Therapy development for open-angle glaucomas

开角型青光眼的治疗开发

• 批准号: 9917768
• 负责人: Andras Komaromy
• 金额: $ 59.24万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917768
• 关键词: Address; Advanced Development; Affect; Affinity; Animal Model; Animals; Aqueous Humor; Biological Process; Biology; Blindness; Canis familiaris; Capsid; Cell Death; Cells; Cicatrix; Clinical; Clinical Trials; Complex; Data; Dependovirus; Disease; Dose; Drainage procedure; Extracellular Matrix; Eye; Fibrosis; Future; Gene Expression; Genes; Genetic Predisposition to Disease; Glaucoma; Goals; Heparin Binding; Human; Individual; Injections; Lead; Libraries; Liquid substance; Mediating; Medical; Metabolism; Methods; Microfibrils; Missense Mutation; Modeling; Modification; Molecular; Molecular Genetics; Mutate; Mutation; Open-Angle Glaucoma; Operative Surgical Procedures; Outcome Measure; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Physiologic Intraocular Pressure; Positioning Attribute; Prevention; Rare Diseases; Regulation; Research; Resistance; Retinal Ganglion Cells; Risk Factors; Role; Safety; Testing; Therapeutic; Therapeutic Effect; Trabecular meshwork structure; Transgenes; Translational Research; Translations; Weill-Marchesani syndrome; adeno-associated viral vector; base; clinically relevant; design; differential expression; disease phenotype; extracellular; gene function; gene replacement; gene replacement therapy; gene therapy; genetic architecture; genetic risk factor; improved; in vivo; innovation; molecular marker; multidisciplinary; mutant; novel; novel therapeutic intervention; novel therapeutics; optic nerve disorder; pressure; prevent; success; therapeutic target; therapy development; tool; transcriptome; transgene expression; translational study; vector

Project Summary Open-angle glaucoma (OAG) is a group of progressive optic neuropathies that together are leading causes of irreversible vision loss. The pathogenic triggering mechanisms that lead to its hallmark, progressive retinal ganglion cell (RGC) death, are unknown, but key risk factors include increased intraocular pressure (IOP) and genetic predisposition. IOP elevation results from increased aqueous humor (AH) outflow resistance via the trabecular meshwork (TM), and correlates with accumulation of pathogenic extracellular plaques. New therapies are needed as current IOP-lowering treatments do not target the contributing pathophysiological mechanisms within the TM, and progressive vision loss often persists. Our long-term goal is to develop novel, improved mechanistic therapeutic strategies to treat high-pressure forms of OAG. This multidisciplinary, collaborative translational study will test the central hypothesis that TM plaque formation can be prevented or halted by selective modification of TM gene expression. We will use adeno-associated virus (AAV) as a tool, based on recent successes in clinical trials supporting safety and efficacy of AAV-mediated ocular gene therapy. We aim to provide proof-of-concept that AAV-mediated gene replacement therapy will prevent IOP elevation in a monogenic form of OAG, seen in ADAMTS10-mutant human patients with Weill-Marchesani syndrome (WMS). Specific Aims: Using a well-established, clinically-relevant canine model of ADAMTS10-OAG as a testing platform, we propose 3 Aims: In Aim 1, we will develop new capsid mutated AAV vectors to more efficiently target and express transgene in the TM. In Aim 2, we will identify OAG-relevant differentially expressed genes within the ADAMTS10-mutant TM and develop them as molecular biomarkers for gene therapy. In Aim 3, we will evaluate the normalization of gene expression and function of ADAMTS10-mutant TM cells following AAV- mediated ADAMTS10-gene replacement, and assess whether it provides long-term prevention of increased trabecular outflow resistance and IOP. Significance: Based on extensive preliminary data and using a large- animal OAG model and the ADAMTS10 transgene as testing platforms, we will provide proof that specific pathogenic mechanisms within the TM can be targeted efficiently with novel capsid mutated AAV, normalizing gene expression and biologic function and providing long-term clinical rescue of disease phenotype, including trabecular outflow resistance, elevated IOP, and RGC loss. Developing such a mechanistic-based therapy will facilitate future animal studies and pave the way towards clinical trials, and also advance understanding of molecular OAG disease mechanisms within the TM. Innovation: Our new therapeutic strategy will selectively modify TM gene expression. We will create new AAV capsid vectors tailored specifically to target TM cells, and assess therapeutic effects by correlating clinical outcome measures with changes in the TM transcriptome, a unique translational advance. Our innovation includes our novel, well-established cross-disciplinary collaborative team with a strong track record in successfully executing translational research in ocular gene therapy.

项目摘要 开角式青光眼（OAG）是一组进行性视神经病，共同导致了主要原因 视力丧失。致病性触发机制，导致其标志性的进行性视网膜 神经节细胞（RGC）死亡是未知的，但关键的风险因素包括眼内压（IOP）和 遗传倾向。 IOP海拔高度是由于水性幽默增加（AH）的流出阻力通过 小梁网（TM），与致病性细胞外斑块的积累相关。新疗法 需要当前的降低IOP治疗并不针对促成病理生理机制 在TM中，渐进的视力损失通常会持续存在。我们的长期目标是开发小说，改进 治疗高压形式的机械治疗策略。这个多学科的协作 翻译研究将检验中心假设，即可以预防或阻止TM斑块形成 TM基因表达的选择性修饰。我们将基于 在支持AAV介导的眼基因治疗的安全性和有效性的临床试验中，最近取得了成功。我们的目标 为了证明AAV介导的基因置换疗法将防止IOP升高 OAG的单基因形式，在Adamts10突变的人类患者中，患有Weill-Marchesani综合征（WMS）。 具体目的：使用ADAMTS10-OAG的公认，临床上的犬类模型作为测试 平台，我们提出3个目标：在AIM 1中，我们将开发新的Capsid变异AAV向量以更有效地 靶标并在TM中表达转基因。在AIM 2中，我们将确定与OAG相关的差异表达基因 在Adamts10突变TM中，并将其作为基因治疗的分子生物标志物开发。在AIM 3中，我们 将评估ADAMTS10突变TM细胞基因表达和功能的归一化 介导的ADAMTS10基因更换，并评估它是否提供了长期预防 小梁的排水阻力和IOP。意义：基于广泛的初步数据，并使用大量 动物OAG模型和ADAMTS10转基因作为测试平台，我们将提供具体的证明 TM内的致病机制可以通过新型的Capsid突变有效地靶向AAV，并归一化 基因表达和生物学功能，并提供长期的疾病表型临床营救，包括 小梁流出阻力，IOP升高和RGC损失。开发这种基于机械的治疗将 促进未来的动物研究，并为临床试验铺平道路，并提高对 TM内的分子OAG疾病机制。创新：我们的新治疗策略将有选择地 修改TM基因表达。我们将创建专门针对TM细胞的专门定制的新AAV CAPSID矢量，以及 通过将临床结果度量与TM转录组的变化相关联，评估治疗效果 独特的翻译前进。我们的创新包括我们的小说，成熟的跨学科合作 在成功执行眼基因疗法的转化研究方面拥有良好的记录。