DMD (of Duchenne muscular dystrophy) is a X-linked muscle disease characterized by anti-dystrophin gene mutations. At the transcriptional level by exon skip mutations, many mutations can be corrected. In mdx mice by tail vein injection of adeno-associated virus vector, we obtained persistent exon skipping, these vectors expressing antisense sequences as part of the stable cell U1 small nuclear RNA. Generalized to give the AAV structure can produce systemic transplantation, lead to the recovery of functional characteristics in vitro significantly reduced the serum creatinine phosphokinase levels, this phenomenon also shows that the overall decline of muscle consumption. These transfected muscle to restore dystrophin expression, and demonstrated a significant functional recovery: a single muscle fiber level nearly reached the normal standard. This approach provides a solid foundation for systemic use in the treatment of DMD AAV-mediated antisense-U1 small nuclear RNA expression.

Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and Institute of Molecular Biology and Pathology, University “La Sapienza,” P. le Aldo Moro 5, 00185 Rome, Italy;

Duchenne muscular dystrophy is an X-linked muscle disease characterized by mutations in the dystrophin gene. Many of these can be corrected at the posttranscriptional level by skipping the mutated exon. We have obtained persistent exon skipping in mdx mice by tail vein injection with an adeno-associated viral (AAV) vector expressing antisense sequences as part of the stable cellular U1 small nuclear RNA. Systemic delivery of the AAV construct resulted in effective body-wide colonization, significant recovery of the functional properties in vivo, and lower creatine kinase serum levels, suggesting an overall decrease in muscle wasting. The transduced muscles rescued dystrophin expression and displayed a significant recovery of function toward the normal values at single muscle fiber level. This approach provides solid bases for a systemic use of AAV-mediated antisense-U1 small nuclear RNA expression for the therapeutic treatment of Duchenne muscular dystrophy.