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: 10442821
• 负责人: Andras Komaromy
• 金额: $ 67.55万
• 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/10442821
• 关键词: Abbreviations; Address; Adherence; Anabolism; Animal Model; Animals; Anterior; Aqueous Humor; Axenfeld-Rieger syndrome; Blindness; Canis familiaris; 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; Eyedrops; Failure; Functional disorder; Future; Gene Transduction Agent; Genes; Glaucoma; Health; Homeobox; Human; Hydrophthalmos; Inherited; Injections; Intervention; Laboratories; Lasers; Life; 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; PTGS2 gene; Painless; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase I/II Clinical Trial; Phenotype; Physiologic Intraocular Pressure; Pituitary Gland; Production; Prostaglandin Receptor; 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; base; canine model; clinical translation; clinically relevant; clinically translatable; 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; overtreatment; 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.

摘要 C 开角型青光眼和先天性青光眼引起的持续性高眼压 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。同时， 使用药物和手术相结合的方法来降低眼压 众所周知，这种策略可以有效地防止青光眼的进展，其治疗效果至关重要。 由于患者依从性差，只有不到25%的患者维持治疗超过一次- 一年期间。由于依从性差，需要维持终身的每日治疗方案， 青光眼患者经常出现一阵阵失控的高眼压，并急剧增加 即使在早期诊断时，也有发生严重威胁视力的并发症的风险。作为一名 因此，显然需要开发一种长效疗法，在不影响眼压的情况下降低眼压 需要每天的干预。在这里，我们建议可以永久和安全地降低眼压 旨在改变角膜细胞和房水流出通路(Ahop)的基因治疗策略 合成和分泌临床上已知的有效降低眼压的药物前列腺素F2α(PgF2α) 在OAG患者中，每天作为眼药水使用。我们提供了稳健的初步数据来证明 角膜和AHOP细胞可以通过腔内注射重组人 腺相关病毒(RAAV)载体、前列腺素F合成酶(Ptgs2)和 前列腺素F受体催化前列腺素F_2α的从头合成和分泌 幽默，这会导致高度显著的、剂量依赖的眼压下降，并持续超过 在血压正常的动物中为12个月。在这种多PI应用中，我们将评估其可行性、安全性和 我们新的基因治疗方法对先天性Pitx2+/-小鼠模型的长期疗效 青光眼(AIM 1)和OAG的ADAMTS10比格犬模型(AIM 2)。展示出有能力 青光眼的永久性低眼压将代表着临床治疗的范式转变 通过消除遵守每日治疗方案的需要和从以下方面产生的数据来预防青光眼 这项工作预计将支持临床翻译和鼓励研究人员领导的临床试验。这个 威斯康星医学院眼科基因治疗实验室，丹尼尔博士指导 利平斯基(联系PI/PD)和安德烈·S·科马罗米博士(PI/PD)在兽医学院的实验室 密歇根州立大学(MSU)的医学院提供了完成学业的完美环境 求婚。最后，我们的建议满足了NEI出版物《愿景》中确定的一个新需求 研究：需要、差距和机会“具体如下：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 并预测新治疗方法的安全性和有效性。