Long-Term Efficacy of AAV9-U7snRNA-Mediated Exon 51 Skipping in mdx52 Mice.

Abstract Gene therapy and antisense approaches hold promise for the treatment of Duchenne Muscular Dystrophy (DMD). The advantages of both therapeutic strategies can be combined by vectorising antisense sequences into an AAV vector. We previously reported the efficacy of AAV-U7snRNA mediated exon-skipping in the mdx mouse, dys-/utr- mouse and the GRMD dog model. Here we examined the therapeutic potential of an AAV-U7snRNA targeting the human DMD exon 51 which could be applicable to 13% of DMD patients. A single injection of AAV9-U7ex51 induces widespread and sustained levels of exon 51 skipping leading to significant restoration of dystrophin and improvement of the dystrophic phenotype in the mdx52 mouse. However, levels of dystrophin re-expression are lower than the skipping levels, in contrast with previously reported results in the mdx mouse, suggesting that efficacy of exon-skipping may vary depending on the targeted exon. Additionally, while low levels of exon-skipping were measured in the brain, the dystrophin protein could not be detected, in line with a lack of improvement of their abnormal behavioral fear response. These results thus confirm the high therapeutic potential of the AAV-mediated exon-skipping approach, yet the apparent discrepancies between exon skipping and protein restoration levels suggest some limitations of this experimental model.