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

Nature Biotechnology volume 28, pages 7982 (2010) | Download Citation



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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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


  1. Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Aravind Asokan
    • , Julia C Conway
    • , Jana L Phillips
    • , Chengwen Li
    • , Rebecca Sinnott
    • , Swati Yadav
    • , Nina DiPrimio
    •  & R Jude Samulski
  2. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Aravind Asokan
  3. Macromolecular Structure Group, University of Florida, Gainesville, Florida, USA.

    • Hyun-Joo Nam
    •  & Mavis Agbandje-McKenna
  4. Mirus BioCorporation, Madison, Wisconsin, USA.

    • Julia Hegge
    •  & Jon Wolff
  5. Asklepios Biopharmaceutical, Inc., Chapel Hill, North Carolina, USA.

    • Scott McPhee


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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.

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.

Corresponding author

Correspondence to Aravind Asokan.

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