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