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Peptide-morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy.
|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 QL, Kole R|
|Journal||Annals of the New York Academy of Sciences|
|Date Published||2009 Sep|
|Keywords||Animals, Codon, Nonsense, Disease Models, Animal, Dystrophin, Mice, Mice, Inbred mdx, Morpholines, Muscular Dystrophy, Duchenne, Oligonucleotides, Peptides|
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.
|Alternate Journal||Ann. N. Y. Acad. Sci.|