Novel therapies to inhibit diabetic retinopathy

 描述（申请人提供）：来自凯斯西储大学医学、药理学、眼科学、儿科学和生物医学工程系的跨学科研究人员联盟，与密歇根大学、哈佛大学合作，波士顿大学提出"加快将疾病机制的基础科学发现转化为复杂视觉系统疾病的治疗方法的步伐，这是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。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糖尿病和其他缺血性视网膜病变的潜在疗法。通过在动物模型中确定具有抑制糖尿病视网膜病变早期临床重要病变能力的药物，我们将在人体试验之前加速其开发。改善药物输送到视网膜也将是一个高度优先事项。传统和新兴技术以及高分辨率成像方法将被用于非侵入性地评估视网膜中的各种过程，并记录治疗效果。本项目的具体目标是：1.使用视黄胺作为先导化合物，开发和测试其他含氨基化合物（来自化学库的衍生物和特别为本项目合成的化学品）捕获活性醛和/或抑制视网膜细胞在葡萄糖浓度下孵育产生超氧化物的能力，这些葡萄糖浓度与糖尿病中发现的浓度相似。将采用系统药理学方法来评价由G蛋白偶联受体（GPCR）的激动剂和拮抗剂组成的第二组化合物实现类似治疗效果的能力。2.测试这些化合物中最好的化合物单独和组合的（a）抑制啮齿类动物和灵长类动物中糖尿病视网膜病变的非增殖期病变（增加的毛细血管渗透性和变性）和（B）抑制氧诱导的视网膜病变模型中毛细血管脱落和视网膜前新生血管形成的能力。3.与全身给药相比，评估通过不同途径递送至视网膜的有前景的试验药物的保留和有效性。选择用于进一步研究的化合物的一个重要标准是它们在所用剂量下不损害视觉功能。最终，这些相互关联的目标的结果将指导我们确定最有前途的治疗方法，以进一步开发减少糖尿病患者视网膜病变和视力丧失的方法。

 DESCRIPTION (provided by applicant): An interdisciplinary consortium of investigators from the Departments of Medicine, Pharmacology, Ophthalmology, Pediatrics and Biomedical Engineering at Case Western Reserve University, in collaboration with the University of Michigan, Harvard University, and Boston University 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 diabetic and other ischemic retinopathies in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By identifying drugs with the capability to inhibit clinically important lesions of the early stages of diabetic retinopathy in animal models, we will accelerate their development before testing in humans. Improving drug delivery to the retina will also be a high priority. Conventional and emerging technologies together with high resolution imaging methods will be used noninvasively to assess various processes in the retina, and document the effect of therapies. Specific goals of this project are to: 1. Use retinylamine as the lead compound to develop and test the ability of other amino-containing compounds (derivatives from chemical libraries and chemicals synthesized especially for this project) to trap reactive aldehydes and/or inhibit superoxide generation by retinal cells incubated in glucose concentrations similar to those found in diabetes. A systems pharmacology approach will be employed to evaluate the ability of a second group of compounds consisting of agonists and antagonists of G protein-coupled receptors (GPCRs) to achieve similar therapeutic effects. 2. Test the best of these compounds singly and in combination for their ability to (a) inhibit lesions of the non-proliferative stage of diabetic retinopathy (increased capillary permeability and degeneration) in rodents and primates, and (b) inhibit capillary dropout and pre-retinal neovascularization in the oxygen- induced retinopathy model. 3. Assess the retention and efficacy of promising test drugs delivered to the retina by different routes compared to systemic delivery. An important criterion for selection of compounds for further study is that they do not impair visual function at the doses used. Ultimately, results of these interrelated aims will guide us in identifying the most promising therapeutics for further development in reducing retinopathy and vision loss in diabetic individuals.