。对于目标 2，我们将在一个明确的视网膜变性遗传模型中评估 BNP 的治疗效果。我们将进行功能、结构、组织学、生化和分子分析来评估功效所提出的治疗方法。我们的方法提供了一种提供持久前药的全新方法无论视网膜变性如何，都能增强视网膜保护。