Novel Therapies to Prevent Blindness Caused by Proliferative Vitreoretinopathy

预防增殖性玻璃体视网膜病变引起失明的新疗法

• 批准号: 7896704
• 负责人: Lynn K Gordon
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896704
• 关键词: Address; Affect; Animal Disease Models; Animal Model; Antibodies; Applications Grants; Behavior; Biochemical Pathway; Biological; Biological Preservation; Blindness; Cell Line; Cell Survival; Cells; Cicatrix; Clinical Trials; Collagen; Dasatinib; Development; Disease; Dose; Down-Regulation; Early treatment; Engineering; Epithelial; Excision; Eye; Eye Injuries; Functional disorder; Future; Gel; Goals; Grant; Health; Healthcare; Human; Immunoglobulin Fragments; In Vitro; Individual; Injury; Interdisciplinary Study; Laboratories; Lead; Link; Membrane; Membrane Proteins; Modeling; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; PTK2 gene; Pathologic; Pathway interactions; Patients; Phosphorylation; Prevention; Prevention strategy; Proliferative Vitreoretinopathy; Proteins; Public Health; Research; Retinal; Retinal Detachment; Retinal Diseases; Risk; Safety; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stratification; Structure of retinal pigment epithelium; Testing; Therapeutic; Time; Toxic effect; Trauma; Vision; Work; Wound Healing; base; cancer therapy; cell type; design; designer antibody; human disease; improved; in vivo; inhibitor/antagonist; novel; novel therapeutic intervention; preclinical study; prevent; prospective; public health relevance; repaired; response; restoration; small molecule; standard of care

DESCRIPTION (provided by applicant): Proliferative vitreoretinopathy (PVR) occurs after retinal detachment and severe ocular trauma and leads to both pre-retinal and subretinal scar formation, one of the major determinants of poor outcomes for these patients. Importantly, PVR may be found in greater than 50% of patients with perforating injuries and in up to 10% of retinal detachment patients. Although the pathophysiology of PVR is not completely understood, current evidence implicates various cell types including the retinal pigment epithelium (RPE) in an aberrant wound healing response. The long term objectives of this work is to develop a new strategy to effectively prevent or treat this response in order to decrease the risk of blindness or permanent loss of vision from PVR. The health relatedness of this proposal is that successful completion of this work could lead to preservation of vision in affected individuals. Recent studies support the hypothesis that control EMP2 (epithelial membrane protein 2), or its downstream signaling pathway, may change the biologic response of RPE cells and prevent or treat PVR. The specific aims proposed in this grant submission will test the hypothesis that downregulation of EMP2 or its signal transduction pathway could be effective in prevention or therapy of PVR both in vitro and in an in vivo animal model of disease. Three different approaches will be used in the animal models including an inhibitor that is used currently in cancer therapy, a designer antibody developed in our laboratory, and a small molecule inhibitor of a biochemical pathway. Successful completion of the work proposed in this grant submission will identify the optimum strategy for prevention or early therapy for PVR. Importantly this work will also define the ocular safety profile in an animal model in order to perform the preclinical studies necessary to contemplate future clinical trials in human disease. The significant impact of this work will be to identify potential therapeutic strategies for prevention of PVR through treatment at the time of initial repair of retinal detachment or perforating ocular injury or as an adjunctive agent in treatment of established PVR. It is anticipated that successful completion of the studies proposed in this grant application would form the basis of the scientific evidence that could quickly lead to clinical trials in human disease. The clinical trials, beyond the scope of the present submission, could potentially lead to new therapies and result in restoration of sight or prevention of blindness following penetrating ocular trauma or retinal detachment. This work has potential to both advance the field of research and to ultimately change the standard of care for affected individuals and is aligned with the strategic goals of improving healthcare through interdisciplinary research. PUBLIC HEALTH RELEVANCE: The purpose of this study is to test whether new observations made in our laboratories could be used in order to design a novel therapeutic approach for proliferative virteoretinopathy (PVR), a potentially blinding disease that is associated with severe eye trauma or retinal detachments. Epithelial membrane protein 2 (EMP2), a protein that is normally found in the eye and may be linked to development of PVR, will be targeted for decreased function using a designer antibody fragment or a small molecule inhibitor. The relevance to public health would be to use the observations that result from this study and develop a new therapy that will either prevent or effectively treat PVR.

描述（由申请人提供）：视网膜脱离和严重的眼部创伤后发生增生性玻璃体肾上腺病（PVR），并导致视网膜前和下疤痕形成，这是这些患者不良结果的主要决定因素之一。重要的是，在超过50％的穿孔损伤患者和多达10％的视网膜脱离患者中，可能会发现PVR。尽管尚未完全了解PVR的病理生理学，但当前的证据表明，在异常伤口愈合反应中，包括视网膜色素上皮（RPE），包括视网膜色素上皮（RPE）。这项工作的长期目标是制定一种新的策略，以有效防止或治疗这种反应，以减少盲目性或永久性视力丧失PVR的风险。该提案的健康相关性是，这项工作的成功完成可能会导致受影响个人的愿景保护。最近的研究支持控制EMP2（上皮膜蛋白2）或其下游信号通路的假设可能会改变RPE细胞的生物学反应并预防或治疗PVR。本赠款提交中提出的具体目的将检验以下假设：EMP2或其信号转导途径的下调可能有效地预防或治疗PVR的体外和体内动物疾病模型。动物模型中将使用三种不同的方法，包括当前用于癌症治疗的抑制剂，在我们的实验室中开发的设计器抗体以及生化途径的小分子抑制剂。成功完成本赠款提交提议的工作将确定预防或早期治疗PVR的最佳策略。重要的是，这项工作还将在动物模型中定义眼部安全性，以便进行考虑到人类疾病的未来临床试验所需的临床前研究。这项工作的重大影响是在视网膜脱离或穿孔眼损伤的初始修复时通过治疗来确定预防PVR的潜在治疗策略，或者是治疗已建立PVR的辅助药。预计成功完成本赠款申请中提出的研究将构成科学证据的基础，该证据可以迅速导致人类疾病的临床试验。临床试验超出了本提交的范围，可能会导致新疗法，并导致视力恢复或预防穿透眼部外伤或视网膜脱离后视力或预防失明。这项工作有潜力既可以推进研究领域，也有可能改变受影响个人的护理标准，并与通过跨学科研究改善医疗保健的战略目标保持一致。 公共卫生相关性：这项研究的目的是测试是否可以使用我们的实验室中的新观察结果来设计一种新型的治疗方法，以实现增殖性病毒性毒素病（PVR），这是一种可能与严重的眼部外伤或视网膜分离有关的潜在盲目疾病。上皮膜蛋白2（EMP2）是一种通常在眼睛中发现并可能与PVR发育有关的蛋白质，将使用设计器抗体片段或小分子抑制剂来降低功能。与公共卫生的相关性是使用本研究产生的观察结果，并开发一种可以预防或有效治疗PVR的新疗法。