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Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart

Nature Biotechnology volume 23, pages 321–328 (2005)Cite this article

Abstract

Systemic gene delivery into muscle has been a major challenge for muscular dystrophy gene therapy, with capillary blood vessels posing the principle barrier and limiting vector dissemination. Previous efforts to deliver genes into multiple muscles have relied on isolated vessel perfusion or pharmacological interventions to enforce broad vector distribution. We compared the efficiency of multiple adeno-associated virus (AAV) vectors after a single injection via intraperitoneal or intravenous routes without additional intervention. We show that AAV8 is the most efficient vector for crossing the blood vessel barrier to attain systemic gene transfer in both skeletal and cardiac muscles of mice and hamsters. Serotypes such as AAV1 and AAV6, which demonstrate robust infection in skeletal muscle cells, were less effective in crossing the blood vessel barrier. Gene expression persisted in muscle and heart, but diminished in tissues undergoing rapid cell division, such as neonatal liver. This technology should prove useful for muscle-directed systemic gene therapy.

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Figure 1: Systemic gene delivery to muscle and heart of neonatal mice by different AAV serotypes via i.p. injection.
Figure 2: Systemic gene delivery to muscle of neonatal mice by different AAV serotypes via i.v. injection.
Figure 3: Systemic gene delivery to muscle and heart by intravenous (i.v.) injection in adult mice and hamsters.
Figure 4: Comparison of gene transfer efficiency of AAV serotype vectors by direct i.m. or i.v. injection on hind limbs.
Figure 5: Time course of GFP gene expression and the presence of vector DNA in liver and heart after i.p. injection of AAV8 in neonatal mice.

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Acknowledgements

We thank Michelle Raab for critical reading of the manuscript; Guangping Gao and James Wilson for the AAV7 and 8 packaging plasmid; David W. Russell for the AAV6 packaging plasmid. This work is supported by National Institutes of Health grants NS46546, AR45967 and AR50595 to X.X.

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Author notes

  1. Zhong Wang and Tong Zhu: These two authors contributed equally to this work.

Authors and Affiliations

  1. Dept. of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, 15261, Pennsylvania, USA

    Zhong Wang, Tong Zhu, Chunping Qiao, Liqiao Zhou, Bing Wang, Jian Zhang, Chunlian Chen, Juan Li & Xiao Xiao

  2. Dept. of Orthopedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, 15261, Pennsylvania, USA

    Xiao Xiao

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Supplementary information

Supplementary Fig. 1

Gene expression and vector DNA in testis after i.v. administration of AAV1, AAV6 and AAV8 in adult mice. (PDF 191 kb)

Supplementary Fig. 2

Comparison of AAV2 and AAV8 in adult hamsters for systemic gene delivery. (PDF 351 kb)

Supplementary Fig. 3

High efficiency δ-sarcoglycan (δ-SG) gene transfer and profound improvement in histophathology of heart and muscle of TO-2 hamsters. (PDF 105 kb)

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Wang, Z., Zhu, T., Qiao, C. et al. Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat Biotechnol 23, 321–328 (2005). https://doi.org/10.1038/nbt1073

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