HSV-1 Amplicon Vectors Are an Efficient Gene Transfer System for Skeletal Muscle Cells

Yaming      Wang

Abstract

HSV-1 amplicon vectors have been considered as a promising gene delivery system for gene therapy of skeletal muscle diseases, due to the ability to infect non-dividing cells such as differentiated muscle cells, and to accommodate large transgenes such as the 14-kb dystrophin cDNA. Studies revealed that HSV-1 amplicons can transduce cultured differentiated and undifferentiated muscle cells with high efficiency. Studies also revealed that HSV-1 amplicons are capable of delivering at least 23-kb transgene DNA, including the full-length dystrophin cDNA into muscle cells. The combination of high transduction efficiency, the ability to accommodate large constructs and ease of manipulation makes HSV-1 amplicons an ideal gene delivery tool for the study of muscle ion channels in which gene transduction is frequently employed in cultured muscle cells that are resistant to all the transfecting reagents. However, intramuscular injection of HSV-1 amplicons has been proven inefficient in mature muscles. Evidence has shown that this is mainly because the basal membrane that sheaths each myofibers blocks HSV-1 virions from myofiber cell surface receptors. This result led to the conclusion that HSV-1 amplicons are more suitable for ex vivo manipulation of diseased muscle progenitors or stem cells for autologous cell therapy than in vivo intramuscular injection. Efforts to confer stable transduction ability on amplicons have made progress. A new generation of HSV/AAV hybrid amplicons has been shown to be capable of integrating large transgenes into the AAVS1 site of the human genome, thus, holding potential to achieve a safe and lasting gene transduction in human muscle cells.

Keywords: Gene therapy, cell therapy, muscle gene transfer, myoblast transplantation, full-length dystrophin, HSV/AAV hybrid amplicon, site-specific integration, Cre-LoxP