Medical Research

Possible Cure for Genetic Disease

Scientists develop active substance for fatal muscle wasting in boys

11.2.2015 | Duchenne muscular dystrophy is a congenital disease causing muscle degeneration and eventual death in adolescence. Now an international research team developed an active substance to combat this disease and tested it successfully in a mouse model.
Prof. Kay E. Davies
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Prof. Kay E. Davies
Duchenne muscular dystrophy (DMD) is a rare congenital disease that only affects boys and leads to irreversible muscle wasting. Around 1 in 3500 newborns is affected. At approximately ten years of age, Duchenne patients are dependent on wheelchairs and need an increasing amount of care. Patients usually don't reach their late 20s, and often die from heart or respiratory failure. There is no cure for DMD, but recently researchers from England, among them the geneticist Prof. Kay Davies, as well as researchers from Switzerland, France and Sweden tested a promising active substance.

In recent years, scientists had found the genetic origin of the disease, which lies in a defect of the gene responsible for the production of dystrophin. Dystrophin is an important protein for normal muscular function. The mutation of this gene means that dystrophin is not produced, or only a non-functional variant of it. Absence of dystrophin means that one single muscle cell cannot function with the others anymore, leading ultimately to a failure of the entire muscle.

A promising therapy approach is to correct the defect in the production of dystrophin with short segments of a chemically modified DNA, so-called antisense oligonucleotides (AO). A significant curative effect with the tested active substances had not been achieved until now, because the corresponding active substances are not yet active enough and do not reach vital muscles like the heart.

The Department for Chemistry and Biochemistry of the University of Bern with the financial support of the Swiss National Foundation SNF and the Association Monégasque contre les Myopathies AMM now developed an oligonucleotide, the so-called tricyclo-DNA, which shows substantial benefits in comparison to the already known active substances. Experiments in mice show evidence that the agent leads to an improved dystrophin production in all muscles, including the heart and the lungs, and subsequently leads to an improved mobility and increased life expectancy in mice.

Surprisingly it was also observed that the dystrophin production in the brain was corrected as well. For the first time it was shown that an oligonucleotide can pass the blood-brain barrier and become active in the brain. This discovery should be particularly significant for other neuromuscular diseases, like spinal atrophy or Huntington's disease.

The next step of the clinical trial is to test tricyclo-DNA in humans. The trial is coordinated by the spin-off enterprise Synthena AG of the University of Bern founded in 2012. The enterprise manufactures tricyclo-DNA and advances the development of a medication for Duchenne patients. Shareholders of the enterprise are the University of Bern, the inventors of the technology and the two charitable patient organisations Duchenne Project France (DPPF) and AMM.

Dame Kay Elizabeth Davies is a professor at the University of Oxford and director of the MRC functional genetics unit. She is also a governor of the Wellcome Trust and a director of the Oxford Centre for Gene Function, together with Frances Ashcroft and Peter Donnelly. Her research group has an international reputation for work on DMD.   (© University of Bern, AcademiaNet)

More information

Source

  • Aurélie Goyenvalle, Graziella Griffith, Arran Babbs, Samir EL Andaloussi, Kariem Ezzat, Aurélie Avril, Branislav Dugovic, Remi Chaussenot, Arnaud Ferry,Thomas Voit, Helge Amthor, Claudia Bühr, Stefan Schürch, Matthew J. A. Wood, Kay E. Davies, Cyrille Vaillend, Christian Leumann,

    Luis Garcia: Functional correction in mouse models of muscular dystrophy using splice-switching tricyclo-DNAoligomers, Nature Medicine, 2015, DOI: 10.1038/nm.3765

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