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Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.

AbstractBACKGROUND:
We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy.
METHOD:
We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597.
FINDINGS:
19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1-10·6) to 16·4% (10·8-22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts.
INTERPRETATION:
The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy.
FUNDING:
UK Medical Research Council; AVI BioPharma.
AuthorsSebahattin Cirak, Virginia Arechavala-Gomeza, Michela Guglieri, Lucy Feng, Silvia Torelli, Karen Anthony, Stephen Abbs, Maria Elena Garralda, John Bourke, Dominic J Wells, George Dickson, Matthew J A Wood, Steve D Wilton, Volker Straub, Ryszard Kole, Stephen B Shrewsbury, Caroline Sewry, Jennifer E Morgan, Kate Bushby, Francesco Muntoni
JournalLancet (London, England) (Lancet) Vol. 378 Issue 9791 Pg. 595-605 (Aug 13 2011) ISSN: 1474-547X [Electronic] England
PMID21784508 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Dystrophin
  • Morpholines
  • Morpholinos
  • Oligonucleotides
  • eteplirsen
Topics
  • Adolescent
  • Alternative Splicing
  • Child
  • Dose-Response Relationship, Drug
  • Dystrophin (genetics, metabolism)
  • Exons (genetics)
  • Humans
  • Infusions, Intravenous
  • Male
  • Morpholines (administration & dosage, pharmacokinetics)
  • Morpholinos
  • Muscle, Skeletal (metabolism)
  • Muscular Dystrophy, Duchenne (drug therapy, genetics, metabolism)
  • Oligonucleotides (administration & dosage, pharmacokinetics)

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