Interrogating the dependency of AAV capsids on AAVR for retinal transduction.

Adeno-associated virus (AAV) is an established vector for gene therapy, yet there remains much that we do not know regarding mechanisms of transduction in target tissues. The retina is an attractive organ for gene therapy with many programs in development. Thus, further research into the mechanisms of retinal transduction could lead to more effective therapies. Since the AAV receptor (AAVR) (KIAA0319L) has been shown to play a critical role in AAV transduction, we intravitreally injected (IVtI) or subretinally injected (SRI) recombinant AAV vectors packaged in a diverse group of AAV capsids into AAVR+/- or AAVR-/- mice and evaluated transduction. We demonstrate that IVtI injected AAVs are completely reliant on AAVR, while SRI injected AAVs such as AAV6, AAV8, AAV9, and AAV5 have partial to near-complete independence from AAVR at higher doses. Interestingly, while SRI AAV2 shows near-complete dependence, deletion of the heparin sulfate-binding residues on the capsid imparts the ability to transduce the outer retina independent of AAVR. Our results demonstrate that reliance on AAVR for transduction is both capsid and cell type specific in the retina and suggest that further examination of the role of AAVR in a capsid-specific manner in other tissues may prove vital to clinical translation.