Development of an IOP-lowering gene therapy treatment for glaucoma

摘要 C 开角型青光眼持续性高眼压与先天性青光眼 视神经变性和视网膜神经节细胞死亡，导致不可逆转的视力丧失。虽然 使用药物和手术方法的组合降低眼内压（IOP）， 已知有效地预防青光眼进展，这种策略的治疗效果是关键的， 由于患者依从性差，只有不到25%的患者在一年内维持治疗， 年期间。由于依从性差和需要维持终生的每日治疗方案， 青光眼患者经常遭受不受控制的高眼压发作， 发展严重的威胁视力的并发症的风险，即使在早期诊断。作为 因此，显然需要开发一种长效疗法，其降低IOP，而不影响眼压。 需要日常干预。在此，我们提出，可以永久和安全地降低IOP， 基因治疗策略，旨在改变角膜和房水流出途径（AHOP）的细胞 合成和分泌前列腺素F2α（PGF 2 α），这是一种临床上已知可有效降低IOP的药物 在OAG患者中，每日作为滴眼剂给药。我们提出了强有力的初步数据证明， 角膜和AHOP的细胞可以使用前房内注射的重组 腺相关病毒（rAAV）载体，前列腺素F合酶（PTGS 2）表达， 前列腺素F受体（PTGFR）催化PGF 2 α的重新生物合成和分泌到水相中 这导致高度显著的、剂量依赖性的IOP降低， 12-在正常血压的动物中为数月。在本多PI应用中，我们将评估其可行性、安全性和 我们的新型基因治疗在先天性巨噬细胞瘤Pitx 2 +/-小鼠模型中的长期治疗效果 青光眼（Aim 1）和OAG的ADAMTS 10比格犬模型（Aim 2）。展示能力， 青光眼患者的永久性低IOP将代表临床管理的范式转变 通过避免需要坚持每天的治疗方案和数据产生的青光眼 预计这项工作将支持临床翻译和推动由研究人员领导的临床试验。的 威斯康星州医学院眼部基因治疗实验室（MCW），由丹尼尔博士指导 Lipinski（联系PI/PD）和兽医学院的András Komáromy博士实验室（PI/PD） 医学在密歇根州立大学（MSU）提供了完美的环境，以完成 提议最后，我们的建议解决了NEI出版物《愿景》中确定的一个新需求 研究：需求，差距和机会”具体而言：1）定义青光眼的遗传结构， 为治疗提供直接的潜在靶点; 2）开发更接近人类的动物模型 青光眼，并预测新治疗的安全性和有效性。

ABSTRACT c Sustained ocular hypertension in open angle glaucoma (OAG) and congenital glaucoma causes degeneration of the optic nerve and death of retinal ganglion cells, leading to irreversible vision loss. Whilst reducing intra-ocular pressure (IOP) using a combination of pharmacological and surgical approaches is known to effectively prevent glaucoma progression, the therapeutic efficacy of such a strategy is critically undermined by poor patient compliance, with fewer than 25% of patients maintaining treatment over a one- year period. Owing to poor compliance and the need maintain a life-long daily treatment regimen, glaucomatous patients regularly suffer bouts of uncontrolled ocular hypertension that dramatically increase the risk of developing severe sight-threatening complications, even when diagnosed early. As a consequence, there is a clear need to develop a long-acting therapy that lowers IOP without requiring daily intervention. Herein we propose that IOP may be permanently and safely lowered using a gene therapy strategy aimed at modifying cells of the cornea and aqueous humor outflow pathway (AHOP) to synthesize and secrete prostaglandin F2α, (PGF2α), a drug that is known clinically to effectively lower IOP in OAG patients when administered daily as an eye drop. We present robust preliminary data demonstrating that cells of the cornea and AHOP can be effectively targeted using intracameral injection of recombinant adeno-associated virus (rAAV) vector, that expression of prostaglandin F synthase (PTGS2) and prostaglandin F receptor (PTGFR) catalyzes de novo biosynthesis and secretion of PGF2α into the aqueous humor, and that this causes a highly significant, dose-dependent reduction in IOP that is maintained for over 12-months in normotensive animals. In this multi-PI application, we will evaluate the feasibility, safety and long-term therapeutic efficacy of our novel gene therapy treatment in the Pitx2+/- mouse model of congenital glaucoma (Aim 1) and the ADAMTS10 beagle model of OAG (Aim 2). Demonstrating the ability to permanently lower IOP in glaucomatous eyes would represent a paradigm shift in the clinical management of glaucoma by obviating the need for adherence to a daily treatment regimen and the data generated from this work is expected to support clinical translation and the instigation of an investigator led clinical trial. The Ocular Gene Therapy Laboratory of the Medical College of Wisconsin (MCW), directed by Dr Daniel Lipinski (contact PI/PD), and the laboratory of Dr András Komáromy (PI/PD) at the College of Veterinary Medicine at Michigan State University (MSU) provide the perfect environment in which to complete the proposal. Finally, our proposal addresses an emerging need identified in the NEI Publication “Vision Research: Needs, Gaps, and Opportunities” specifically: 1) Define the genetic architecture of glaucoma to provide direct potential targets for therapy; 2) develop animal models that better approximate human glaucoma and predict safety and efficacy of novel treatments.