Pharmacological Treatment of Retinal Diseases

描述（由申请人提供）： 来自凯斯西储大学药理学、眼科学和生物医学工程系的跨学科研究人员联盟与辛辛那提大学药物发现中心、华盛顿大学和宾夕法尼亚大学合作，提出“加快将疾病机制的基础科学发现转化为复杂视觉系统障碍和疾病的治疗方法的步伐”，R24国家眼科研究所（NEI）视觉障碍治疗转化研究计划的既定目标。这一科学合作伙伴关系将利用其多样化的科学专业知识，通过结合尖端的生理、化学、分析和成像方法，在动物模型中表征和测试视网膜疾病的潜在疗法。通过筛选食品和药物管理局（FDA）批准的药物，以确定其在模拟Stargardt病，年龄相关性黄斑变性（AMD）和视网膜色素变性（RP）的动物模型中预防视网膜病变的能力，我们将在人体试验之前加速药物开发。作为这些实验的一个组成部分，改善药物向眼睛的输送也将是一个高度优先事项。 该项目的具体目标是：（1）测试FDA批准的药物降低眼内全反式视黄醇毒性水平并防止其凝结为有害共轭物的能力;（2）通过使用动物模型研究中发现有效和安全的批准化合物，评估FDA批准药物的类似物作为治疗视网膜疾病的潜在先导化合物;（3）评估这些药剂的生物利用度和分布，以确定其穿透和保留在眼睛中而不影响正常光传导和视觉循环反应的能力;以及（4）探索不同的药物递送模式，并开发新的可生物降解的聚合物，其在眼睛中提供治疗药物浓度。最终，这些相互关联的目标的实验结果将指导我们为目前无法治愈的致盲疾病患者开发更成功的疗法。相关性（参见说明）：在美国，法定失明人数超过130万，其中约800万至1000万老年人将受到年龄相关性黄斑变性（AMD）的影响。利用Stargardt病的机制相关模型，我们已经证明了快速筛选可以潜在地重新利用广泛的FDA批准的分子。这一提议提供了一个引人注目的机会来攻击这一严重的risfiasfi和nthsr cnnditinn.c; inditriinn AMD。

DESCRIPTION (provided by applicant): An interdisciplinary consortium of investigators from the Departments of Pharmacology, Ophthalmology and Biomedical Engineering at Case Western Reserve University in collaboration with the University of Cincinnati Drug Discovery Center, Washington University and the University of Pennsylvania, proposes "to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for complex visual system disorders and disease", a stated goal of the R24 National Eye Institute (NEI) Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse scientific expertise to characterize and test potential therapies for retinal diseases in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By screening Food and Drug Administration (FDA)-approved drugs for their ability to prevent retinal pathology in animal models that mimic Stargardt's disease, age-related macular degeneration (AMD), and retinitis pigmentosa (RP), we will accelerate drug development before testing in humans. Improving drug delivery to the eye as an integral part of these experiments will also be a high priority. Specific goals of this project are to: (1) Test FDA-approved drugs for their ability to reduce toxic levels of all-trans-retinal in the eye and prevent its condensation to harmful conjugates; (2) Evaluate analogues of FDA-approved drugs as potential lead compounds for treating retinal diseases by using approved compounds found effective and safe in animal model studies; (3) Assess the bioavailability and distribution of these agents to determine their ability to penetrate and remain in the eyes without affecting normal phototransduction and visual cycle reactions; and (4) Explore different modes of drug delivery and develop novel biodegradable polymers that provide therapeutic drug concentrations in the eyes. Ultimately, the experimental results of these interrelated aims will guide us in developing more successful therapies for patients affected by currently incurable blinding diseases. RELEVANCE (See instructions): The number of persons who are legally blind in the USA exceeds 1.3 million with about 8-10 million aging persons who will be affected with age-related macular degeneration (AMD). Utilizing a mechanistically relevant model of Stargardt's disease, we have demonstrated rapid screening to potentially repurpose a broad set of FDA approved molecules. This proposal offers a compelling opportunity to attack this grievous riisfiasfi and nthsr cnnditinn.c; inditriinn AMD.