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

项目总结/摘要 视网膜色素上皮（RPE）和神经细胞的变性或急性损伤 由于视网膜病变相关的黄斑变性（AMD）是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 一种新的信号通路的表征和一种新的 药物干预以控制AMD中RPE细胞和神经元的变性。本 最后，将进行新治疗策略的临床前测试，沿着眼内 生物转化、运输和分布研究。 这些实验将确定治疗在终止和/或预防AMD中的功效 相关的神经元损失和视觉功能的保护，并产生数据，以支持 可行性，并将积极的发现转移到1期和2期临床试验。具体来说，我们将测试 一种双管齐下的假设，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递送保护RPE细胞和神经元免于凋亡， 建立的人AMD模型，因此导致预防或改善视觉损害。 与AMD相关的损伤和功能缺陷。神经元活力的测定 以及所获得的关于相关生物制药学和药理学参数的知识 将指出该方法的潜力，以补救AMD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一个 使用局部而非全身或全身性药物治疗干性AMD的一流药物治疗方法 侵入性给药途径。该战略的潜在高影响力在于它能够 预防性和治疗性的，并补充现有的治疗设计， 解决AMD治疗其他方面的基本原理， 新生血管形成

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.