The principles of gene therapy in Duchenne muscular dystrophy

Somatic cell gene therapy (GT) for genetic disease such as Duchenne muscular dystrophy entails the introduction of normal, or at least functionally adequate, alleles of a gene into target cells for correction or mitigation of deleterious consequences of the disease's characteristic mutation. The following factors have a major impact upon the efficiency of GT: the artificial gene construct, the promoter, the delivery system, and the mode of dissemination of the therapeutic genes. For skeletal muscles, replication-defective adenovirus represents an efficient delivery system, but only if immature muscle cells are abundant in the muscle. The major drawback of adenoviruses is that the maximal insert capacity is only about 7.5 kb, which is only sufficient to accommodate a dystrophin minigene (6.3 kb) with a constitutive promoter. These and many other problems still require solution in experimental animals before single-muscle pilot studies of GT can be undertaken for such human muscle diseases as Duchenne muscular dystrophy.