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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要视网膜上皮（RPE）和视网膜神经细胞的变性或急性损伤由于年龄相关的黄斑变性（AMD）是视觉丧失和失明的主要原因美国和全球。拟议的多学科研究项目将重点放在新颖的信号传导途径的表征和新颖的发展药理干预以控制AMD中RPE细胞和神经元的变性。对此结束时，将对新治疗策略进行临床前测试以及眼在人类AMD的既定模型中生物转化，运输和分配研究。这些实验将确定终止和/或预防AMD的治疗效率相关的神经元丢失和视觉功能的保存，并生成数据以支持可行性和将正面发现的可行性转移到第1阶段和2阶段的临床试验中。具体来说，我们将测试基于新化学化学的眼部靶向治疗的两种普通假设抗氧化剂策略通过局部递送保护RPE细胞和神经元免受凋亡既定的人类AMD模型，因此可以预防或改善视觉与AMD相关的障碍和功能缺陷。确定神经元的生存力以及有关相关生物药物和药物参数的获得的知识将表明该方法记住AMD作为项目的总体目标的潜力。 AMD中治疗开发的新方法专注于完成和替代方法细胞保护和神经保护。创新策略有可能产生使用局部性而不是全身性或侵入性药物输送途径。该策略的潜在高影响在于它的能力本质上的预防性和治疗性都可以补充现有的治疗设计以及解决AMD治疗的其他方面的理由，例如针对性新血管形成。