Abstract
SummaryBackgroundWe 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.MethodWe 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.Findings19 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.InterpretationThe safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy.FundingUK Medical Research Council; AVI BioPharma.
Highlights
Duchenne muscular dystrophy is a progressive, severely disabling neuromuscular disease that affects one in 3500 newborn boys and causes premature death.[1]
Interpretation The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a diseasemodifying drug for Duchenne muscular dystrophy
Dystrophin is located underneath the sarcolemma and assembles with sarcolemmal proteins such as dystroglycan, α-sarcoglycan, and neuronal nitric oxide synthase (NOS) to form the dystrophin-associated glycoprotein complex
Summary
Duchenne muscular dystrophy is a progressive, severely disabling neuromuscular disease that affects one in 3500 newborn boys and causes premature death.[1]. In the milder allelic Becker muscular dystrophy, dystrophin mutations do not disrupt the open reading frame, a shortened but functional dystrophin protein is produced, and most patients are able to walk into late adulthood and have a normal lifespan.[3] induction of exon skipping to restore the open reading frame is an attractive therapeutic strategy in Duchenne muscular dystrophy that can be achieved with spliceswitching oligomers. Spliceswitching oligomers targeting dystrophin exons have been successfully used to restore dystrophin expression in vitro and in various animal models of Duchenne muscular dystrophy.[5,6] In the mdx mouse, administration of 2 ́O-methyl-ribooligonucleosidephosphorothioate (2 ́OMe) and phosphorodiamidate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
