AVI-4658, a targeted antisense therapy to restore expression of dystrophin, a key protein which patients with Duchenne muscular dystrophy lack, shows promise, researchers from the Neuromuscular Centre, UCL Institute of Child Health, London, UK, wrote in the journal The Lancet.
Professor Francesco Muntoni and team wrote that approximately 1 in every 3,500 British males has Duchenne muscular dystrophy (DMD). The patient's muscle cells break down and are lost, leading to progressive muscle weakness. By the time the boy is between the age of 8 and 12 years he can no longer walk. By the time they reach late adolescence or early adulthood their condition has deteriorated so much that many die.
AVI-4658 might be an effective treatment for a considerable number of patients.
This open-label, phase 2, dose-escalation study with 19 patients was carried out at three centers - Great Ormond Street Hospital, or Children NHS Trust (GOSH), both in London, and the Royal Victoria Infirmary, Newcastle, England.
When treatment was completed, a muscle biopsy was taken from each child. The team discovered that the patients' ability to produce functional mRNA through "exon skipping' was repaired with the use of AVI-4658 - eventually allowing them to manufacture functional dystrophin protein.
The researchers said:
"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 concluded:
"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." Comment in the same journal 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, wrote:
"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."
"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"
Sebahattin Cirak*, Virginia Arechavala-Gomeza*, Michela Guglieri, Lucy Feng, Silvia Torelli, Karen Anthony, Stephen Abbs, Maria Elena Garralda, John Bourke, Dominic J Wells, George Dickson, Matthew J A Wood, Steve D Wilton, Volker Straub, Ryszard Kole, Stephen B Shrewsbury, Caroline Sewry, Jennifer E Morgan, Kate Bushby, Francesco Muntoni
The Lancet July 25, 2011. DOI:10.1016/S0140-6736(11)60756-3
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