Development of an IOP-lowering gene therapy treatment for glaucoma

开发治疗青光眼的降低眼压的基因疗法

• 批准号: 10630351
• 负责人: Andras Komaromy
• 金额: $ 63.84万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630351
• 关键词: Abbreviations; Address; Adherence; Anabolism; Animal Model; Animals; Anterior; Aqueous Humor; Axenfeld-Rieger syndrome; Blindness; Canis familiaris; Cell Reprogramming; Cells; Cessation of life; Clinic; Clinical; Clinical Management; Clinical Trials; Complex; Cornea; Data; Defect; Development; Dinoprost; Disease; Disease Progression; Disintegrins; Dose; Drainage procedure; Early Diagnosis; Electrophysiology (science); Electroretinography; Ensure; Environment; Eye; Eye diseases; Eyedrops; Failure; Functional disorder; Future; Gene Transduction Agent; Genes; Glaucoma; Health; Heterozygote; Homeobox; Human; Hydrophthalmos; Inherited; Injections; Intervention; Laboratories; Lasers; Mediating; Metalloproteases; Michigan; Modeling; Multimodal Imaging; Mus; Nature; Nerve Degeneration; Nerve Fibers; Neuropathy; Ocular Hypertension; Open-Angle Glaucoma; Operative Surgical Procedures; Ophthalmoscopy; Optic Atrophy; Optic Disk; Optic Nerve; Optical Coherence Tomography; Outcome; Painless; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I/II Clinical Trial; Phenotype; Physiologic Intraocular Pressure; Pituitary Gland; Production; Prostaglandins; Publications; Recombinant adeno-associated virus (rAAV); Research; Research Personnel; Retina; Retinal Diseases; Retinal Ganglion Cells; Risk; Risk Factors; Safety; Scanning; Serotyping; Technology; Testing; Therapeutic; Therapeutic Intervention; Thrombospondins; Tissues; Topical application; Trabecular meshwork structure; Translations; Treatment Efficacy; Treatment Protocols; Universities; Veterinary Medicine; Vision; Vision research; Visual Fields; Wisconsin; Work; adeno-associated viral vector; analog; anterior chamber; canine model; clinical translation; clinically relevant; college; compliance behavior; design; gene therapy; genetic architecture; human model; medical schools; medication compliance; minimally invasive; mouse model; nerve damage; normotensive; novel; optic nerve disorder; pharmacologic; prevent; receptor; targeted treatment; therapeutic effectiveness; therapy design; transgene expression; translational barrier

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.

抽象的 c 开角型青光眼（OAG）和先天性青光眼导致持续高眼压的原因 视神经变性和视网膜神经节细胞死亡，导致不可逆的视力丧失。虽然 结合药物和手术方法降低眼内压（IOP） 已知可以有效预防青光眼进展，这种策略的治疗效果至关重要 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。由于依从性差且需要维持终生每日治疗方案， 青光眼患者经常患有无法控制的高眼压症，这种情况会急剧增加 即使早期诊断，也有发生严重危及视力的并发症的风险。作为一个 因此，显然需要开发一种长效疗法，可以在不影响眼压的情况下降低眼压。 需要日常干预。在此，我们建议使用以下方法可以永久、安全地降低眼压： 旨在改变角膜细胞和房水流出途径（AHOP）的基因治疗策略 合成和分泌前列腺素 F2α (PGF2α)，这是一种临床上已知能有效降低眼压的药物 对于 OAG 患者，每天以滴眼剂形式给药。我们提供了强有力的初步数据证明 使用前房内注射重组体可以有效地靶向角膜和 AHOP 细胞 腺相关病毒（rAAV）载体，表达前列腺素F合酶（PTGS2）和 前列腺素 F 受体 (PTGFR) 催化 PGF2α 从头生物合成并分泌到房水中 幽默，这会导致眼压出现非常显着的、剂量依赖性的降低，这种降低可以维持超过 血压正常的动物为 12 个月。在这个多PI应用中，我们将评估可行性、安全性和 我们的新型基因疗法在先天性 Pitx2+/- 小鼠模型中的长期治疗效果 青光眼（目标 1）和 OAG 的 ADAMTS10 小猎犬模型（目标 2）。展示能力 青光眼眼永久降低眼压将代表临床管理的范式转变 通过消除遵守每日治疗方案的需要以及产生的数据来治疗青光眼 这项工作预计将支持临床转化和研究者主导的临床试验的发起。这 威斯康星医学院 (MCW) 眼部基因治疗实验室，由 Daniel 博士指导 Lipinski（联系 PI/PD）和兽医学院 András Komáromy 博士（PI/PD）实验室 密歇根州立大学 (MSU) 的医学专业为完成医学课程提供了完美的环境 提议。最后，我们的提案解决了 NEI 出版物“Vision 研究：需求、差距和机遇”具体而言：1) 定义青光眼的遗传结构，以 提供直接的潜在治疗目标； 2）开发更接近人类的动物模型 青光眼并预测新疗法的安全性和有效性。