Novel pro-drug pharmacotherapy to prevent neuronal and cell degeneration in AMD

预防 AMD 神经元和细胞变性的新型前药药物疗法

• 批准号: 10018027
• 负责人: Peter Koulen
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018027
• 关键词: Acute; Address; Affect; Age related macular degeneration; Animal Model; Antioxidants; Apoptosis; Apoptotic; Area; Basic Science; Biological; Biological Products; Blindness; Cell Death; Cells; Characteristics; Chemicals; Choroidal Neovascularization; Clinical Research; Complement; Cytoprotection; Data; Development; Disease; Disease Outcome; Drug Delivery Systems; Drug Design; Drug Kinetics; Effectiveness; Eye; Eye diseases; Feasibility Studies; Future; Genetic; Goals; Health; Healthcare; Human; In Vitro; Interdisciplinary Study; Intervention; Knowledge; Measures; Mediating; Metabolic; Metabolic Biotransformation; Methods; Minority; Nature; Neurons; Nonexudative age-related macular degeneration; Oral Administration; Oxidative Stress; Pathogenesis; Performance; Pharmacology; Pharmacotherapy; Phase I Clinical Trials; Phase II Clinical Trials; Photoreceptors; Population; Preclinical Testing; Prevention; Prodrugs; Property; Research; Research Project Grants; Retina; Retinal Degeneration; Retinal Photoreceptors; Retinal Pigments; Role; Route; Signal Pathway; Structure; Structure of retinal pigment epithelium; Testing; Therapeutic; Topical application; Treatment Efficacy; United States; Vision; Visual; Visual Acuity; Visual impairment; Vitamin E; age related; base; clinical efficacy; clinically relevant; design; experimental study; gamma-Tocopherol; gene therapy; health care delivery; health disparity; human model; improved; in vivo; innovation; insight; neovascularization; neuron apoptosis; neuron loss; neuroprotection; novel; novel therapeutic intervention; novel therapeutics; preservation; prevent; retinal damage; retinal neuron; side effect; small molecule; therapy design; therapy development; treatment strategy

PROJECT SUMMARY/ABSTRACT Degeneration or acute damage of retinal pigment epithelial (RPE) and nerve cells in the retina due to Age-related Macular Degeneration (AMD) is a major cause of visual loss and blindness in the United States and worldwide. The proposed multidisciplinary research project will focus on the characterization of a novel signaling pathway for and the development of a novel pharmacological intervention to control degeneration of RPE cells and neurons in AMD. To this end, preclinical testing of the new therapeutic strategy will be performed, along with ocular biotransformation, transport and distribution studies, in established models of human AMD. These experiments will determine efficacy of treatment in terminating and/or preventing AMD associated neuronal loss and preservation of visual function, and to generate data to support feasibility for and move positive findings to phase 1 and 2 clinical trials. Specifically, we will test the two-pronged hypothesis that treatment based on the ocular targeting of a novel chemical antioxidant strategy protects RPE cells and neurons from apoptosis by topical delivery in established models of human AMD and, therefore, leads to prevention or improvement of visual impairment and functional deficits associated with AMD. The determination of neuronal viability and the acquired knowledge on associated biopharmaceutical and pharmacological parameters will indicate the potential of the method to remedy AMD as the overall goal of the project. This novel approach for therapy development in AMD focuses on complementary and alternative cellular protection and neuroprotection. The innovative strategy has the potential to generate a first-in-class pharmacotherapy approach for dry AMD using a topical rather than a systemic or invasive route of drug delivery. The strategy’s potentially high impact lies in its capacity to be both preventative and therapeutic in nature and to complement existing treatment designs and rationales addressing other aspects of AMD treatment such as those targeting neovascularization.

项目概要/摘要 视网膜色素上皮（RPE）和神经细胞变性或急性损伤 年龄相关性黄斑变性（AMD）是导致视力丧失和失明的主要原因 美国和全世界。拟议的多学科研究项目将重点关注 新型信号通路的表征和新型信号通路的开发 药物干预控制 AMD 中 RPE 细胞和​​神经元的退化。对此 最后，将对新治疗策略进行临床前测试，同时进行眼部测试 在已建立的人类 AMD 模型中进行生物转化、运输和分布研究。 这些实验将确定终止和/或预防 AMD 的治疗效果 相关的神经元损失和视觉功能的保留，并生成数据来支持 可行性并将积极结果转移至 1 期和 2 期临床试验。具体来说，我们将测试 双管齐下的假设，即基于新型化学物质眼部靶向的治疗 抗氧化策略通过局部递送来保护 RPE 细胞和​​神经元免于凋亡 建立了人类 AMD 模型，因此可以预防或改善视力 与 AMD 相关的损伤和功能缺陷。神经元活力的测定 以及获得的相关生物制药和药理学参数的知识 将表明补救 AMD 的方法的潜力作为该项目的总体目标。这 AMD 治疗开发的新方法侧重于补充和替代 细胞保护和神经保护。创新战略有可能产生 干性 AMD 的一流药物治疗方法，使用局部而非全身或 侵入性给药途径。该战略的潜在重大影响在于其能够 本质上具有预防性和治疗性，并补充现有的治疗设计和 解决 AMD 治疗其他方面的基本原理，例如针对 新血管形成。