MicroRNAs for therapy of visual disorders

MicroRNA用于治疗视觉障碍

基本信息

批准号：
8446967
负责人：
MARTIN FRIEDLANDER
金额：
$ 208.52万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446967
关键词：
3&apos Untranslated Regions Affect Age related macular degeneration Angiogenesis Promoter Animal Model Attenuated Binding Biochemical Biomedical Engineering Blindness Blood Vessels Chemistry Clinic Clinical Clinical Trials Collaborations Combined Modality Therapy Complex Critical Pathways Development Diabetic Retinopathy Disease Dose Drug Formulations Drug Kinetics Drug Targeting Endothelial Cells Eye Eye diseases FDA approved Gene Targeting Gliosis Growth Growth Factor Hemorrhage Human Image Immunohistochemistry Individual Injection of therapeutic agent Instruction Lead Macular degeneration MicroRNAs Modeling Molecular Molecular Target Outcome Pathologic Neovascularization Pathway interactions Patients Pharmaceutical Preparations Process Qualifying Reagent Recruitment Activity Regulation Rest Retinal Retinal Edemas Retinal Neovascularization Role Series Signal Pathway Signal Transduction Site Small RNA Specimen Structure System Therapeutic Time Tissues Toxicology Translations Vascular Endothelial Growth Factors Vision Disorders angiogenesis antiangiogenesis therapy base cell type choroidal angiogenesis improved in vitro Model inhibitor/antagonist insight mouse model nanoparticle neovascular neovascularization novel novel strategies ocular angiogenesis ocular neovascularization p120 GTPase Activating Protein receptor research study response retinal angiogenesis

项目摘要

PROJECT SUMMARY (See instaictions): The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis and associated retinal edema, hemorrhage and gliosis. Current anti-angiogenic strategies used in the clinics to treat complications of neovascularization in diseases like macular degeneration and diabetic retinopathy target vascular endothelial growth factor (VEGF) or its receptors. However, potential problems with anti-VEGF therapy limits its utility; the need for repeated injections, potential secondary effects on other, non-endothelial, cell types and the involvement of non-VEGF angiogenic mechanisms may limit or attenuate patient responses. Combination therapy, targeting multiple pathways with multiple drugs, may achieve synergistic angiostatic activity that can circumvent these problems but this approach is limited by the absence of FDA-approved clinical drugs that target angiogenesis either upstream or downstream of VEGF. We propose modulating pathways critical to pathological angiogenesis by targeting micro RNAs (miRs); miRs generally function to silence expression of target genes by binding to specific sites on their 3' untranslated region (UTR) and recruiting a silencing complex that blocks translation. We have identified miR-132 as a microRNA which is not expressed in normal blood vessels, but which is up-regulated in angiogenic tissues and in endothelial cells stimulated with growth factors. Expression of miR-132 is sufficient to drive vascular sprouting and proliferation, whereas inhibition of miR-132 with a complementary anti-miR-132 blocks these responses. Thus, we have identified miR-132 as activating endothelial ceils to promote angiogenesis and an anti-miR that neutralizes miR-132, thereby suppressing retinal neovascularization without affecting normal vessels. We have shown that the molecular target of miR-132, p120RasGAP, is a potent negative regulator of Ras in resting vessels. Thus, p120RasGAP is targeted and suppressed by the pro-angiogenic miR-132. In this proposal, we will explore the potential utility of anti-miR-132 and other anti-mlRs delivered to the eye using a novel nanoparticle delivery platform, as a potent and sustained anti-angiogenic strategy for therapy of neovascular eye diseases.

项目摘要（参见说明）：绝大多数导致灾难性视力丧失的疾病都是由于异常的结果造成的血管生成和相关的视网膜水肿、出血和神经胶质增生。目前的抗血管生成策略在临床上用于治疗黄斑变性等疾病的新生血管并发症糖尿病视网膜病变的靶标是血管内皮生长因子（VEGF）或其受体。然而，潜力抗 VEGF 疗法的问题限制了其实用性；需要重复注射，潜在的继发性对其他非内皮细胞类型的影响以及非 VEGF 血管生成机制的参与可能限制或减弱患者的反应。联合治疗，针对多种药物的多种途径，可能会实现协同血管抑制活性，从而避免这些问题，但这种方法是有限的由于缺乏 FDA 批准的针对血管生成上游或下游血管生成的临床药物血管内皮生长因子。我们建议通过靶向 micro RNA 来调节对病理性血管生成至关重要的途径（miR）； miR 通常通过结合到 3' 端的特定位点来沉默靶基因的表达非翻译区（UTR）并招募阻止翻译的沉默复合物。我们已经确定 miR-132 作为一种 microRNA，在正常血管中不表达，但在血管中表达上调血管生成组织和用生长因子刺激的内皮细胞。 miR-132 的表达是足以驱动血管出芽和增殖，而用互补的 miR-132 抑制抗 miR-132 阻断这些反应。因此，我们已经确定 miR-132 可以激活内皮细胞促进血管生成和中和 miR-132 的抗 miR，从而抑制视网膜新生血管形成而不影响正常血管。我们已经证明 miR-132 的分子靶标， p120RasGAP 是静息血管中 Ras 的有效负调节因子。因此，p120RasGAP 是有针对性的并且被促血管生成的 miR-132 抑制。在本提案中，我们将探讨以下内容的潜在效用：使用新型纳米颗粒递送平台将抗 miR-132 和其他抗 MLR 递送至眼部，作为用于治疗新生血管性眼病的有效且持续的抗血管生成策略。