A study published Online First by The Lancet shows it is possible, using a targeted antisense therapy called AVI-4658, to restore expression of a key protein that is lacking in patients with the seriously debilitating condition Duchenne muscular dystrophy. The Article is by Professor Francesco Muntoni, Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK, and colleagues. The study was part funded by the UK Medical Research Council and AVI BioPharma.
Around 1 in 3500 males (in the UK) have Duchenne muscular dystrophy. The condition causes progressive muscle weakness due to the breakdown and loss of muscle cells. Patients are deficient in a single important protein in muscle fibres called dystrophin. By about 8 to 12 years of age boys become unable to walk, and by their late teens or twenties the condition is so serious it often leads to an early death. Antisense therapy has potential to treat many, but not all, patients with DMD.
19 patients aged 5 to 15 years received the study drug for 12 weeks at either Great Ormond Street Hospital for Children NHS Trust (GOSH), London, UK, or the Royal Victoria Infirmary, Newcastle, UK. Each boy had a muscle biopsy before and after treatment. The team found that use of AVI-4658 helped ‘repair’ the boys’ ability to produce a functional mRNA through ‘exon skipping’ and eventually allow them to produce functional dystrophin protein. The authors say: “Seven patients had a significant dose response, six of whom were in the two high-dose cohorts, showing restoration of dystrophin protein expression up to 18% of normal levels.”
They conclude: “On the basis of our data and recent preclinical data, we expect that extended administration of AVI-4658 at doses of 10 mg/kg or higher will result in sufficient dystrophin expression to have a positive effect on the prevention of muscle degeneration in Duchenne muscular dystrophy… 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.”
In a linked Comment, Dr Akinori Nakamura, Shinshu University School of Medicine, Matsumoto, Japan, and Dr Shin’ichi Takeda, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan, conclude: “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. 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.”
Date: July 24, 2011
Source: The Lancet
Filed Under: Drug Discovery
