Long-Term Rescue of Skeletal and Cardiac Muscles in Dystrophic Mdx Mice by Peptide- Conjugated Morpholino

• Published in: Molecular therapy 2012-09, Vol.20 (9), p.24-24
• Main Authors: Wu, Bo, Lu, Peijuan, Cloer, Caryn, Shaban, Mona, Grewal, Snimar, Milazi, Stephanie, Shah, Sapana N, Moulton, Hong, Lu, Qi Long
• Format: Article
• Language: English
• ISSN: 1525-0016; 1525-0024

Exon skipping has been demonstrated with capability to correct frame-shift and nonsense mutations of Duchenne Muscular Dystrophy (DMD). PhaseI/II clinical trials in UK and Netherlands have reported induction of dystrophin expression in muscles of DMD patients by local and systemic administrations of both phosphorodiamidate morpholino oligomers (PMO) and 2'O methyl phosphorothioate (2OMePS). Long-term rescue of dystrophin and muscle functions has also been achieved with PMO, but at considerable higher doses in animal models systemically than those reported in the clinic trials. Peptide-conjugated PMO (PPMO) offers significantly higher efficiency than PMO with the ability to induce near normal levels of dystrophin and restore functions in both skeletal and cardiac muscles. Here, we examined the long-term (one year) efficacy and toxicity of systemic administration of PPMO targeting exon 23 of dystrophin gene in mdx mice. Half life of the dystrophin expression was about 2 months in skeletal muscles but shorter in cardiac muscle. Biweekly injection of 1.5 mg/kg PPMO induced less than 5% dystrophin expression in skeletal muscles with limited muscle function improvements and no dystrophin in the cardiac muscle. Monthly injections of 30mg/kg PPMO restored dystrophin to more than 50% normal levels in all muscles including cardiac muscle. The levels of serum CK were reduced to near normal level with muscles showing significantly decreased CNF with no inflammatory cell accumulation and muscle fiber population became highly uniform. Significant improvement in skeletal muscle function was clearly observed by grip force measurement. Our result demonstrated for the first time that long-term repeated administration of PPMO could be safely applied to achieve significant therapeutic effect for long-term treatment of DMD with tolerable toxicity.