Clinical advancement of a novel AAV lung gene therapy platform

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Monogenic lung diseases (MLDs) include a variety of disorders that cause chronic lung disease. These diseases often begin in early childhood, lead to respiratory failure and early death, and have few targeted therapies. Surfactant protein deficiencies are a group of severe MLDs caused by mutations in the genes encoding for surfactant proteins A, B, C, and D as well as the ATP-binding cassette sub-family A member 3 (ABCA3). Surfactant protein B (SPB) deficiency is the most severe, leading to respiratory failure after full-term birth. Treatment with exogenous surfactant provides only transient improvement and without lung transplantation, SPB is lethal within the first year of life. MLDs are amenable to targeted delivery of viral vectors via intratracheal administration. Further, as SPB only affects the lungs, targeted delivery of gene therapy to the respiratory tract should be sufficient to treat this disease. We have engineered an innovative viral vector (AAV6.2FF) to treat SPB. AAV6.2FF selectively transduces alveolar type II cells (AT2) cells that produce surfactant and leads to rapid expression of SPB. Our compelling preliminary data in SPB-conditional knockout mice (Kang et al., in revision at Nat Commun) shows that AAV6.2FF efficiently transduces AT2 cells, delivers SPB to the lungs, and dramatically improves lung function and survival. These results demonstrate the promise of AAV6.2FF to treat, and potentially cure, SPB. Our goal is to advance AAV6.2FF gene therapy to clinical trials for the treatment of a variety of MLDs. We will expand our lung gene therapy platform to achieve the following objectives: 1.Evaluate safety and transducing efficiency of AAV6.2FF in neonatal lambs 2.Extend the therapeutic application of AAV6.2FF to other MLDs By combining our expertise in viral vectors, lung biology, and stem cells we aim to develop a variety of clinical trial-ready AAV6.2FF vectors that will transform the treatment of MLDs.