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：
10457555
负责人：
James T Handa
金额：
$ 0.85万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457555
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/antagonist 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.

项目概要/摘要年龄相关性黄斑变性 (AMD) 是主要原因，并且由于婴儿潮一代的老龄化，这一问题日益严重在美国，不可逆转的视力丧失与接触香烟烟雾密切相关（CS）和高脂肪饮食（HFD）。虽然新生血管性 AMD 有有效的治疗方法，但 AREDS II 抗氧化维生素是治疗中度干性 AMD 的唯一经过验证的治疗方法。不幸的是，AREDSII 不是对于早期或晚期的干性疾病有效，对于中期 AMD，它只是减缓进展为晚期疾病。针对干性 AMD 的治疗将对患者产生巨大影响，并节省数十亿美元每年医疗保健美元。氧化应激反应、自噬、线粒体功能受损，未折叠的蛋白质反应以及先天免疫失调与 AMD 有关，并且因此，已将其作为治疗目标进行研究。最终，这些异常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介导的细胞死亡是包括 AMD 在内的许多视网膜疾病中外视网膜细胞损失的主要机制。没有治疗以预防 AMD 中 Fas 介导的外层视网膜细胞死亡，合理的治疗策略是预防 Fas- 介导的信号传递，无论上游损伤如何。 ONL Therapeutics，一种眼科生物技术该公司正在开发预防视网膜细胞死亡的创新疗法，以改善视力结果已在急性模型中证明 Fas 抑制可有效预防视网膜细胞死亡 AMD 的。此外，一种抑制 Fas 信号传导的基因疗法已被开发出来，并在急性和慢性疾病中进行了测试。青光眼的慢性模型，其中载体提供显着的视网膜内神经保护。由于 Fas 在 AMD 中的作用以及 Fas 抑制在眼部应激后保护视网膜的作用，该提案将检查 Fas 抑制剂在急性和慢性萎缩性 AMD 模型中的作用。拟建项目本行政补充文件中将生成关键数据，帮助公司了解最近的发现重复剂量兔子安全性研究，并为即将进行的 6 个月 GLP 重复剂量毒理学设计提供信息使ONL1204能够用于慢性适应症（包括干性AMD）的研究。成功执行该项目将支持干性 AMD 的 Fas 抑制剂的持续临床前开发，并帮助吸引额外的投资者对公司的兴趣。