Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy

Introduction of dystrophin by gene transfer into the dystrophic muscles of Duchenne muscular dystrophy (DMD) patients has the possibility of triggerin g an immune response as many patients will not have been exposed to some (o r ail) of the epitopes of dystrophin. This could in turn lead to cytotoxic destruction of transfected muscle fibres. We assessed such concerns in the dystrophin-deficient mdx mouse using plasmid DNA as the gene transfer syste m. This avoids complications associated with the administration of viral pr oteins. Gene transfer of cDNAs encoding mouse full-length or a truncated mi nidystrophin did not evoke either a humoral or cytotoxic immune response. M dx mice may be tolerant due to the presence of rare 'revertant' dystrophin- positive fibres in their skeletal muscles. In contrast, gene transfer of hu man full-length or minidystrophin provoked both humoral and cytotoxic respo nses leading to destruction of the transfected fibres. These experiments de monstrate the potential risk of deleterious effects following gene therapy in DMD patients and lead us to suggest that patients enrolled in gene thera py trials should ideally have small, preferably point, mutations and eviden ce of 'revertant' dystrophin-positive muscle fibres.