Therapy development for open-angle glaucomas

开角型青光眼的治疗开发

基本信息

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
项目类别：
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

项目摘要

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.

项目概要开角型青光眼 (OAG) 是一组进行性视神经病变，共同导致青光眼不可逆转的视力丧失。导致其标志性进行性视网膜病变的致病触发机制神经节细胞 (RGC) 死亡尚不清楚，但关键危险因素包括眼内压 (IOP) 升高和遗传倾向。眼压升高是由于房水 (AH) 流出阻力增加所致小梁网（TM），并与致病性细胞外斑块的积累相关。新疗法需要，因为目前的降低眼压治疗并未针对起作用的病理生理机制在 TM 内，进行性视力丧失常常持续存在。我们的长期目标是开发新颖、改进的治疗高压形式 OAG 的机械治疗策略。这个多学科、协作的转化研究将检验以下中心假设：TM 斑块的形成可以通过以下方式预防或停止：选择性修饰TM基因表达。我们将使用腺相关病毒（AAV）作为工具，基于最近在临床试验中取得的成功支持了 AAV 介导的眼部基因治疗的安全性和有效性。我们的目标提供 AAV 介导的基因替代疗法将预防眼压升高的概念证明 OAG 的单基因形式，见于 ADAMTS10 突变的 Weill-Marchesani 综合征 (WMS) 人类患者。具体目标：使用 ADAMTS10-OAG 完善的临床相关犬模型作为测试平台上，我们提出了3个目标：在目标1中，我们将开发新的衣壳突变AAV载体，以更有效地在 TM 中靶向并表达转基因。在目标 2 中，我们将鉴定 OAG 相关的差异表达基因 ADAMTS10 突变体 TM 中，并将其开发为基因治疗的分子生物标志物。在目标 3 中，我们将评估 AAV- 后 ADAMTS10 突变 TM 细胞的基因表达和功能的正常化介导 ADAMTS10 基因替换，并评估它是否可以长期预防增加的小梁流出阻力和眼压。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新型衣壳突变 AAV 可以有效靶向 TM 内的致病机制，使基因表达和生物学功能，并提供疾病表型的长期临床拯救，包括小梁流出阻力、眼压升高和 RGC 损失。开发这种基于机制的疗法将促进未来的动物研究并为临床试验铺平道路，并加深对 TM 内的分子 OAG 疾病机制。创新：我们的新治疗策略将选择性地修改TM基因表达。我们将创建专门针对目标 TM 细胞定制的新 AAV 衣壳载体，以及通过将临床结果指标与 TM 转录组的变化相关联来评估治疗效果独特的翻译进展。我们的创新包括新颖、完善的跨学科协作团队在成功执行眼部基因治疗转化研究方面拥有良好的记录。