240. Immunogenicity of Dystrophins Delivered to Mice by Gutted Adenoviral Vectors

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder resulting from mutations in the dystrophin gene. Delivery of a therapeutic dystrophin gene back into the diseased muscle has been suggested as a means of gene therapy for DMD. Previous work in this lab has demonstrated that using a gutted adenovirus vector (gAd), a full-length dystrophin cDNA expression cassette can be delivered into muscles of the mdx (dystrophin-deficient) mouse, resulting in efficient transduction of myofibers with dystrophin. A long-term follow-up study has revealed that the gAd delivered, muscle-specific promoter-driven, gene expression could be sustained for up to six months in adult mdx mice when delivering mouse dystrophin or mouse utrophin. In contrast, delivery of full-length human dystrophin (hDys) using gAd vectors resulted in a slow loss of gene expression over the 6-month window. Furthermore, an increase in the number of infiltrating CD4+ and CD8+ T-cells was observed in muscles injected with the human, but not the mouse, dystrophin-expressing gAd vectors. These results suggest that a host immune response has been elicited, albeit possibly mild, against the hDys-expressing muscle fibers. Despite this slow loss of hDys expression, a number of small caliber, regenerating myofibers were observed at the 6 month time point that expressed the human protein, suggesting that gAd vectors can be retained for many months in satellite cells even in the presence of an immune response against dystrophin expression in myofibers.