Adenovirus mediated gene transfer to skeletal muscle

Abstract

Transfer of therapeutic genes into muscle tissue has promise for the treatment of a variety of muscular dystrophies. Various vectors have been used to deliver genes to skeletal muscle but their application has faced several major limitations including: (1) the lack of transgene persistence caused by the immune rejection of transduced myofibers and/or vector toxicity, and (2) the maturation dependence of viral transduction. While the immunorejection and/or cytotoxic problems are being overcome with the development of new vectors, maturation-dependent viral transduction is still a major hurdle in gene transfer to skeletal muscle. Poor adenoviral transduction in mature myofibers has been attributed to: (1) the extracellular matrix of mature myofibers may form a physical barrier and prevent the passage of large viral particles; (2) viral receptors are down-regulated with muscle maturation; and (3) loss of myoblasts with muscle maturation, which serve as intermediaries in the viral transduction. In this review, we will focus on recent developments in overcoming those hurdles of gene therapy in skeletal muscle, especially to adenovirus (Ad), including: (1) new mutant vectors lacking all viral genes to decrease immunogenicity, and hence, improve persistence of transgene expression in muscle in vivo; (2) using tissue specific promoters to evade immunorejection; (3) permeabilization of the extracellular matrix; (4) modifying the viral receptors in mature myofibers; and (5) myoblast or muscle stem cell mediated ex vivo gene transfer.