Novel Antiangiogenic Peptides for Treatment of Exudative AMD

描述（申请人提供）：来自威斯康星州大学眼科和儿科系的跨学科研究人员联盟，与西北大学生命过程化学研究所、生物医学工程、泌尿科和儿科以及内布拉斯加大学药物输送和纳米医学中心合作，建议加快将关于疾病机制的基础科学发现转化为渗出性年龄相关性黄斑变性（AMD）疗法的步伐，R24国家眼科研究所视觉障碍治疗转化研究项目的既定目标。该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渗出性AMD的潜在疗法。通过筛选源自内源性血管生成抑制剂的新型肽，以确定其在模拟AMD的动物模型中预防新血管形成的能力，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）确定肽在眼中的作用机制是否是通过它们对这些天然抑制剂的模拟;（2）产生并鉴定最适合于AMD的玻璃体内治疗的基准肽的最佳新衍生物，其中这些衍生物通过CNV模型中的功效单独地和组合地进行排名;（3）选择并测试最具活性的肽及其最缓慢清除的制剂在AMD模型中的功效。最佳候选物将进行GLP生产，然后进行安全性测试，包括视网膜安全性，以选择用于临床开发的合适的新的基于肽的实体;以及（4）通过经由最先进的体内视网膜成像和组织病理学分析检查的视网膜疾病的动物模型，为该实体的最终人类治疗方案建立临床前基础。最终，这些相互关联的目标的实验结果将指导我们为那些患有目前无法治愈的致盲性疾病的人开发更成功的治疗方法。

DESCRIPTION (provided by applicant): An interdisciplinary consortium of investigators from the Departments of Ophthalmology and Pediatrics at the University of Wisconsin in collaboration with the Northwestern University Chemistry of Life Processes Institute, Biomedical Engineering, Urology, and Pediatrics, and the University of Nebraska Center for Drug Delivery and Nanomedicine, proposes to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for exudative age-related macular degeneration (AMD), a stated goal of the R24 National Eye Institute Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse scientific expertise to characterize and test potential therapies for exudative AMD in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By screening novel peptides derived from endogenous inhibitors of angiogenesis for their ability to prevent neovascularization in animal models that mimic AMD, 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) determin whether the peptide mechanisms of action in the eye are through their mimicry of these natural inhibitors; (2) Produce and identify optimal new derivatives of benchmark peptides best suited to intravitreal treatment of AMD, where these are ranked by efficacy in CNV models, individually and in combination; (3) Select and tested the most active peptide(s) and their most slowly cleared formulations for efficacy in AMD models. The best candidate(s) will undergo GLP production and then safety testing, including retinal safety to select a suitable new peptide-based entity for clinical development; and (4) Establish preclinical basis for ultimate human treatment protocol for this entity through animal models of retinal disease examined via state-of-the art in vivo retinal imaging and histopathological analysis. Ultimately, the experimental result of these interrelated aims will guide us in developing more successful therapies for those afflicted by currently incurable blinding diseases with a neovascular component.