Development of AAV-AXN-007 gene therapy to treat glaucoma abstract: glaucoma represents the world's leading cause of irreversible blindness, with its prevalence increasing as the population ages

Vision loss in glaucoma is caused by a progressive degeneration of retinal ganglion cells (RGCS), yet there are no approved therapies that can directly prevent RGC loss. Because elevated intraocular pressure (IOP) is only known modifiable risk factor, current standard of care involves IOP-lowering treatments via pharmacological and surgical approaches. This chronic, progressive, age-related neurodegenerative disorder is an urgent, unmet, global and growing problem, with the number of people worldwide suffering with glaucoma expected to double to ~120 million by 2040, and the annual medical costs of glaucoma in US projected treble to >$17 billion by 2050. To address this escalating medical and socioeconomic burden, and to improve lives of glaucoma patients and their families, novel disease-modifying therapies are needed. Progressive RGC degeneration in glaucoma is thought to result from an intrinsic sensitivity of RGCS that over time succumb to the chronic pathological stresses of this complex neurodegenerative disease. Intervening during this time period in the remaining RGCS of glaucoma patients could prevent their degeneration. To identify new therapeutic targets, an unbiased in vivo AAV2-crispr/CAS9 screen of >2,000 genes (tested one-by-one) for RGC neuroprotection in the mouse optic nerve crush model was conducted. This forward genetic screen in an animal model of optic neuropathy discovered a neuroprotective HIT gene that, when targeted with AAV2-sgrna, could prevent RGCS from degeneration following axon damage. Additionally, this pathway has been reported to be activated in post-mortem retinal tissue from glaucoma patients and after optic nerve damage. In this sbir application, our goal is to validate and test a novel neuroprotective target and AAV2-AXN-007 gene therapeutic approach for its ability to protect RGCS, their axons and visual function in the widely-used mouse microbead occlusion model of glaucoma.