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02-08-2011 | Genetics | Article

Exon-skipping holds early promise for Duchenne treatment

Abstract

Free abstract

MedWire News: Treatment with an intravenous antisense oligonucleotide, AVI-4658, restores dystrophin expression in the muscles of boys with Duchenne muscular dystrophy, show results of a phase II study.

"AVI-4658 has the potential to ameliorate the progressive natural history of Duchenne muscular dystrophy and now needs to be investigated in clinical efficacy trials," say Francesco Muntoni (UCL Institute of Child Health, London, UK) and colleagues.

Treatment with antisense oligonucleotides specific to parts of the gene encoding dystrophin induces skipping of particular portions of the gene during transcription. This restores the open reading frame and allows production of a functional protein. In the case of AVI-4658, exon 51 is skipped - a strategy that could potentially be applied to about 15% of patients.

Skipping exon 51 results in production of a truncated, but functional, version of dystrophin, similar to that produced in patients with the much milder allelic Becker muscular dystrophy.

As reported in The Lancet, Muntori et al administered various doses of AVI-4658 to 19 ambulant boys, aged 6-13 years, with Duchenne muscular dystrophy, who had mutations treatable by exon 51 skipping.

They found that from doses 2.0 to 20.0 mg/kg, treatment resulted in increased expression of new dystrophin protein in muscle biopsies taken after 12 once-weekly AVI-4658 infusions, relative to that in baseline biopsies.

The effect varied between patients, however. One of the largest increases, from 1% to 21% dystrophin-positive muscle fibers, occurred in a patient given AVI-4658 2.0 mg/kg, whereas one of the smallest increases, from 3% to 5% (nonsignificant), occurred in a patient given AVI-4658 20.0 mg/kg.

In all, seven patients had significant responses to treatment. Patients with restored dystrophin expression also had increases in expression of the dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase. They also had reduced numbers of cytotoxic T cells in their muscle biopsies after compared with before treatment.

"This finding is encouraging because it suggests that the restored dystrophin attenuates the inflammation that is a hallmark of the disease's pathology," say the researchers. "It also suggests that the newly produced dystrophin does not produce novel immunogenic epitopes."

There were no adverse effects that the researchers believed to be related to treatment, apart from local rashes caused by application of local anesthetic cream before four infusions.

"The absence of drug-related adverse events after 12 weeks is encouraging, but caution is still needed because any splice switching oligomer would need to be given lifelong," says the team.

In a related commentary, Akinori Nakamura (Shinshu University School of Medicine, Matsumoto, Japan) and Shin'ichi Takeda (National Center of Neurology and Psychiatry, Tokyo, Japan) described the study as a "milestone."

However, they noted that, in animal models, such treatments work better in skeletal than heart muscles. "Since many patients with the disorder die of heart failure or lethal arrhythmias, an improvement in the transduction efficiency of antisense oligonucleotides in the cardiac muscle is crucial," they said.

But Nakamura and Takeda noted that the "regulatory and practical (ie, scaling up) barriers to clinical use of exon-skipping therapy are much less daunting than those for gene therapy with viral vectors or cell transplantation therapy."

They concluded: "Therefore, successful clinical trials of exon-skipping therapy in patients with Duchenne muscular dystrophy could have a great effect on development of treatments for other intractable hereditary neuromuscular disorders."

By Eleanor McDermid

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