One-year treatment of morpholino antisense oligomer improves skeletal and cardiac muscle functions in dystrophic mdx mice.

Abstract

Antisense therapy has been successful to skip targeted dystrophin exon with correction of frameshift and nonsense mutations of Duchenne muscular dystrophy (DMD). Systemic production of truncated but functional dystrophin proteins has been achieved in animal models. Furthermore, phase I/II clinical trials in United Kingdom and the Netherlands have demonstrated dystrophin induction by local and systemic administrations of antisense oligomers. However, long-term efficacy and potential toxicity remain to be determined. The present study examined 1-year systemic effect of phosphorodiamidate morpholino oligomers (PMO) treatment targeting mutated dystrophin exon 23 in mdx mice. PMO induced dystrophin expression dose-dependently and significantly improved skeletal muscle pathology and function with reduced creatine kinase (CK) levels by a regimen of 60 mg/kg biweekly administration. This regimen induced <2% dystrophin expression in the heart, but improved cardiac functions demonstrated by hemodynamics analysis. The results suggest that low levels of dystrophin induction may be able to provide detectable benefit to cardiac muscle with limited myopathy. Body weight, serum enzyme tests, and histology analysis showed no sign of toxicity in the mice treated with up to 1.5 g/kg PMO for 6 months. These results indicate that PMO could be used safely as effective drugs for long-term systemic treatment of DMD.

• Authors: Bo Wu, Bin Xiao, Caryn Cloer, Mona Shaban, Arpana Sali, Peijuan Lu, Juan Li, Kanneboyina Nagaraju, Xiao Xiao, Qi Long Lu
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 3 Pg. 576-83 (Mar 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21179007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Dystrophin
• Morpholines
• Morpholinos

Topics

• Animals
• Disease Models, Animal
• Dystrophin (genetics, metabolism)
• Exons (genetics)
• Gene Expression Regulation (drug effects)
• Genetic Therapy
• Heart (drug effects)
• Hemodynamics (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred mdx
• Morpholines (pharmacology, therapeutic use)
• Morpholinos
• Muscle, Skeletal (metabolism, pathology)
• Muscular Dystrophy, Duchenne (drug therapy)
• Myocardium (metabolism, pathology)
• Time Factors