Duchenne muscular dystrophy affects the muscular system of young boys. The affection is progressive, the patient becomes more and more invalidated and death inevitably occurs, around the age of twenty, due to failure of the respiratory muscles and the heart. The genetic defect is now identified: it concerns the gene of a large molecule called "dystrophin", located on the p21 region of chromosome X.
In healthy patients dystrophin is localized just under the cell membrane. It is absent in the Duchenne patient. The pathogenesis of the disease is unknown. Since the discovery and cloning of the dystrophin gene, potential gene therapy is the object of intense research. The group of the Institut Gustave Roussy in Villejuif (France) has succeeded in inserting a large part of the dystrophin cDNA into an adenovirus. The resulting protein has been called "minidystrophin" and is stably expressed in transfected muscle fibres of young mice. It is essential to test if minidystrophin can confer a functional recovery where it is expressed. The possibility to sustain forced elongations during contraction will be a critical test for the evaluation of the functional recovery. A study has been conducted in the laboratory of the Department of Physiologie in Brussels (Belgium) which shows that fast skeletal muscles from mdx mice are very sensitive to mechanical stress when they are forcibly stretched while already contracted, a finding which points towards a genuine membrane weakness in dystrophin lacking fibres. The group of the II Institute of Physiology in Heidelberg (Germany) has shown that native sarcolemma vesicles obtained from mdx muscle fibres are less stable when the osmolarity of the surrounding medium is reduced compared to normal controls. Similar experiments will be carried out on minidystrophin containing membrane vesicles and the tensile strength of these minidystrophin membranes will be determined. The group of the II Institute of Physiology in Heidelberg will also measure the activity of single mechanosensitive ion channels and of acetylcholine ion channels as these ion channels may contribute to the calcium overload thought to induce necrosis. Given the high efficiency of the minidystrophin transfection with the adenoviral carrier, this method is likely to become the first realistic gene therapy in Duchenne patients. However, before investing in developing this therapy, it is essential to know if minidystrophin can functionally replace dystrophin. The project is suitably designed to bring the answer.
Funding SchemeCSC - Cost-sharing contracts