For the first time, children with severe congenital myopathy may have a better chance at learning to walk thanks to a new therapeutic approach using enzyme-inhibiting cancer drugs, as reported in the journal eLife.
Professor Susan Treves remembers seeing one child affected by the condition at the age of six months. The boy seemed more like a newborn, she said. Today, several years later and thanks to intensive physiotherapy, he is at least able sit. “He made it,” she said. As yet there is no cure for children like this one. Their first priority is survival. Another child with mutations in the same gene as the boy mentioned above, did not survive. However, his genetic alterations now form the basis of a therapeutic approach presented by the research group led by Professors Susan Treves and Francesco Zorzato.
The affected gene is for the calcium channel RYR1 in skeletal muscle. The mutations render the gene useless, which severely impacts muscle function. The researchers used the gene alterations found in a patient, as a template to develop a mouse model for this type of congenital myopathy. “The mice don’t die, but their muscle system is severely impaired,” says Treves. “They’re smaller, and move much less.” With a combination of two drugs, however, the research team was able to significantly improve muscle function and movement of the mice.
The therapy is based on the observation that certain enzymes are produced in excessive quantities in the skeletal muscles of affected patients. These enzymes – histone deacetylases and DNA methyltransferases – affect how densely genes are packed, making them less accessible to the cellular machinery that reads them and translates them into instructions for protein production.
Prof Treves and her team used inhibitors against these enzymes, which are already approved as cancer drugs or are in clinical trials. The treatment significantly improved the mice’s movement ability, although they were still smaller. No adverse side effects were noted during the study period.
The approach is still far from being a clinical therapy, said Prof Treves. “But it’s a first step in the right direction.” The researchers aim to further optimise the treatment and test combinations of newly developed drugs targeting the same enzymes for even better effects. “We anticipate around about two more years of optimisation and testing before we can initiate a phase I clinical trial,” she said.
For Profs Treves and Zorzato, these first promising results are the culmination of 10 years of research – especially as Prof Zorzato was the one who first isolated the gene affected in these muscle disorders years ago. “We’ve now succeeded in bridging the gap from the isolation of the affected gene to a therapeutic approach,” said Prof Treves.
Source: University of Basel
