Novel Antiangiogenic Peptides for Treatment of Exudative AMD

描述(由申请人提供)：威斯康星大学眼科和儿科的研究人员与西北大学生命过程化学研究所、生物医学工程、泌尿外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，提议加快疾病机制的基础科学发现转化为渗出性老年性黄斑变性(AMD)治疗的步伐，这是R24国家眼科研究所视觉疾病治疗翻译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的潜在治疗方法。通过筛选来自内源性血管生成抑制物的新多肽，研究它们在模拟AMD的动物模型中防止新生血管的能力，我们将在人类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)确定眼部的多肽作用机制是否是通过对这些天然抑制剂的模仿；(2)产生并确定最适合玻璃体内治疗AMD的基准多肽的最佳新衍生物，这些多肽分别和联合应用于CNV模型中的疗效排名；(3)选择和测试最具活性的多肽(S)及其清除速度最慢的制剂在AMD模型中的有效性。最佳候选者(S)将接受GLP生产，然后进行安全性测试，包括视网膜安全性测试，以选择适合临床开发的新多肽实体；以及(4)通过最先进的活体视网膜成像和组织病理学分析，通过检查视网膜疾病的动物模型，为该实体的最终人类治疗方案奠定临床前基础。最终，这些相互关联的目标的实验结果将指导我们开发更成功的疗法，以治疗那些目前无法治愈的具有新生血管成分的致盲疾病。

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.