Systemic administration of PRO051 in Duchenne's muscular dystrophy

N Engl J Med. 2011 Apr 21;364(16):1513-22. doi: 10.1056/NEJMoa1011367. Epub 2011 Mar 23.


Background: Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes. The present phase 1-2a study aimed to assess the safety, pharmacokinetics, and molecular and clinical effects of systemically administered PRO051.

Methods: We administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients, with each of four possible doses (0.5, 2.0, 4.0, and 6.0 mg per kilogram of body weight) given to 3 patients. Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points. All patients subsequently entered a 12-week open-label extension phase, during which they all received PRO051 at a dose of 6.0 mg per kilogram per week. Safety, pharmacokinetics, serum creatine kinase levels, and muscle strength and function were assessed.

Results: The most common adverse events were irritation at the administration site and, during the extension phase, mild and variable proteinuria and increased urinary α(1)-microglobulin levels; there were no serious adverse events. The mean terminal half-life of PRO051 in the circulation was 29 days. PRO051 induced detectable, specific exon-51 skipping at doses of 2.0 mg or more per kilogram. New dystrophin expression was observed between approximately 60% and 100% of muscle fibers in 10 of the 12 patients, as measured on post-treatment biopsy, which increased in a dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the 12-week extension phase, there was a mean (±SD) improvement of 35.2±28.7 m (from the baseline of 384±121 m) on the 6-minute walk test.

Conclusions: Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment. (Funded by Prosensa Therapeutics; Netherlands National Trial Register number, NTR1241.).

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alternative Splicing*
  • Child
  • Child, Preschool
  • Creatine Kinase / urine
  • Dose-Response Relationship, Drug
  • Dystrophin / genetics
  • Dystrophin / metabolism
  • Exercise Test
  • Exons
  • Humans
  • Injections, Subcutaneous
  • Male
  • Muscle Strength / drug effects
  • Muscle, Skeletal / chemistry
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Muscular Dystrophy, Duchenne / genetics
  • Mutation
  • Oligonucleotides / administration & dosage
  • Oligonucleotides / adverse effects
  • Oligonucleotides / blood
  • Oligonucleotides / therapeutic use*
  • RNA / analysis


  • Dystrophin
  • Oligonucleotides
  • PRO051
  • RNA
  • Creatine Kinase