Title | Peptide-morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Moulton, HM, Wu, B, Jearawiriyapaisarn, N, Sazani, P, Lu, QLong, Kole, R |
Journal | Annals of the New York Academy of Sciences |
Volume | 1175 |
Pagination | 55-60 |
Date Published | 2009 Sep |
Keywords | Peptides |
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. |
DOI | 10.1111/j.1749-6632.2009.04976.x |