Novel Therapies to Prevent Blindness Caused by Proliferative Vitreoretinopathy

描述（由申请人提供）：视网膜脱离和严重眼外伤后发生增生性玻璃体视网膜病变（PVR），导致视网膜前和视网膜下瘢痕形成，这是这些患者预后不良的主要决定因素之一。重要的是，PVR可在超过50%的穿孔损伤患者和高达10%的视网膜脱离患者中发现。虽然PVR的病理生理学尚未完全了解，但目前的证据表明，包括视网膜色素上皮（RPE）在内的各种细胞类型都参与了异常的伤口愈合反应。这项工作的长期目标是开发一种新的策略来有效地预防或治疗这种反应，以降低PVR导致失明或永久性视力丧失的风险。这项建议的健康相关性是，成功完成这项工作可能会导致受影响的个人的视力保护。最近的研究支持这样一种假设，即控制EMP2（上皮膜蛋白2）或其下游信号通路，可能会改变RPE细胞的生物学反应，从而预防或治疗PVR。本研究申请中提出的具体目标将检验EMP2或其信号转导通路的下调可能在体外和体内疾病动物模型中有效预防或治疗PVR的假设。在动物模型中将使用三种不同的方法，包括目前用于癌症治疗的抑制剂，我们实验室开发的设计抗体和生化途径的小分子抑制剂。成功完成本资助申请中提出的工作将确定预防或早期治疗PVR的最佳策略。重要的是，这项工作还将确定动物模型中的眼部安全性，以便进行必要的临床前研究，以考虑未来在人类疾病中的临床试验。这项工作的重大影响将是确定潜在的治疗策略，通过在视网膜脱离或穿孔性眼损伤的初始修复时进行治疗或作为治疗已建立的PVR的预防剂来预防PVR。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，这些证据可能很快导致人类疾病的临床试验。临床试验超出了本申报资料的范围，可能导致新的治疗方法，并导致穿透性眼外伤或视网膜脱离后视力恢复或失明预防。这项工作有可能推进研究领域，并最终改变受影响个体的护理标准，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：本研究的目的是测试我们实验室的新观察结果是否可以用于设计一种新的治疗方法，用于治疗增殖性视网膜病变（PVR），这是一种与严重眼外伤或视网膜脱离相关的潜在致盲性疾病。上皮膜蛋白2（EMP2）是一种通常在眼睛中发现的蛋白质，可能与PVR的发展有关，将使用设计抗体片段或小分子抑制剂靶向功能降低。与公共卫生的相关性将是使用本研究的观察结果，并开发一种新的治疗方法，可以预防或有效治疗PVR。

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.