Research ArticleMuscular Dystrophy

Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy

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Science Translational Medicine  18 Apr 2018:
Vol. 10, Issue 437, eaan0713
DOI: 10.1126/scitranslmed.aan0713

Exon skipping to treat DMD

Duchenne muscular dystrophy (DMD) is an inherited muscle disorder that is ultimately fatal. A deficiency in normal dystrophin, a structural protein that is indispensable for muscle cell function, causes severe damage to muscle cells. This dystrophin deficiency is due to mutations in the gene encoding dystrophin. Komaki et al. have now developed a morpholino antisense oligonucleotide, NS-065/NCNP-01, designed to recover dystrophin function and halt muscle damage by skipping exon 53 in the dystrophin gene. These authors report the results of a phase 1 clinical trial of NS-065/NCNP-01 conducted in 10 patients with DMD. The drug showed a favorable safety profile and pharmacokinetics, and the authors demonstrated that it effectively skipped exon 53 in the dystrophin gene, suggesting that a phase 2 trial of the drug is warranted.


Duchenne muscular dystrophy (DMD) is a lethal hereditary muscle disease caused by mutations in the gene encoding the muscle protein dystrophin. These mutations result in a shift in the open reading frame leading to loss of the dystrophin protein. Antisense oligonucleotides (ASOs) that induce exon skipping correct this frame shift during pre-mRNA splicing and partially restore dystrophin expression in mouse and dog models. We conducted a phase 1, open-label, dose-escalation clinical trial to determine the safety, pharmacokinetics, and activity of NS-065/NCNP-01, a morpholino ASO that enables skipping of exon 53. Ten patients with DMD (6 to 16 years old), carrying mutations in the dystrophin gene whose reading frame would be restored by exon 53 skipping, were administered NS-065/NCNP-01 at doses of 1.25, 5, or 20 mg/kg weekly for 12 weeks. The primary endpoint was safety; the secondary endpoints were pharmacokinetics and successful exon skipping. No severe adverse drug reactions were observed, and no treatment discontinuation occurred. Muscle biopsy samples were taken before and after treatment and compared by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence, and Western blotting to assess the amount of exon 53 skipping and dystrophin expression. NS-065/NCNP-01 induced exon 53 skipping in dystrophin-encoding mRNA in a dose-dependent manner and increased the dystrophin/spectrin ratio in 7 of 10 patients. Furthermore, the amount of exon skipping correlated with the maximum drug concentration in plasma (Cmax) and the area under the concentration-time curve in plasma (AUC0-t). These results indicate that NS-065/NCNP-01 has a favorable safety profile and promising pharmacokinetics warranting further study in a phase 2 clinical trial.

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