“I think the myotonic dystrophy field has made great gains in understanding the mechanisms of this disease, and there a number of exciting therapeutic strategies underway,” Andrew Berglund says. “This includes clinical trials with antisense oligonucleotides that target the toxic RNA as well as other strategies that target other aspects of the disease.” 

Andrew Berglund, professor of biochemistry and molecular biology at the University of Florida in Gainesville, received an MDA research grant totaling $300,000 over three years to develop a therapeutic strategy for both types 1 and 2 myotonic dystrophy (DM1, DM2).

It is thought that the genetic defect underlying DM causes a toxic RNA, which accumulates in the nucleus of the cell and causes protein dysfunction by trapping proteins important for normal cell function. (RNA is the chemical step between DNA and protein manufacturing.) Some therapeutic approaches aim at degrading these toxic RNAs, or prevent them from trapping important cellular proteins. Berglund’s approach is to prevent the toxic RNA from even being produced in the first place.   

With colleagues, Berglund recently published proof-of-principle data supporting the approach they’ve developed, called IMPEDE (inhibition of microsatellite promoted expression of deleterious expansions), which showed that treatment with an FDA-approved drug called actinomycin D reduced toxic RNA production in DM1 cell and mouse models.

Now Berglund’s team is working to further develop this small-molecule approach. Small molecules have some advantages over other types of treatments — such as the ability to be given systemically and to get across the blood-brain-barrier.

If successful, this approach potentially could be used alone or in combination with other therapeutic strategies to treat myotonic dystrophy.

"I feel that the DM field is making impressive strides in deciphering the exact pathogenic mechanisms unleashed by the trinucleotide repeat expansion,” Auinash Kalsotra says. “This knowledge will undoubtedly lead to the development of new treatment modalities for this debilitating disease."

Auinash Kalsotra, assistant professor and Beckman Fellow at the University of Illinois in Urbana, was awarded an MDA research grant totaling $300,000 over three years to shed light on how defects develop in the heart in type 1 myotonic dystrophy (DM1).

While the mutation that underlies DM1 affects multiple tissues, cardiac defects are the second leading cause of death in individuals with DM1. However, the molecular mechanism(s) responsible for the cardiac pathogenesis remain poorly understood.

Kalsotra and colleagues have discovered that in DM1-diseased heart, the fetal non-muscle isoform of an RNA binding protein called RBFOX2 is significantly upregulated. By forcing the expression of the non-muscle isoform of RBFOX2 in adult mouse hearts, they have reproduced many of the cardiac dysfunctions observed in DM1, including arrhythmias and cardiac conduction defects.

Now, the team will determine how the balance between muscle and non-muscle isoforms for RBFOX2 is achieved during normal heart development. In addition, they will investigate how this regulation is disrupted in DM1 and why the selective expression of non-muscle RBFOX2 isoform triggers a cardiac disease phenotype.

These finding will offer important insight into how cardiac abnormalities develop in DM1, and may inform new approaches for cardiac care in individuals with DM1.