AAVmyo3 Serotype

Characteristics

AAVS10 was isolated by in vivo cycling of shuffled AAV1/6/8/9 libraries in mouse quadriceps, diaphragm and heart, but was less efficient than AAVMYO. Inserting P1 in variable region VIII (G585-L594 in the modeled VP3 monomer) raised mRNA barcode counts in muscle above those of AAVS10, to within twofold of AAVMYO, with barcodes nearly absent in liver and brain (CMV-eyfp, C57BL/6J and NMRI mice). With SPc5-12-driven luciferase (1e11 vg, CB17 mice), expression was two to three logs higher in skeletal muscles than from the AAV9 vector with the DES promoter, and undetectable in liver.

Applications: Intravenous gene delivery to skeletal muscle, diaphragm and heart in mice. In Mtm1-KO mice (X-linked myotubular myopathy), MTM1 vectors at 4e12, 2e13 and 1e14 vg/kg rescued survival of all treated animals. In mdx mice, micro-dystrophin expression in quadriceps exceeded AAV9 at 2e11 to 2e12 vg per mouse with MCKE or CMV promoters.

Limitations: Tested in mice only; the cellular receptor is unknown. In mdx mice, improvements in hanging time and grip strength over AAV9 were trends without statistical significance. In Mtm1-KO mice, 1e14 vg/kg did not normalize TA fiber size and cardiac fibrotic lesions appeared at high doses. Replacing P1 with peptide P4 in AAVS10 shifted vector toward liver with much lower muscle activity.

References

1. El Andari et al. (2022). Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. Sci Adv - El Andari 2022 AAVMYO2 AAVMYO3