Species-specific AAVR dominates species-tropism of adeno-associated virus (AAV) vectors.

The variation in AAV vector mediated transduction between species makes it difficult to predict and translate from preclinical animal studies to clinical trials. We previously demonstrated that a 265G insertion (AAV-AM) into the AAV-LK03 primate selective capsid allows robust transduction between species. Here we demonstrate that the capsid species specificity cannot be complemented in trans and hence the transduction properties are cis mediated. We found that the 265G is in a surface-exposed region of AAV virion, facilitating its accessibility for binding to the universal AAVR receptor. We further demonstrated that human AAVR (hAAVR) supplementation rescued the low murine transduction of AAV-LK03 in vitro and in vivo. Sequence swap experiments demonstrated the four amino acid variation of mouse vs human PKD2 domain was important for the varied species tropism of AAV-LK03, with I426V having the greatest effect. Our findings imply that transduction efficiencies between various AAV capsids are substantially influenced by sequence variation in the AAVR protein observed between species. This may facilitate better approaches for translating preclinical to clinical application of AAV-based gene therapeutics.