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

项目总结/摘要 视网膜相关性黄斑变性（AMD）是主要的，并且由于婴儿潮一代的老龄化， 在美国，不可逆转的视力丧失与吸烟密切相关。 (CS)高脂饮食（High Fat Diets，HFD）虽然有效的治疗可用于新生血管性AMD， 抗氧化维生素是治疗中度干性AMD的唯一有效方法。不幸的是，AREDSII不是 对早期或晚期干性疾病有效，在中期AMD中，它仅减缓进展到晚期 疾病针对干性AMD的治疗将对受折磨的个体产生巨大影响，并节省数十亿美元。 每年的医疗费用。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， 因此，已经作为治疗目标进行了研究。最终，这些异常会导致视网膜坏死。 色素上皮（RPE）细胞和光感受器（PR），导致永久性视力丧失。Fas介导细胞 死亡是包括AMD在内的许多视网膜疾病中外部视网膜细胞损失的主要机制。没有 为了预防AMD中Fas介导的外视网膜细胞死亡，合理的治疗策略是预防Fas- 介导的信号传导，无论上游损伤如何。ONL Therapeutics，眼科生物技术 公司开发创新疗法，防止视网膜细胞死亡，以改善视力结果， 已经证明了Fas抑制剂在急性模型中预防视网膜细胞死亡的有效性 关于AMD此外，已经开发了抑制Fas信号传导的基因疗法，并在急性和慢性炎症中进行了测试。 慢性青光眼模型，其中所述载体提供显著的内部视网膜神经保护。由于 Fas在AMD中的作用以及抑制Fas对眼应激后视网膜的保护作用， 将检查Fas抑制剂在萎缩性AMD的急性和慢性模型中的作用。该项目提议 将生成关键数据，帮助公司了解最近的调查结果 在重复给药家兔安全性研究中，并为即将进行的6个月GLP重复给药毒理学设计提供信息 研究，以使ONL 1204能够用于慢性适应症，包括干性AMD。成功执行 该项目将支持Fas抑制剂治疗干性AMD的持续临床前开发，并有助于吸引 投资者对公司的兴趣。

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.