Recombinant adeno-associated virus type 2 mediates highly efficient gene transfer in regenerating rat skeletal muscle

The recent identification of genes responsible for several muscle diseases, particularly inherited myopathies, has made gene transfer to pathologic muscle tissue an attractive research field. As early pathologic changes in myopathic muscle involve repeated necrosis-regeneration cycles, leading to the coexistence of myofibers at different stages of maturity, a delivery system for efficient, durable gene therapy of inherited muscle diseases should allow gene transfer into myofibers at any stage of maturity. Experiments with rat skeletal muscles showed that recombinant adeno-associated virus (rAAV) type 2 can be highly efficient and even improve gene transfer in regenerating as compared with mature muscle, provided that vector injection is performed during the myotube growth period of the regenerative pro-cess. At this early period of muscle regeneration, young regenerating myotubes strongly express heparan sulfate proteoglycan AAV type 2 receptor. Improvement was associated with a greater number of transduced myofibers in muscle samples and an increase in viral genomic copies in transduced muscle. No significant deleterious effects on muscle phenotype or any evident alterations in the regenerative process were observed in transduced muscles, Unlike other available viral vectors, whose transduction efficiencies are highly maturation-dependent, rAAV type 2-based vectors provide efficient in vivo gene transfer in myofibers at various stages of maturity, making AA V a promising delivery system for pathological muscle tissue.