Development of AAV-AXN-007 gene therapy to treat glaucoma.

开发 AAV-AXN-007 基因疗法来治疗青光眼。

• 批准号: 10547231
• 负责人: Shane Hegarty
• 金额: $ 29.88万
• 依托单位: AXONIS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547231
• 关键词: Academic Medical Centers; Action Potentials; Address; Adult; Age; Agreement; Animal Model; Attenuated; Autopsy; Axon; Blindness; Boston; Brain; CRISPR screen; CRISPR/Cas technology; Cell Death; Cell Line; Cells; Chronic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Conserved Sequence; Contralateral; Crush Injury; Development; Disease; Down-Regulation; Drug Kinetics; Eye; Family; Foundations; Gene Deletion; Genes; Genetic Screening; Glaucoma; Goals; Human; In Vitro; Injections; Lead; Legal patent; MAPK8 gene; Measurement; Measures; Mediating; Medical; Medical Care Costs; Microspheres; Mitogen-Activated Protein Kinase Kinases; Modeling; Mus; N-terminal; Nerve; Nerve Crush; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Ophthalmology; Optic Nerve; Optics; Pathologic; Pathology; Pathway interactions; Patients; Pediatric Hospitals; Persons; Pharmacology; Phase; Phosphotransferases; Physiologic Intraocular Pressure; Plasmids; Population; Prevalence; Proteins; Publishing; Rattus; Reflex action; Reporting; Retina; Retinal Diseases; Retinal Ganglion Cells; Risk Factors; Rodent; Saimiri; Saline; Scaffolding Protein; Secure; Signal Transduction; Small Business Innovation Research Grant; Stress; Techniques; Testing; Therapeutic; Time; Tissues; Translations; Virus; Vision; age related neurodegeneration; aged; anterograde transport; axon injury; base; cell type; drug metabolism; effectiveness evaluation; efficacy testing; gene therapy; genetic testing; improved; in vivo; in vivo evaluation; internal control; intravitreal injection; knock-down; lead candidate; medical schools; modifiable risk; nerve damage; neuroblastoma cell; neuroprotection; new therapeutic target; nonhuman primate; novel; optic nerve disorder; pharmacodynamic biomarker; preservation; prevent; professor; prototype; retinal ganglion cell degeneration; small hairpin RNA; socioeconomics; standard of care; stress kinase; success; therapeutic gene; vector; vector control

Development of AAV-AXN-007 gene therapy to treat Glaucoma Abstract: Glaucoma represents the world’s leading cause of irreversible blindness, with its prevalence increasing as the population ages. Vision loss in glaucoma is caused by a progressive degeneration of retinal ganglion cells (RGCs), yet there are no approved therapies that can directly prevent RGC loss. Because elevated intraocular pressure (IOP) is only known modifiable risk factor, current standard of care involves IOP-lowering treatments via pharmacological and surgical approaches. This chronic, progressive, age-related neurodegenerative disorder is an urgent, unmet, global and growing problem, with the number of people worldwide suffering with glaucoma expected to double to ~120 million by 2040, and the annual medical costs of glaucoma in US projected treble to >$17 billion by 2050. To address this escalating medical and socioeconomic burden, and to improve lives of glaucoma patients and their families, novel disease-modifying therapies are needed. Progressive RGC degeneration in glaucoma is thought to result from an intrinsic sensitivity of RGCs that over time succumb to the chronic pathological stresses of this complex neurodegenerative disease. Intervening during this time period in the remaining RGCs of glaucoma patients could prevent their degeneration. To identify new therapeutic targets, an unbiased in vivo AAV2-CRISPR/Cas9 screen of >2,000 genes (tested one-by-one) for RGC neuroprotection in the mouse optic nerve crush model was conducted. This forward genetic screen in an animal model of optic neuropathy discovered a neuroprotective hit gene that, when targeted with AAV2-sgRNA, could prevent RGCs from degeneration following axon damage. Additionally, this pathway has been reported to be activated in post-mortem retinal tissue from glaucoma patients and after optic nerve damage. In this SBIR application, our goal is to validate and test a novel neuroprotective target and AAV2-AXN-007 gene therapeutic approach for its ability to protect RGCs, their axons and visual function in the widely-used mouse microbead occlusion model of glaucoma.

AAV-AXN-007基因治疗青光眼的研究进展 摘要： 青光眼是世界上导致不可逆失明的主要原因，其患病率随着年龄的增长而增加。 人口老龄化。青光眼的视力丧失是由视网膜神经节细胞的进行性变性引起的 然而，目前还没有批准的治疗方法可以直接预防RGC损失。因为眼内升高 眼压（IOP）是唯一已知的可改变的风险因素，目前的标准治疗包括降低IOP的治疗 通过药理学和手术方法。这种慢性的，进行性的，与年龄相关的神经退行性疾病 疾病是一个紧迫的、未得到解决的、全球性的和日益严重的问题，全世界有许多人患有 到2040年，青光眼预计将翻一番，达到约1.2亿，美国青光眼的年度医疗费用 预计到2050年将增加两倍至170亿美元。为了解决日益加重的医疗和社会经济负担， 为了改善青光眼患者及其家庭生活，需要新的疾病改善疗法。 青光眼中进行性RGC变性被认为是RGC内在敏感性的结果 随着时间的推移屈服于这种复杂的神经退行性疾病的慢性病理压力。 在这段时间内对青光眼患者剩余的RGC进行干预可以防止其 退化为了鉴定新的治疗靶点，使用无偏的体内AAV 2-CRISPR/Cas9筛选> 2，000 在小鼠视神经挤压模型中进行RGC神经保护的基因（逐个测试）。 在视神经病变的动物模型中，这种正向遗传筛选发现了一种神经保护性命中基因， 当用AAV 2-sgRNA靶向时，可以防止RGCs在轴突损伤后的变性。 此外，据报道，该途径在青光眼的死后视网膜组织中被激活 患者和视神经损伤后。在这个SBIR应用程序中，我们的目标是验证和测试一种新的 神经保护性靶标和AAV 2-AXN-007基因治疗方法，其保护RGC的能力， 广泛使用的小鼠微珠阻塞青光眼模型中的轴突和视觉功能。