[HTML][HTML] Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment …

S Cirak, V Arechavala-Gomeza, M Guglieri, L Feng… - The Lancet, 2011 - thelancet.com
S Cirak, V Arechavala-Gomeza, M Guglieri, L Feng, S Torelli, K Anthony, S Abbs…
The Lancet, 2011thelancet.com
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 …
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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