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.

项目摘要脉络膜新血管形成（CNV）均在年龄相关的黄斑变性（AMD）和糖尿病中均出现视网膜病（DR）。尽管抗VEGF治疗已大大改善了视觉结果，但它们远非达到100％的成功率（无响应性在8％至50％之间）。继承的视网膜变性（IRD）是一组异构，进步的，视觉使人衰弱的疾病，可能导致失明和当前批准的少数疗法的功效有限。另一种治疗选择，一种具有与VEGF抑制和基因增强疗法不同的治疗机制将有助于现有疗法抑制CNV和IRD治疗的辅助或替代方案。众所周知许多视网膜变性与蛋白质错误折叠有关。组蛋白脱乙酰基酶抑制剂（HDACI）为用于癌症中蛋白质错误折叠疾病的治疗。他们还衰减CNV并展示神经保护作用对于irds。丁酸是一种有效的内源性HDACI。丁酸的变化，特别是4-苯基丁基酸（4-PBA）已被吹捧为IRD中潜在的治疗干预措施。但是，临床翻译丁酸及其形式由于其相对较短的半衰期而受到限制。克服的有效策略眼科治疗剂的局限性丁酸是为了综合其亲毒品，一种自组装的丁酸酯纳米颗粒（BNP）。 BNP较小，均匀且稳定在各种pH水平和冷藏储存下状况。该建议重点是评估BNP在预防中的安全性和治疗功效脉络膜新生血管形成和视网膜保护。对于AIM 1，我们将测试BNP在在特征良好的激光诱导的CNV模型中预防脉络膜新生血管形成（CNV）。对于目标2，我们将评估BNP在视网膜变性良好的遗传模型中的治疗效率。我们将执行功能，结构，组织学，生化和分子分析以评估功效拟议的治疗学。我们的方法提供了一种全新的方式来交付长期的亲毒品无论视网膜变性如何，这都增强了视网膜保护。