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

基本信息

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
项目类别：
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

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

展开

项目摘要

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 持续的眼高血压在开角型青光眼（OAG）和先天性青光眼原因视神经神经节细胞的视神经和死亡的变性，导致视力丧失。在使用药物和外科手术方法组合减少眼内压（IOP）是已知可以有效预防青光眼进展，这种策略的治疗效率至关重要受患者依从性差而破坏，只有不到25％的患者维持治疗年期。由于依从性差，并且需求保持终身治疗方案，青光眼患者经常遭受不受控制的眼高血压的回合，这些高血压急剧增加即使早期被诊断出来，也会出现严重的视力并发症的风险。作为结果，显然需要开发长效疗法，以降低IOP 需要日常干预。在此，我们建议使用iop永久且安全地降低基因治疗策略旨在改变角膜和水性幽默出口通路（AHOP）的细胞合成和分泌前列腺素F2α（PGF2α），该药物在临床上已知可有效降低IOP 在OAG患者中，每天将其作为眼部滴注。我们提供强大的初步数据证明通过腔内注入重组的角膜和AHOP的细胞可以有效地靶向腺相关病毒（RAAV）载体，前列腺素F合酶的表达（PTGS2）和前列腺素F受体（PTGFR）催化从头生物合成和PGF2α分泌到水性幽默，这会导致IOP的高度显着，依赖于剂量的减少正常动物中的12个月。在此多PI应用程序中，我们将评估可行性，安全性和我们的新型基因治疗治疗的长期治疗效率青光眼（AIM 1）和OAG的ADAMTS10 Beagle模型（AIM 2）。证明能力长绿糖型眼睛中永久降低IOP将代表临床管理的范式转移通过消除对每日治疗方案的依从性的需求以及从预计这项工作将支持临床翻译和研究者LED临床试验的启动。威斯康星州医学院（MCW）的眼科基因治疗实验室，由丹尼尔博士执导 Lipinski（联系PI/PD）和兽医学院的AndrásKomáromomy博士（PI/PD）实验室密歇根州立大学（MSU）的医学提供了完美的环境提议。最后，我们的提议解决了NEI出版物“愿景”中确定的新兴需求研究：需要，差距和机会”，具体：1）将青光眼的遗传结构定义为提供治疗的直接潜在目标； 2）开发更好近似人类的动物模型青光眼并预测新型治疗的安全性和效率。