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.