Fragments of TrpRS to Treat Neovascular Eye Diseases

TrpRS 片段治疗新生血管性眼病

• 批准号: 7101752
• 负责人: MARTIN FRIEDLANDER
• 金额: $ 202.26万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101752
• 关键词: SDS polyacrylamide gel electrophoresis; aminoacid tRNA ligase; angiogenesis inhibitors; clinical research; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; eye disorder chemotherapy; genetically modified animals; human tissue; laboratory mouse; laboratory rabbit; laboratory rat; liquid chromatography mass spectrometry; pharmacokinetics; photocoagulation therapy; polymerase chain reaction; receptor binding; toxicant screening; vision disorders; western blottings

DESCRIPTION (provided by applicant): The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis. Pathological retinal or choroidal neovascularization lead to visual loss in diabetic retinopathy (DR) and age related macular degeneration (ARMD), respectively. While inhibition of abnormal angiogenesis would not necessarily cure the underlying diseases, it would preserve vision by preventing complications associated with neovascularization such as hemorrhage and edema. We have been studying the anti-angiogenic activity of fragments of tryptophanyl-tRNA synthetase (TrpRS). In normal human cells TrpRS exists as both the full length form and a truncated form (mini-TrpRS) in which an amino-terminal domain is deleted due to alternative splicing of the pre-mRNA. This latter form is preferentially synthesized in cells exposed to interferon-w. Further truncation of mini-TrpRS results in a 42 kD form (T2) that is the most potent of the angiostatic forms of TrpRS evaluated to date. In this application we propose to further characterize the anti-angiogenic activity of TrpRS fragments and identify a candidate drug and delivery system for use in clinical trials of neovascular eye diseases. Specifically, we will: (1) examine the physiological role of TrpRS fragments in the regulation of normal and abnormal ocular angiogenesis; (2) identify and characterize the retinal receptor to which these fragments bind; (3) characterize the structural aspects of TrpRS fragments with anti-angiogenic activity and use this information to model small molecular antagonists with similar activity; (4) develop viral-, cell- and targeted liposome-based vectors for the delivery of T2 to inhibit ocular neovascularization in a variety of animal models; and (5) begin pharmacokinetic and toxicology studies on these vector, recombinant protein and/or small molecule therapeutics as a first step towards human clinical trials for the treatment of neovascular eye diseases such as neovascular ARMD, proliferative DR and rubeotic glaucoma.

描述（由申请人提供）：绝大多数导致灾难性视力丧失的疾病都是由于血管生成异常造成的。病理性视网膜或脉络膜新生血管形成分别导致糖尿病视网膜病变（DR）和年龄相关性黄斑变性（ARMD）的视力丧失。虽然抑制异常血管生成不一定能治愈潜在疾病，但可以通过预防与新生血管形成相关的并发症（例如出血和水肿）来保护视力。我们一直在研究色氨酰-tRNA 合成酶 (TrpRS) 片段的抗血管生成活性。在正常人类细胞中，TrpRS 以全长形式和截短形式（迷你 TrpRS）存在，其中由于前 mRNA 的选择性剪接，氨基末端结构域被删除。后一种形式优先在暴露于干扰素-w的细胞中合成。 mini-TrpRS 的进一步截短产生 42 kD 形式 (T2)，这是迄今为止评估的最有效的 TrpRS 血管抑制形式。 在此应用中，我们建议进一步表征 TrpRS 片段的抗血管生成活性，并确定用于新生血管性眼病临床试验的候选药物和递送系统。具体来说，我们将：（1）研究TrpRS片段在调节正常和异常眼部血管生成中的生理作用； (2) 识别并表征这些片段所结合的视网膜受体； (3) 表征具有抗血管生成活性的TrpRS片段的结构，并利用该信息来模拟具有相似活性的小分子拮抗剂； (4) 开发基于病毒、细胞和靶向脂质体的载体，用于递送 T2，以抑制多种动物模型中的眼部新生血管形成； (5)开始对这些载体、重组蛋白和/或小分子疗法进行药代动力学和毒理学研究，作为治疗新生血管性眼病（例如新生血管性ARMD、增殖性DR和红斑性青光眼）的人体临床试验的第一步。