Gene therapy to treat glaucoma by reducing intraocular pressure

摘要 在美国，青光眼是导致不可逆失明的主要原因，在270多万人中约有12万人患有青光眼。 青光眼是致盲的。值得注意的是，随着美国的发展，青光眼的患病率预计将显著上升。 人口老龄化，预计到2050年，每年的医疗费用将超过170亿美元。开角型青光眼 (OAG)是一组缓慢进展、潜在致盲的视神经病变，其特征为无症状， 视神经轴突和视网膜神经节细胞的不可逆损失。在美国，OAG是三大领先的 失明的原因和不可逆视力丧失的前两个原因。OAG病理学涉及高眼内 眼压（IOP），已明确显示会增加发展和进展的风险 神经退行性疾病的风险。约占美国人口的7-8% 40岁以上的人眼压升高。值得注意的是，IOP是OAG的唯一可改变的风险因素，并且IOP降低 仍然是该疾病治疗干预的唯一有效靶点。许多已确立的治疗方法 在过去50年中开发的用于青光眼治疗的药物以滴眼液的形式存在。这些需要定期 （通常一天多次）给药，通常由多种药物组成，并且通常 不能解决流出组织中疾病的潜在病理学。频繁给药的必要性 长时间限制了患者的依从性，并可能导致IOP控制不良。因此，需要 新的治疗方法不仅可以抵消或纠正流出组织的病理学， 而且还将患者从输送系统中取出。为了满足这一需求，Advanced Vision Technologies正在开发一种新的基于AAV的基因疗法，用于治疗青光眼性IOP升高。 这种疗法使用敲低SERPINE 1的新策略靶向流出组织，SERPINE 1是一种具有关键作用的基因， 调节流出设施的效果。所提出的基因治疗将改变流出系统的设定点， 使得治疗与青光眼病因无关。在第一阶段项目中，先进视觉技术 试图通过完成以下具体目标来建立这种方法的可行性：1）测试基因 击倒以确定击倒效率高的前导候选者，2）确定击倒是否 SERPINE 1的增加了TGF-β处理的人工常规流出系统中的模拟流出设施 （ACOS），和3）确认在人灌注器官培养系统（HumOCAS）中的效果。成功完成 这些目标的实现将证明这种方法的可行性，并确定基因治疗靶点的准备 第二阶段，重点是开发一种载体，将RNA治疗剂输送到流出组织 并将在相关疾病的动物模型中测试其功效。这些步骤将构成未来的基础 人类临床试验和基因疗法作为OAG治疗的发展。

Abstract In the U.S., glaucoma is the leading cause of irreversible blindness, with ~120,000 of the over 2.7 million people with glaucoma being blind. Notably, the prevalence of glaucoma is expected to climb significantly as the U.S. population ages, with annual medical costs predicted to reach over $17 billion by 2050. Open angle glaucoma (OAG) is a group of slowly progressive, potentially blinding, optic neuropathies characterized by asymptomatic, irreversible loss of optic nerve axons and retinal ganglion cells. In the U.S., OAG is among the three leading causes of blindness and the top two causes of irreversible vision loss. OAG pathology involves high intraocular pressure (IOP), which has been conclusively shown to increase the risk for both development and progression of glaucomatous neurodegeneration once the disease is established. Approximately 7–8% of the U.S. population above 40 have elevated IOP. Notably, IOP is the only modifiable risk factor for the OAG, and IOP lowering remains the only effective target for therapeutic intervention for the disease. Many established therapies developed over the past 50 years for glaucoma treatment exist in the form of eye drops. These require regular (often multiple times a day) administration, are often comprised of multiple agents, and more often than not do not address the underlying pathology of the disease in the outflow tissues. The need for frequent administration over long periods of time limits patient adherence and can result in poor IOP control. Thus, there is a need for new therapies to not only counteract or correct the pathology of the outflow tissues and normalize IOP but to also take the patient out of the delivery system. To address this need, Advanced Vision Technologies is developing a novel AAV-based gene therapy that treats glaucomatous IOP elevation. This therapy targets outflow tissues using a novel strategy of knocking down SERPINE1, a gene with critical effects in regulating outflow facility. The proposed gene therapy will change the set-point of the outflow system, enabling treatment independent of glaucoma etiology. In this Phase I project, Advanced Vision Technologies seeks to establish feasibility of this approach through the completion of the following Specific Aims: 1) Test gene knockdown to determine the lead candidate with high knockdown efficiency, 2) Determine whether knockdown of SERPINE1 increases simulated outflow facility in a TGF-β-treated Artificial Conventional Outflow System (ACOS), and 3) Confirm effects in a human perfused organ culture system (HumOCAS). Successful completion of these aims will demonstrate the feasibility of this approach and confirm the gene therapy target in preparation for Phase II, which will focus on the development of a vector to deliver RNA therapeutics to the outflow tissues and will test its efficacy in relevant animal models of the disease. These steps will form the basis for a future human clinical trial and development of gene therapy as a treatment for OAG.