Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle


Reengineering the receptor footprints of adeno-associated virus (AAV) isolates may yield variants with improved properties for clinical applications. We generated a panel of synthetic AAV2 vectors by replacing a hexapeptide sequence in a previously identified heparan sulfate receptor footprint with corresponding residues from other AAV strains. This approach yielded several chimeric capsids displaying systemic tropism after intravenous administration in mice. Of particular interest, an AAV2/AAV8 chimera designated AAV2i8 displayed an altered antigenic profile, readily traversed the blood vasculature, and selectively transduced cardiac and whole-body skeletal muscle tissues with high efficiency. Unlike other AAV serotypes, which are preferentially sequestered in the liver, AAV2i8 showed markedly reduced hepatic tropism. These features of AAV2i8 suggest that it is well suited to translational studies in gene therapy of musculoskeletal disorders.

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Figure 1: Structure-function correlates of AAV2i vectors with reengineered receptor footprints.
Figure 2: Selective muscle tropism of AAV2i8.
Figure 3: Blood transport profile of AAV2i8.

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We would like to thank the American Heart Association (A.A.; no. 0735637N); National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.A. & R.J.S.; R21AR055712); National Institute of Allergy and Infectious Diseases (R.J.S. and A.A.; R01AI072176); National Heart, Lung, and Blood Institute (A.A.; R01HL089221); Senator Paul Wellstone Center for Muscular Dystrophy (R.J.S.; U54AR056953); National Institute of General Medical Sciences (M.A.-M.; R01GM082946); and Asklepios Biopharmaceutical for research support. We would also like to MirusBio Corp. for assistance with isolated limb perfusion studies.

Author information

A.A. conceived the strategy, designed the project and analyzed data. A.A., S.M. and R.J.S. supervised the project and prepared the manuscript. J.C.C. and R.S. built capsid mutants, J.L.P. and C.L. carried out animal experiments, and J.H., S.M. and J.W. designed and carried out isolated limb perfusion studies. S.Y. carried out Q-PCR studies and N.D., H.-J.N. and M.A.-M. carried out molecular modeling studies.

Correspondence to Aravind Asokan.

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Competing interests

R.J.S. is the scientific founder and CEO of Asklepios Biopharmaceutical, Inc. J.W. is the scientific founder and CEO of Mirus BioCorporation. A.A. and R.J.S. are inventors on patents arising from this work.

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Asokan, A., Conway, J., Phillips, J. et al. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol 28, 79–82 (2010).

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