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

• 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
• 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

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 与年龄相关的黄斑变性（AMD）是领导者，并且由于衰老的婴儿潮一代，这是一个日益增长的原因 美国不可逆转的视力丧失，与暴露于香烟烟雾密切相关 （CS）和高脂饮食（HFD）。虽然有效治疗可用于新血管AMD，但AREDS II 抗氧化剂维生素是中间干AMD的唯一​​经过验证的治疗方法。不幸的是，aredsii不是 对早期或晚期干性疾病有效，并且在中间AMD中，它只是减慢了先进的发展 疾病。针对干燥AMD的治疗方法将对受苦的人产生巨大影响，并节省数十亿个 每年的医疗保健美元。氧化应激反应的损害，自噬，线粒体功能， 以及未折叠的蛋白质反应以及失调的先天免疫与AMD有关，并且 因此，已被研究为治疗靶标。最终，这些异常导致视网膜死亡 色素上皮（RPE）细胞和感光体（PR），导致永久视力丧失。 FAS介导的细胞 死亡是包括AMD在内的许多视网膜疾病中视网膜外细胞损失的主要机制。没有 预防FAS介导的AMD中视网膜外细胞死亡的疗法，逻辑治疗策略是防止FAS- 介导的信号传导，无论上游损害如何。 Onl Therapeutics，一种眼科生物技术 公司开发创新疗法，以防止视网膜细胞死亡改善视觉效果 患者已经证明了FAS抑制在预防视网膜细胞死亡中的有效性 AMD。此外，在急性和 青光眼的慢性模型，其中载体提供了明显的内部视网膜神经保护。由于 FA在AMD中的作用以及FAS抑制在眼部压力下保护视网膜中的作用，该提议 将检查FAS抑制剂在萎缩AMD的急性和慢性模型中的作用。该项目提出了 在此行政补充中，将生成关键数据，以帮助公司了解最新发现 在一项重复剂量兔安全研究中，并告知即将到来的6个月GLP重复剂量毒理学的设计 研究以使ONL1204在慢性适应症中使用，包括干燥AMD。成功执行 项目将支持FAS抑制剂进行干燥AMD的持续临床前开发，并帮助吸引 公司对公司的额外利益。