The newly appointed RNA Institute Director, Dr. Andrew Berglund, recently published new research with clinical significance for myotonic dystrophy (DM) therapies in the American Chemistry Society’s journal Chemical Biology. He presented this work at the Myotonic Dystrophy Foundation’s 2018 Annual Conference on September 14-15 in Nashville Tennessee.
As potential new therapies for DM progress through preclinical and clinical evaluation, drug developers need new tools to design and conduct clinical trials. Research in the Berglund lab focuses on the identification of potential biomarkers and potential therapeutic molecules for microsatellite diseases such as myotonic dystrophy types 1 and 2, spinocerebellar ataxias, and amyotrophic lateral sclerosis (ALS). Previously, Drs. Andy Berglund, Eric Wang, Charles Thornton, and colleagues have shown that the levels of cell free MBNL from patient muscle samples, and the resulting differences seen in gene splicing events, correlated with the severity of DM symptoms present in patients. Identification of disease specific biomarkers is an essential tool in the evaluation of new drugs in early-stage clinical trials as they provide a much needed gauge in determining the effectiveness of new drugs to treat myotonic dystrophy. More recent studies in the Berglund lab have identified the mechanism of action for a small molecule, furamidine, previously shown to reduce CUG foci and rescue mis-splicing in both a DM1 HeLa cell model and the HSALR DM1 mouse model. Studies lead by Jana Jenquin demonstrated that use of furamidine in nanomolar concentrations led to an up-regulation of MBNL1 and MBNL2 protein levels and a reduction of ribonuclear RNA in a cell model system and also rescued many mis-splicing events in the HSALR DM1 mouse model. In addition, their studies revealed that furamidine had the lowest number of off-target gene expression changes compared to other small molecules that have been studied globally for DM.
Their work highlights the importance of assessing the activity of potential molecules for DM1 across various concentration ranges and in multiple model systems to fully assess their potential as therapeutic agents. The discovery of the mechanism of action for furamidine could also benefit many other related microsatellite diseases such as myotonic dystrophy type 2, spinocerebellar ataxia-8, and Fuchs’ corneal dystrophy to name just a few.
A copy of this paper can be found here: