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The Lancet. 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
[Fonte: The Lancet, full text: (LINK). Abstract, edited.]
The Lancet, Early Online Publication, 25 July 2011
doi:10.1016/S0140-6736(11)60756-3
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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
Original Text
Sebahattin Cirak MD, Virginia Arechavala-Gomeza PhD, Michela Guglieri MD, Lucy Feng PhD, Silvia Torelli PhD, Karen Anthony PhD, Stephen Abbs PhD, Prof Maria Elena Garralda MD, John Bourke MD, Prof Dominic J Wells VetMB PhD, Prof George Dickson PhD, Matthew JA Wood MD PhD, Prof Steve D Wilton PhD, Prof Volker Straub MD, Prof Ryszard Kole PhD, Stephen B Shrewsbury MD, Prof Caroline Sewry PhD, Jennifer E Morgan PhD, Prof Kate Bushby MD, Prof Francesco Muntoni MD
Summary
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.
Funding
UK Medical Research Council; AVI BioPharma.
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The Lancet, Early Online Publication, 25 July 2011
doi:10.1016/S0140-6736(11)60756-3
Cite or Link Using DOI
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
Original Text
Sebahattin Cirak MD, Virginia Arechavala-Gomeza PhD, Michela Guglieri MD, Lucy Feng PhD, Silvia Torelli PhD, Karen Anthony PhD, Stephen Abbs PhD, Prof Maria Elena Garralda MD, John Bourke MD, Prof Dominic J Wells VetMB PhD, Prof George Dickson PhD, Matthew JA Wood MD PhD, Prof Steve D Wilton PhD, Prof Volker Straub MD, Prof Ryszard Kole PhD, Stephen B Shrewsbury MD, Prof Caroline Sewry PhD, Jennifer E Morgan PhD, Prof Kate Bushby MD, Prof Francesco Muntoni MD
Summary
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.
Funding
UK Medical Research Council; AVI BioPharma.
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