Peptide-morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy.
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.
AVI BioPharma, Corvallis, Oregon 97333, USA. hongmoulton@yahoo.com
Hong M
HM
Moulton
Bo
B
Wu
Natee
N
Jearawiriyapaisarn
Peter
P
Sazani
Qi Long
QL
Lu
Ryszard
R
Kole
D000818:Animals; D018389:Codon, Nonsense / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics*; D051379:Mice; D018101:Mice, Inbred mdx; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000628:therapy*; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D018389:Codon, Nonsense; D016189:Dystrophin; D009025:Morpholines; D009841:Oligonucleotides; D010455:Peptides