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

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.PROJECT NARRATIVEAge-Related Macular Degeneration (AMD) is the leading and growing cause of irreversible blindness in the United States and the developed world, resulting in tremendous social and economic impact for patients and society. ONL Therapeutics, Inc. is dedicated to developing innovative therapies that will prevent outer retinal cell death and improve visual outcomes for patients with retinal disease, and our treatments exhibited strong evidence of their potential utility in treating atrophic (dry) AMD, for which no approved therapies exist. The successful extension of our inhibitors to the treatment of dry AMD will have a large and positive impact on the life-quality of millions of patients every year.