Pharmacological Treatment of Retinal Diseases

描述(由申请人提供)： 凯斯西储大学药理学、眼科和生物医学工程系的研究人员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，组成了一个跨学科联盟，提议“加快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速度”，这是R24国家眼科研究所(NEI)视觉疾病治疗转化研究计划的一个明确目标。这一科学伙伴关系将利用其不同的科学专业知识，通过结合使用尖端的生理、化学、分析和成像方法，在动物模型中表征和测试潜在的视网膜疾病治疗方法。通过筛选食品和药物管理局(FDA)批准的药物，在模拟Stargardt病、老年性黄斑变性(AMD)和视网膜色素变性(RP)的动物模型中预防视网膜病理的能力，我们将在人体试验之前加快药物开发。作为这些实验的一个组成部分，改善药物对眼睛的传递也将是一个高度优先的问题。该项目的具体目标是：(1)测试FDA批准的药物在降低眼睛中全反式视网膜毒性水平并防止其与有害结合物缩合的能力；(2)通过使用在动物模型研究中被证明有效且安全的化合物，评估FDA批准的药物作为潜在的治疗视网膜疾病的先导化合物的类似物；(3)评估这些药物的生物利用度和分布，以确定它们在不影响正常光传导和视觉周期反应的情况下穿透并留在眼睛内的能力；以及(4)探索不同的给药方式，开发新型可在眼睛内提供治疗药物浓度的可生物降解聚合物。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治疗方法。相关性(参见说明)：美国合法失明的人数超过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查可以潜在地重新调整FDA批准的广泛分子的用途。这项提议提供了一个令人信服的机会来攻击这种严重的Riisfiasfi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.