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 lungdisease. These diseases often begin in early childhood, lead to respiratory failure and earlydeath, and have few targeted therapies. Surfactant protein deficiencies are a group of severeMLDs caused by mutations in the genes encoding for surfactant proteins A, B, C, and D aswell 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 lungtransplantation, SPB is lethal within the first year of life. MLDs are amenable to targeteddelivery of viral vectors via intratracheal administration. Further, as SPB only affects thelungs, targeted delivery of gene therapy to the respiratory tract should be sufficient to treatthis 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 andleads to rapid expression of SPB. Our compelling preliminary data in SPB-conditionalknockout mice (Kang et al., in revision at Nat Commun) shows that AAV6.2FF efficientlytransduces AT2 cells, delivers SPB to the lungs, and dramatically improves lung function andsurvival. 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 avariety of MLDs. We will expand our lung gene therapy platform to achieve the followingobjectives:1.Evaluate safety and transducing efficiency of AAV6.2FF in neonatal lambs2.Extend the therapeutic application of AAV6.2FF to other MLDsBy combining our expertise in viral vectors, lung biology, and stem cells we aim to develop avariety of clinical trial-ready AAV6.2FF vectors that will transform the treatment of MLDs.