Researchers studying characteristics of cells isolated from muscular dystrophy patients may have found a new target to develop precision medicine. The research team found that certain molecules are increased in defective muscle fibers, and treatments that act against these molecules, such as anti-inflammatories, may be able to block their action.
Becker muscular dystrophy (BMD), a less severe form of muscular dystrophy, is caused by a mutation in the gene encoding dystrophin (DMD). Although the DMD gene is mutated, the portion that allows for dystrophin protein production is preserved. Rather than ablate dystrophin protein, the mutation causes a shortened version of the protein to be produced by cells at a lower level than full-length dystrophin.
Interestingly, the level of dystrophin production is variable between muscle fibers of the same patient with BMD, rather than the same in each cell. Additionally, dystrophin levels are variable between patients with BMD. This suggests that there may be something inside cells that leads to post-transcriptional dystrophin regulation. Lead author Dr. Alyson A. Fiorillo and principal investigator Dr. Eric P. Hoffman, of the Center for Genetic Medicine Research at Children’s National Medical Center in Washington, DC, hypothesized that miRNAs (molecules that negatively regulate protein production) may be the underlying reason for variable dystrophin production.
Using a cohort of patients with the same mutation in DMD (Δ45–47 exon deletion), Dr. Fiorillo, Dr. Hoffman, and colleagues were able to draw a number of conclusions regarding variable dystrophin levels in BMD patients. They reported their results in “TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy,” which was published in Cell Reports.
First, as was expected, the level of DMD gene expression did not correlate to the level of dystrophin protein in cells. Dystrophin protein content in BMD cells ranged from 8% to 63% of that of normal cells. Patients with greater than 20% dystrophin were considered “high,” and less than 20% were considered “low.” In order to protect muscle fibers, patients must have more than 20% dystrophin.
Looking closer, the researchers next found a set of miRNAs that were elevated in the cells and that targeted dystrophin mRNA. The team exposed cells grown in vitro to these miRNAs and found that miR-146b, miR-31, and miR-374a yielded the greatest inhibition of dystrophin. It appeared as these miRNAs were induced by the pro-inflammatory molecule TNF-α. Going into an animal model, treating mice with anti-inflammatory molecules protected the animals from developing a severe phenotype of muscular dystrophy.
“Here, we show proof of principle that dystrophin is reduced by inflammation-induced miRNAs that are elevated in dystrophic muscle,” wrote Dr. Fiorillo. “This work could potentially provide an avenue for molecular-based therapy for BMD patients and an adjuvant therapy in DMD to increase exon skipping effectiveness.” Testing patients for expression of these miRNAs and then providing appropriate anti-inflammatory treatment may serve as a viable option to reduce the severity of BMD.