Duchenne's myodystrophy: a modest but successful
Blocking the TRPC6 ion channel reduced the symptoms of Duchenne myodystrophy in mice
Mikhail Orlov, PCR.news
Duchenne myodystrophy is a severe genetic muscle disease that is diagnosed at the age of 2-4 years, mainly in boys. The disease progresses rapidly, leads to severe muscle atrophy and greatly reduces life expectancy — on average it is about 30 years. The prevalence of Duchenne myodystrophy is approximately 1 case per 5,000 boys born alive.
The pathogenesis of the disease is associated with a lack of the protein dystrophin, which is necessary for the normal functioning of muscle cells and protects them from mechanical damage. Dystrophin deficiency leads to destabilization of the sarcolemma membrane (the cell membrane of a muscle cell or muscle fiber) and affects mechanosensitive ion channels, as a result they pass more calcium ions. This causes damage to myocytes and impaired muscle function. The disease remains incurable, but physical therapy and corticosteroids slow down the loss of muscle mass and mitigate other manifestations of the disease.
TRPC6 (transient receptor potential canonical 6) is of particular importance in the development of Duchenne myodystrophy. This is a membrane protein, one of the ion channels that passes mainly calcium into the cell. TRPC6 activates stress hormones and mechanical effects. It has been shown that the pathological influx of calcium ions into myocytes devoid of dystrophin, leading to damage and ultimately cell death, occurs through this channel.
The authors of a new article in the Journal of Clinical Investigation — Insight (Lin et al. Pharmacological TRPC6 inhibition improves survival and muscle function in mice with duchenne muscular dystrophy), scientists from Johns Hopkins University, back in 2014 showed that when stretching muscle cells, the calcium flow in them in people with Duchenne myodystrophy increases more than in healthy people's cells. They also found that blocking the TRPC6 channel prevents excessive influx of Ca2+ into the heart cells and thereby reduces arrhythmia.
Unfortunately, the ion channel inhibitor that the authors used in the first experiments was metabolized too quickly in the body of laboratory animals, which made it unsuitable for use in the clinic.
It was necessary to find another substance with the same activity. It was the drug BI 749327, to which the new article is devoted. The drug was developed by Boehringer-Ingelheim, it can be taken orally, and BI 749327 derivatives are already undergoing clinical trials. It is known that it suppresses mainly fat metabolism genes and cellular signaling involving the cytokine TGFß1.
The effectiveness of the drug was tested on mouse models of Duchenne myodystrophy. The first model is a HET mouse line that does not have dystrophin and is haplon—sufficient for utrophin, a cytoskeleton protein whose expression is usually elevated in patients (mdx/utrn+/-). Such mice live on average only about two months. Starting from the third day of life, rodents of both sexes received either a TRPC6 inhibitor or a placebo in the form of subcutaneous injections. As expected, all the mice from the control group died by the 9th week. At the same time, the animals receiving BI 749327 lived twice as long. The condition of their muscles and heart, according to the tests, was 50% better. The animals receiving therapy moved one and a half times more and also faster.
"Although this molecule does not compensate for the absence of dystrophin, it successfully suppresses the pathological activity of another protein caused by the absence of dystrophin," comments David Kass, one of the authors of the article.
Similar results were obtained in experiments on the second model with much more severe manifestations — the homozygous line (mdx/utrn-/-). TRPC6 expression was blocked in these mice using BI 749327. Such animals lived almost three times longer than the control. The condition of mice in this line was also improved by knockout of the Trpc6 gene.
The researchers performed RNA sequencing of left ventricular myocardial cells in mdx/utrn-/-mice with Trpc6 knockout and without knockout, as well as those who received and did not receive the drug; expression changes affected lipid and glucose metabolism pathways, growth signaling pathways and fibrosis
The authors of the study believe that an oral drug based on BI 749327 can significantly prolong the life of patients with Duchenne myodystrophy.
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