Abstract
Advances in adeno-associated virus (AAV) engineering have provided exciting new tools for research and potential solutions for gene therapy. However, the lung has not received the same tailored engineering as other major targets of debilitating genetic disorders. To address this, here we engineered the surface-exposed residues AA452-458 of AAV9 capsid proteins at the three-fold axis of symmetry and employed a Cre-transgenic-based screening platform to identify AAV capsids targeted to the lung after intravenous delivery in mice. Using a custom image processing pipeline to quantify transgene expression across whole tissue images, we found that one engineered variant, AAV9.452sub.LUNG1, displays dramatically improved transgene expression in lung tissue after systemic delivery in mice. This improved transduction extends to alveolar epithelial type II cells, expanding the toolbox for gene therapy research for diseases specific to the lung.