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Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD

治疗性抑制干性 AMD 中 Fas 介导的视网膜细胞死亡和炎症

基本信息

批准号：
10523617
负责人：
James T Handa
金额：
$ 12万
依托单位：
ONL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10523617
关键词：
Acute Administrative Supplement Age related macular degeneration Aging Antioxidants Atrophic Autophagocytosis Biotechnology Blindness Cause of Death Cell Death Cells Chronic Data Disease Dose Effectiveness Exhibits Exudative age-related macular degeneration Glaucoma Healthcare High Fat Diet Impairment Individual Inflammation Innovative Therapy Mediating Mitochondria Modeling Natural Immunity Nonexudative age-related macular degeneration Oryctolagus cuniculus Oxidative Stress Patient-Focused Outcomes Patients Photoreceptors Proteins Quality of life Retina Retinal Diseases Role Signal Transduction Social Impacts Societies Stress Structure of retinal pigment epithelium Testing Therapeutic Toxicology United States Visual Vitamins advanced disease baby boomer biological adaptation to stress design economic impact effective therapy exposure to cigarette smoke gene therapy improved inhibitor interest neuroprotection preclinical development prevent response safety study treatment strategy vector

项目摘要

PROJECT SUMMARY / ABSTRACT Age-related macular degeneration (AMD) is the leading, and due to the aging baby boomers, a growing cause of irreversible vision loss in the United States, and is strongly associated with exposure to cigarette smoke (CS) and high fat diets (HFD). While effective treatment is available for neovascular AMD, the AREDS II antioxidant vitamins are the only proven treatment for intermediate dry AMD. Unfortunately, AREDSII is not effective for early or late dry disease, and in intermediate AMD, it merely slows the progression to advanced disease. Treatments that target dry AMD will have a huge impact on the afflicted individual and save billions of health care dollars per year. Impairment of the oxidative stress response, autophagy, mitochondrial function, and the unfolded protein response, as well as dysregulated innate immunity have been implicated in AMD, and thus, have been investigated as treatment targets. Ultimately, these abnormalities cause death of retinal pigment epithelial (RPE) cells and photoreceptors (PR), leading to permanent vision loss. Fas-mediated cell death is the major mechanism of outer retinal cell loss in many retinal diseases including AMD. With no therapy to prevent Fas-mediated outer retinal cell death in AMD, a logical treatment strategy is to prevent Fas- mediated signaling, irrespective of the upstream impairment. ONL Therapeutics, an ophthalmic biotechnology company developing innovative therapies that prevent retinal cell death to improve visual outcomes for patients, has demonstrated the effectiveness of Fas inhibition in preventing retinal cell death in an acute model of AMD. Additionally, a gene therapy that inhibits Fas signaling has been developed and tested in acute and chronic models of glaucoma, wherein the vector provided significant inner retinal neuroprotection. Due to the role of Fas in AMD and the effect of Fas inhibition in protecting the retina following ocular stress, this proposal will examine the effect of the Fas inhibitors in acute and chronic models of atrophic AMD. The project proposed in this Administrative Supplement will generate key data that will help the company understand recent findings in a repeat dose rabbit safety study and inform the design of upcoming 6-month GLP repeat dose toxicology studies to enable the use of ONL1204 in chronic indications, including dry AMD. Successful execution of the project will support the continued pre-clinical development of the Fas inhibitors for dry AMD and help attract additional investor interest in the company.

项目摘要/摘要年龄相关性黄斑变性(AMD)是主要的，由于婴儿潮一代的老龄化，一个日益增长的原因在美国，不可逆转的视力丧失，与暴露在香烟烟雾中密切相关 (CS)和高脂饮食(HFD)。虽然对新生血管性AMD有有效的治疗方法，但AREDS II 抗氧化剂维生素是唯一被证实的治疗中度干性AMD的方法。不幸的是，AREDSII并非如此对早期或晚期的干性疾病有效，而对于中期的AMD，它只会减缓进展到晚期疾病。针对干性AMD的治疗将对患者产生巨大影响，并挽救数十亿美元每年的医疗保健费用。氧化应激反应、自噬、线粒体功能受损，而未折叠的蛋白质反应以及调节失调的先天免疫与AMD有关，以及因此，已被研究为治疗的靶点。最终，这些异常会导致视网膜死亡。色素上皮(RPE)细胞和光感受器(PR)，导致永久性视力丧失。Fas介导的细胞在包括AMD在内的许多视网膜疾病中，死亡是视网膜外层细胞丢失的主要机制。没有预防Fas介导的AMD视网膜外细胞死亡的治疗，合理的治疗策略是预防Fas- 介导的信号传递，而不考虑上游的损害。眼科生物技术--ONL治疗该公司正在开发创新的疗法，以防止视网膜细胞死亡，以改善患者的视力结果已经证明了抑制Fas在急性模型中预防视网膜细胞死亡的有效性 AMD的。此外，一种抑制Fas信号转导的基因疗法已经开发出来，并在急性和慢性疾病中进行了测试。慢性青光眼模型，其中该载体提供了显著的视网膜内神经保护。由于 Fas在AMD中的作用以及抑制Fas在眼压后保护视网膜中的作用将检查Fas抑制剂在急性和慢性萎缩性AMD模型中的作用。建议的项目将生成有助于公司了解最新调查结果的关键数据在一项重复剂量的兔安全性研究中，并为即将到来的6个月GLP重复剂量毒理学设计提供信息能够将ONL1204用于包括干性AMD在内的慢性适应症的研究。成功执行了该项目将支持干性AMD的Fas抑制剂的持续临床前开发，并帮助吸引投资者对该公司的额外兴趣。