Peptide-morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy.

TitlePeptide-morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy.
Publication TypeJournal Article
Year of Publication2009
AuthorsMoulton HM, Wu B, Jearawiriyapaisarn N, Sazani P, Lu QL, Kole R
JournalAnnals of the New York Academy of Sciences
Volume1175
Pagination55-60
Date Published2009 Sep
ISSN1749-6632
KeywordsAnimals, Codon, Nonsense, Disease Models, Animal, Dystrophin, Mice, Mice, Inbred mdx, Morpholines, Muscular Dystrophy, Duchenne, Oligonucleotides, 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.

DOI10.1111/j.1749-6632.2009.04976.x
Alternate JournalAnn. N. Y. Acad. Sci.