Vector mediated anti-vascular and anti-inflammatory therapy for AMD

Abstract Bedrock Therapeutics, Inc., is developing a method of controlling the inflammatory, vascular, and immunologic response in neovascular age-related macular degeneration (nAMD). nAMD is the leading cause of blindness in people over 50 years of age. Intravitreal (IVT) injection of anti-vascular therapy has been successfully used in the past decade to reduce and delay the onset of blindness in patients, however, regular monitoring and repeat monthly treatment are required. Even with this therapy, substantial visual decline due to macular atrophy occurs in nearly half the patients. Further, risks of repeated IVT injections can be severe, including endophthalmitis, and prolonged anti-vascular use may increase the risk of systemic adverse events in patients with diabetes, such as thromboembolism. Finally, up to one-third of nAMD patients treated with anti-vascular treatments, such as aflibercept, continue to have active retinal exudation. Therefore, a significant unmet need exists for effective and practical treatment for nAMD. Bedrock has developed a potent HLA-G- derived therapeutic strategy using AAV gene delivery that is both safe and effective for treating various ocular diseases caused by inflammation and/or neovascularization. This strategy combines two of our licensed products, a novel neutralizing antibody evasive capsid derived from human tissue, AAVLP2-10, and our single-chain ImmunoModulating transgene (scIM). scIM proteins are secreted and overcome the rate limiting steps for anti-vascular and immunomodulatory activities of Human Leukocyte Antigen G (HLA-G), which are natural proteins that induce ocular immune privilege and also act to prevent maternal rejection of the developing fetus. Our innovative optimized gene therapy for the treatment of vascularization and inflammation of nAMD will rely on the combination of our human tropic AAV capsid and our novel engineered, HLA-G-based, scIM transgene (collectively termed BDRK-501). This therapeutic shows great promise in solving the unmet need for a safe and effective single-dose drug for nAMD and other back-of-the-eye diseases, such as diabetic macular edema. Bedrock Therapeutics proposes in this Phase I application to produce BDRK-501, establish BDRK-501 potency assays (Aim 1), and determine the efficacy of BDRK-501 in a well- described model of nAMD, the rat laser-induced choroidal neovascularization (CNV) model (Aim 2).