Abstract In the U.S., glaucoma is the leading cause of irreversible blindness, with ~120,000 of the over 2.7 million people with glaucoma being blind. Notably, the prevalence of glaucoma is expected to climb significantly as the U.S. population ages, with annual medical costs predicted to reach over $17 billion by 2050. Open angle glaucoma (OAG) is a group of slowly progressive, potentially blinding, optic neuropathies characterized by asymptomatic, irreversible loss of optic nerve axons and retinal ganglion cells. In the U.S., OAG is among the three leading causes of blindness and the top two causes of irreversible vision loss. OAG pathology involves high intraocular pressure (IOP), which has been conclusively shown to increase the risk for both development and progression of glaucomatous neurodegeneration once the disease is established. Approximately 7–8% of the U.S. population above 40 have elevated IOP. Notably, IOP is the only modifiable risk factor for the OAG, and IOP lowering remains the only effective target for therapeutic intervention for the disease. Many established therapies developed over the past 50 years for glaucoma treatment exist in the form of eye drops. These require regular (often multiple times a day) administration, are often comprised of multiple agents, and more often than not do not address the underlying pathology of the disease in the outflow tissues. The need for frequent administration over long periods of time limits patient adherence and can result in poor IOP control. Thus, there is a need for new therapies to not only counteract or correct the pathology of the outflow tissues and normalize IOP but to also take the patient out of the delivery system. To address this need, Advanced Vision Technologies is developing a novel AAV-based gene therapy that treats glaucomatous IOP elevation. This therapy targets outflow tissues using a novel strategy of knocking down SERPINE1, a gene with critical effects in regulating outflow facility. The proposed gene therapy will change the set-point of the outflow system, enabling treatment independent of glaucoma etiology. In this Phase I project, Advanced Vision Technologies seeks to establish feasibility of this approach through the completion of the following Specific Aims: 1) Test gene knockdown to determine the lead candidate with high knockdown efficiency, 2) Determine whether knockdown of SERPINE1 increases simulated outflow facility in a TGF-β-treated Artificial Conventional Outflow System (ACOS), and 3) Confirm effects in a human perfused organ culture system (HumOCAS). Successful completion of these aims will demonstrate the feasibility of this approach and confirm the gene therapy target in preparation for Phase II, which will focus on the development of a vector to deliver RNA therapeutics to the outflow tissues and will test its efficacy in relevant animal models of the disease. These steps will form the basis for a future human clinical trial and development of gene therapy as a treatment for OAG.

Narrative – Open angle glaucoma (OAG) is the most common form of glaucoma and one of the leading causes of blindness and irreversible vision loss in the U.S. The disease pathology involves high intraocular pressure (IOP), which has been conclusively shown to increase the risk for both development and progression of glaucomatous neurodegeneration once the disease is established. Advanced Vision Technologies is developing a novel gene therapy that treats glaucomatous IOP elevation in order to provide an effective treatment option for OAG that will enable treatment independent of the underlying etiology of disease.