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Novel Antiangiogenic Peptides for Treatment of Exudative AMD

用于治疗渗出性 AMD 的新型抗血管生成肽

基本信息

批准号：
8415053
负责人：
NADER SHEIBANI
金额：
$ 124.35万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415053
关键词：
Adverse effects Age Age related macular degeneration American Amino Acids Angiogenesis Inhibitors Animal Model Animals Apoptosis Apoptotic Attenuated Avastin Basic Science Benchmarking Biomedical Engineering Blindness Blood Vessels Bypass Charge Chemicals Chemistry Choroid Choroidal Neovascularization Chronic Clinical Clinical Research Collaborations Cyclic GMP Development Disease Disease Progression Dose Drug Delivery Systems Drug Formulations Epithelial Event Exudative age-related macular degeneration Eye Frequencies Genetic Transcription Goals Growth Half-Life Human Hydrolysis Image Imaging technology In Vitro Injectable Injection of therapeutic agent Institutes Label Lasers Lead Life Light Longitudinal Studies Lucentis Marketing Modeling Molecular Mimicry Monoclonal Antibody R24 Mus NanoGel National Eye Institute Nebraska Neurons Ophthalmology Parents Pathogenesis Pediatrics Peptides Pharmaceutical Preparations Phase Phase I Clinical Trials Photochemotherapy Physiological Pigments Polymers Process Prodrugs Production Proteins Regimen Research Personnel Retinal Retinal Diseases Rodent Safety Schedule Signal Transduction Testing Thrombospondin 1 Toxic effect Toxicology Translating Translational Research Treatment Protocols Universities Urology Variant Vascular Endothelial Growth Factors Vision Disorders Wisconsin angiogenesis aqueous base blocking factor design drug development effective therapy efficacy testing improved in vivo inhibitor/antagonist mimetics mimicry nanoformulation nanomedicine neovascular neovascularization new growth novel ocular angiogenesis ocular neovascularization pre-clinical prevent programs public health relevance research study residence safety testing screening tumor growth

项目摘要

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.

描述（由申请人提供）：威斯康星大学眼科和儿科学系的跨学科研究人员与西北大学生命过程化学研究所、生物医学工程、泌尿科和儿科以及内布拉斯加州大学药物输送和纳米医学中心合作，建议加快将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）的治疗方法的步伐，这是R24国家眼科研究所视觉疾病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渗出性AMD的潜在疗法。通过筛选来自内源性血管生成抑制剂的新肽，在模拟AMD的动物模型中发现它们阻止新生血管形成的能力，我们将加速药物开发，然后再进行人体试验。作为这些实验的一个组成部分，改善药物输送到眼睛也将是一个高度优先考虑的问题。该项目的具体目标是：(1)确定肽在眼睛中的作用机制是否通过它们对这些天然抑制剂的模仿；(2)生产和鉴定最适合于玻璃体内治疗AMD的基准肽的最佳新衍生物，并根据CNV模型中单独和联合的疗效对其进行排名；(3)选择并检测活性最强的肽及其清除最慢的制剂对AMD模型的疗效。最佳候选药物将进行GLP生产，然后进行安全性测试，包括视网膜安全性测试，以选择合适的新肽类实体进行临床开发；(4)通过最先进的体内视网膜成像和组织病理学分析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。