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

项目摘要/摘要 视网膜色素上皮(RPE)和神经细胞变性或急性损伤 由于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侧重于 一种新的信号转导途径的特征及其发展 控制AMD视网膜色素上皮细胞和神经元变性的药物干预。对这件事 最后，将与眼科一起进行新治疗策略的临床前测试 在已建立的人类AMD模型中，进行生物转化、运输和分布的研究。 这些实验将决定终止和/或预防AMD的治疗效果。 相关神经元的丧失和视觉功能的保存，并产生数据支持 将阳性结果转移到1期和2期临床试验的可行性。具体地说，我们将测试 双管齐下的假说，即基于一种新型化学物质的眼靶向治疗 抗氧化剂策略通过局部给药保护RPE细胞和神经元免受凋亡 建立了人类AMD的模型，因此导致预防或改善视力 与AMD相关的损害和功能缺陷。神经元存活率的测定 以及获得的有关相关生物制药和药理参数的知识 将表明该方法的潜力，以补救AMD作为项目的总体目标。这 AMD治疗发展的新途径侧重于互补和替代 细胞保护和神经保护。这一创新战略有可能产生 使用局部药物而不是全身药物治疗干性AMD的一流药物治疗方法 侵入性的药物输送途径。该战略的潜在高影响在于其能力 同时具有预防和治疗性质，并补充现有的治疗设计和 解决AMD治疗的其他方面的理论基础，如靶向 新生血管。

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.