A highly mobile adeno-associated virus targeting vascular smooth muscle cells for the treatment of pulmonary arterial hypertension.

In pulmonary arterial hypertension (PAH), a phenotypic switch in pulmonary arterial smooth muscle cells (PASMCs) that is primarily caused by aberrant gene regulatory networks can lead to dysregulated vascular remodelling, heart failure or death. No curative therapies for PAH are currently available, presumably because of a lack of viral vectors specifically targeting PASMCs. Here we show that a highly mobile and PASMC-tropic adeno-associated virus variant developed via directed evolution overcomes physical barriers that inhibit its transfer from bronchial airways to vascular layers, ultimately boosting therapeutic efficacy in murine models of PAH. Intratracheal administration of the adeno-associated virus variant carrying a transgene for fibroblast growth factor 12-a key factor regulating the PASMC phenotype-suppressed pulmonary vascular remodelling, prevented the development of PAH in mice and reversed established PAH in rats. The variant's mobility and enhanced tropism for PASMCs may enable curative treatments for PAH.