High-Level Dystrophin Expression after Adenovirus-Mediated Dystrophin Minigene Transfer to Skeletal Muscle of Dystrophic Dogs: Prolongation of Expression with Immunosuppression

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Abstract
Replication-deficient adenovirus vectors (AdV) have been successfully used to transfer a truncated human dystrophin cDNA to skeletal muscle of dystrophin-deficient mdx mice. A dystrophin-deficient golden retriever dog model (GRMD) has been identified, which, unlike the mouse model, leads to a clinicopathological phenotype similar to that of Duchenne muscular dystrophy (DMD). We show for the first time that high-level dystrophin expression in skeletal muscle of GRMD dogs can be achieved by AdV-mediated gene transfer. However, a humoral and cellular immune response of the host against antigens of viral and transgene origin (similar to that occuring in mdx mice after AdV-mediated dystrophin gene transfer) leads to a decline of dystrophin expression over a 2-month period. Immunosuppression by cyclosporin significantly prolonged transgene expression. The GRMD model may help to solve the open questions pertaining to dystrophin gene transfer such as systemic delivery and improvement of muscle function before human trials for gene replacement therapy in DMD may be considered. Duchenne muscular dystrophy (DMD) is characterized by the lack of the subsarcolemmal protein dystrophin leading to progressive weakness of skeletal muscle. So far, effective treatment is not available for DMD. Recently, preclinical trials have focussed on dystrophin gene replacement therapy using the dystrophin-deficient mdx-mouse as a model for DMD. In this study, we report on high-level dystrophin expression after adenovirus-mediated dystrophin minigene transfer to skeletal muscle of dystrophic golden retriever dog model (GRMD) dogs. Immunosuppression by cyclosporin was required to achieve dystrophin expression over a 2-month period. Unlike mdx mice, GRMD dogs show the full spectrum of clinicopathological changes as seen in DMD. Therefore, the GRMD dog model is well suited to investigate clinical and functional consequences of dystrophin gene transfer to pave the way for future clinical trials of DMD.

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