title: Systemic administration of PRO051 in Duchenne's muscular dystrophy.
abstract: 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.).
authors.affiliation: Department of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Goemans
authors.forename: Mar
authors.initials: M
authors.lastname: Tulinius
authors.forename: Johanna T
authors.initials: JT
authors.lastname: van den Akker
authors.forename: Brigitte E
authors.initials: BE
authors.lastname: Burm
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ekhart
authors.forename: Niki
authors.initials: N
authors.lastname: Heuvelmans
authors.forename: Tjadine
authors.initials: T
authors.lastname: Holling
authors.forename: Anneke A
authors.initials: AA
authors.lastname: Janson
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Platenburg
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Sipkens
authors.forename: J M Ad
authors.initials: JM
authors.lastname: Sitsen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Gunnar
authors.initials: G
authors.lastname: Buyse
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Verschuuren
authors.forename: Giles V
authors.initials: GV
authors.lastname: Campion
authors.forename: Sjef J
authors.initials: SJ
authors.lastname: de Kimpe
authors.forename: Judith C
authors.initials: JC
authors.lastname: van Deutekom
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing; D002648:Child; D002675:Child, Preschool; D003402:Creatine Kinase / Q000652:urine; D004305:Dose-Response Relationship, Drug; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005080:Exercise Test; D005091:Exons; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D012313:RNA / Q000032:analysis
chemical_list: D016189:Dystrophin; D009841:Oligonucleotides; C525434:PRO051; D012313:RNA; D003402:Creatine Kinase