Gene transfer to muscle.

In humans the skeletal musculature can constitute over 50% of the body mass, and a range of anatomical, physiological and cellular features makes this tissue an attractive candidate for gene transfer procedures designed to augment normal gene function, express heterologous therapeutic products or immunize the host organism. Under normal conditions, skeletal myofibres are stable post-mitotic cells with good vascularity and, if necessary, high regenerative capacity. Tissues are easily accessible for administration of genetic vehicles and, if necessary, for removal of treated areas. In addition, myofibres are multinucleated cells deriving from the fusion of mononucleate stem (or precursor) cells known as satellite cells. The syncytial nature of the myofibres means that limited gene delivery to a few nuclei may lead to expression of the cognate gene product over a considerable area, and that engineering of satellite cells in tissue culture allows an efficient mechanism of ex vivo gene transfer via transplantation and fusion into existing myofibre cells. The transfer of genetic material to skeletal muscle has been proposed for inherited neuromuscular diseases such as Duchenne muscular dystrophy (DMD), for disorders affecting mucopolysaccharide, carbohydrate, amino acid or lipid metabolism, for common acquired disorders such as diabetes mellitus, hyperlipidaemia and cardiovascular disease, and for vaccination against a number of infectious agents. An extensive range of gene transfer techniques have now been applied to muscle tissues. On the one hand there are virus-based vector systems. Viruses have evolved highly efficient mechanisms for evading the host immune defence and delivering their genetic material to the nucleus, and an immense amount of research has been directed at harnessing these properties to deliver foreign genes using genetically modified viruses. As the major objective of gene therapy is long-term expression, deletion of key regulatory viral genes is essential to ensure replication deficiency and that infection does not lead to target cell death.