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- Title
Peptide-Morpholino Conjugate: A Promising Therapeutic for Duchenne Muscular Dystrophy.
- Authors
Moulton, Hong M.; Wu, Bo; Jearawiriyapaisarn, Natee; Sazani, Peter; Lu, Qi Long; Kole, Ryszard
- Abstract
Steric-blocking oligos can correct reading frame errors or skip premature termination codons. For Duchenne muscular dystrophy (DMD), systemic administration of oligos produces limited delivery into muscle cells. Conjugation to a cell-penetrating peptide greatly enhances muscle uptake of morpholino oligos. A peptide-morpholino conjugate (PPMO) restored dystrophin in mdx mice to > 80% and 50% of normal levels in skeletal and cardiac muscles, respectively, after a single intravenous 30-mg/kg injection. Six injections over 3 months restored dystrophin to nearly normal levels in all muscles. One PPMO injection daily at 12 mg/kg each for 4 days caused exon skipping clearly detectable in the muscles of the mdx mice 9 weeks later, showing prolonged activity. PPMO significantly improved muscle pathology, strength and function, and the survival rate of mice whose hearts were challenged by chemical-induced heart failure. No toxicity or immunogenicity was detected. Our studies demonstrated that muscle functions can be restored with a low dose of PPMO, making it a promising therapeutic for DMD.
- Subjects
TREATMENT of Duchenne muscular dystrophy; DYSTROPHIN; MUSCLE cells; HEART failure; METABOLIC conjugation
- Publication
Annals of the New York Academy of Sciences, 2009, Vol 1175, Issue 1, p55
- ISSN
0077-8923
- Publication type
Article
- DOI
10.1111/j.1749-6632.2009.04976.x