Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 39; pp. 14814 - 14819
• Main Authors: Wu, Bo, Moulton, Hong M, Iversen, Patrick L, Jiang, Jiangang, Li, Juan, Li, Jianbin, Spurney, Christopher F, Sali, Arpana, Guerron, Alfredo D, Nagaraju, Kanneboyina, Doran, Timothy, Lu, Peijuan, Xiao, Xiao, Lu, Qi Long
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.09.2008; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cardiology; Duchenne muscular dystrophy; Dystrophin - genetics; Exons; Gene Transfer Techniques; Genetic Therapy - methods; Heart; Heart - physiopathology; Messenger RNA; Mice; Mice, Inbred mdx; Morpholines - chemistry; Morpholines - metabolism; Morpholines - therapeutic use; Morpholinos; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Muscular dystrophy; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - physiopathology; Muscular Dystrophy, Duchenne - therapy; Musculoskeletal system; Mutation; Myocardium; Myocardium - metabolism; Myocardium - pathology; Oligomers; Oligonucleotides, Antisense - chemistry; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - therapeutic use; Pathology; Peptides - chemistry; Peptides - metabolism; Peptides - therapeutic use; Reverse transcriptase polymerase chain reaction; Rodents; Skeletal muscle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0805676105

Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application is limited by low potency and inefficiency in systemic delivery, especially failure to restore dystrophin in heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with a designed cell-penetrating peptide (PPMO) targeting a mutated dystrophin exon. Systemic delivery of the novel PPMO restores dystrophin to almost normal levels in the cardiac and skeletal muscles in dystrophic mdx mouse. This leads to increase in muscle strength and prevents cardiac pump failure induced by dobutamine stress in vivo. Muscle pathology and function continue to improve during the 12-week course of biweekly treatment, with significant reduction in levels of serum creatine kinase. The high degree of potency of the oligomer in targeting all muscles and the lack of detectable toxicity and immune response support the feasibility of testing the novel oligomer in treating Duchenne muscular dystrophy patients.