An adeno-associated virus vector efficiently and specifically transduces mouse skeletal muscle

Isao Murakami, Takamasa Takeuchi, Mayuyo Mori-Uchino, Seiichiro Mori, Takuma Fujii, Daisuke Aoki, Keiichi Nakagawa, Tadahito Kanda

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Abstract

Expression of a therapeutic gene in the skeletal muscle is a practical strategy to compensate a patients' insufficient circulating factor. Its clinical application requires a muscle-targeting vector capable of inducing a continuous high-level transgene expression. We modified an adeno-associated virus serotype 2 (AAV2) vector expressing luciferase from the mouse muscle creatine kinase gene promoter-enhancer (Ckm). First, AAVS1 insulator was inserted into the vector genome for transcriptional enhancement. This increased transduction of mouse quadriceps muscle by 11-fold at 4 weeks after intramuscular injection. Second, two capsid modifications were combined (21F capsid): incorporation of a segment of AAV1 capsid to produce a hybrid capsid and substitution of a tyrosine with a phenylalanine. Use of 21F capsid increased muscle transduction further by 18-fold, resulting in 200-fold higher efficacy than that of the unmodified vector. Compared with a vector having human elongation factor 1α promoter which showed similar efficacy in the muscle, this vector having Ckm transduced non-muscle organs less efficiently after intravenous administration. The AAV2 vector composed of the modified genome and capsid provides a backbone to develop a clinical vector expressing a therapeutic gene in the muscle.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalMolecular Biotechnology
Volume49
Issue number1
DOIs
Publication statusPublished - 09-2011

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Biochemistry
  • Applied Microbiology and Biotechnology
  • Molecular Biology

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    Murakami, I., Takeuchi, T., Mori-Uchino, M., Mori, S., Fujii, T., Aoki, D., Nakagawa, K., & Kanda, T. (2011). An adeno-associated virus vector efficiently and specifically transduces mouse skeletal muscle. Molecular Biotechnology, 49(1), 1-10. https://doi.org/10.1007/s12033-010-9369-z