Status: Open to recruitment
Sponsor: University College London, United Kingdom;University of Copenhagen, Denmark
Start date: January 2015
Funder: Muscular Dystrophy Campaign
PI: Dr Ros Quinlivan, Prof. John Vissing
Recruitment target: 15 people with McArdle disease
What are the researchers aiming to do?
McArdle disease is a rare condition caused by the lack of a particular enzyme - called muscle glycogen phosphorylase - that helps to provide muscles with energy. This enzyme converts energy stored in the form of starch to sugar that the muscle can use as fuel during exercise. This lack of energy causes people with McArdle disease to experience severe muscle pain and fatigue. If they rest for a few minutes once the pain occurs, they can usually then continue to exercise without pain - this is called the "second wind". Exercising through the pain however, can cause severe muscle spasms and then damage. This damage causes muscle breakdown which can in some cases lead to kidney failure.
In the brain there is an enzyme similar to muscle glycogen phosphorylase called brain glycogen phosphorylase. The brain form of the enzyme has been seen in muscle fibres after they have been damaged, suggesting that it might be possible to "switch on" the brain enzyme in muscle to compensate for the missing muscle glycogen phosphorylase. Some drugs are known to have the ability to make the body "switch on" certain genes and when one of these was tested in an animal model of McArdle disease it was shown that the drug could switch on the foetal/brain enzyme in the muscle. A recent clinical trial in McArdle sheep that were given sodium valproate showed the presence of phosphorylase positive muscle fibres [1]. The result is probably due to the effect of sodium valproate on gene expression. Sodium valproate is a drug usually prescribed to treat epilepsy. This drug is also part of a group of drugs known to affect gene expression by having a direct effect on chromatin (histone deacetylase inhibitors – HDACIs).
Main Aim: The aim of this clinical trial is to determine whether treatment with sodium valproate can cause expression of the different isoforms of glycogen phosphorylase in skeletal muscle in people with McArdle disease.
How will the outcomes of the research benefit patients?
In this pilot study, 15 people with GSDV (8 from the United Kingdom and 7 from Denmark) will receive sodium valproate administered orally once daily for six months. Muscle biopsy will be performed to confirm the expression of muscle phosphorylase following treatment. Exercise tests, questionnaires, blood samples and symptoms diary will be performed to evaluate functional capacity, safety (tolerability and adverse events), improvement in the quality of life and in the GSDV symptoms. If the results of this pilot study are positive, this could lead to a larger placebo-controlled clinical trial to test this drug in more detail. This pilot study might be the initial step in exploring a novel treatment option for patients with McArdle disease to reduce or prevent the pain and fatigue that is brought on by exercising.
Further information and links
Find out more about McArdle disease
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References:
1. Howell, J.M., et al., Investigating sodium valproate as a treatment for McArdle disease in sheep. Neuromuscul Disord, 2014.
