Journal article
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
The Lancet, Vol.378(9791), pp.595-605
2011
Abstract
Background
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.
Details
- Title
- 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
- Authors/Creators
- S. Cirak (Author/Creator)V. Arechavala-Gomeza (Author/Creator)M. Guglieri (Author/Creator)L. Feng (Author/Creator)S. Torelli (Author/Creator)K. Anthony (Author/Creator)S. Abbs (Author/Creator)M.E. Garralda (Author/Creator)J. Bourke (Author/Creator)D.J. Wells (Author/Creator)G. Dickson (Author/Creator)M.J.A. Wood (Author/Creator)S.D. Wilton (Author/Creator)V. Straub (Author/Creator)R. Kole (Author/Creator)S.B. Shrewsbury (Author/Creator)C. Sewry (Author/Creator)J.E. Morgan (Author/Creator)K. Bushby (Author/Creator)F. Muntoni (Author/Creator)
- Publication Details
- The Lancet, Vol.378(9791), pp.595-605
- Publisher
- Elsevier
- Identifiers
- 991005541593907891
- Copyright
- © 2011 Elsevier Ltd
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Clinical Neurology
- ESI research areas
- Clinical Medicine