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92 reviewsSUMMARYEfficient gene delivery vectors are crucial for respiratory and lung disease therapies. We report that AAV.CPP.16, an engineered adeno-associated virus (AAV) variant derived from AAV9, efficiently transducesairway and lung cells in mice and non-human primates via intranasal administration. AAV.CPP.16 outperforms AAV6 and AAV9, two wild-type AAVs with demonstrated tropism for respiratory tissues, and efficientlytargets key respiratory cell types. It supports gene supplementation and editing therapies in two clinicallyrelevant mouse models of respiratory and lung diseases. A single intranasal dose of AAV.CPP.16 expressinga dual-target, vascular endothelial growth factor (VEGF)/transforming growth factor (TGF)-β1-neutralizingprotein protected lungs from idiopathic pulmonary fibrosis, while a similar application of AAV.CPP.16 carrying an ‘‘all-in-one’’ CRISPR-Cas13d system inhibited transcription of the SARS-CoV-2-derived RNAdependent RNA polymerase (Rdrp) gene. Our findings highlight AAV.CPP.16 as a promising vector for respiratory and lung gene therapy.
