Myotonic Dystrophy is a Multi-Organ Disease Mediated by Abnormalities in the RNA of a Key Gene
The Expansion Therapeutics Difference
Expansion’s approach to treating DM1 is focused on designing novel small molecule medicines that can selectively bind the disease-causing toxic r(CUG) structures in DMPK RNA. By doing so, these molecules can displace MB from the RNA and free it to fulfill its function and regulate pre-mRNA splicing. In this way, the splicing of hundreds of genes will be corrected across multiple tissues, including brain and heart, as well as muscle, thus restoring function across the whole body.
Myotonic dystrophy type 1 (DM1) is a common muscular dystrophy, affecting 1:8,000 people worldwide and over 40,000 people in the US. DM1 is an inherited condition that impacts multiple organ systems and is broadly characterized by progressive muscle weakness and delayed muscle relaxation (myotonia), cardiac conduction abnormalities, excessive daytime sleepiness, severe fatigue, and endocrine dysfunction. Difficulties in cognitive function and social interactions can also occur, especially in young-onset patients.
DM1 results from a mutation in the DMPK gene that encodes the myotonic dystrophy protein kinase. The mutation is termed a repeat expansion mutation because it is characterized by long repeats of the trinucleotide CUG in the DMPK pre-mRNA. Whereas most healthy people have less than 40 repeats, DM1 patients can have hundreds of repeats. These CUG repeats form stable, RNA structures which in turn bind to and sequester a protein called muscleblind (MB). Under normal conditions, MB regulates the splicing of hundreds of pre-mRNAs encoding proteins critical for the proper function of skeletal and cardiac muscle, as well as the brain and nervous system. When sequestered, MB cannot coordinate correct pre-mRNA splicing. Hundreds of critical genes are therefore mis-spliced, leading to the diverse array of muscular, cardiac and neurological abnormalities seen in this disorder.
Current medical approaches can only treat the symptoms of the disease. Many patients are fitted with a pacemaker to avoid severe cardiac arrythmias. Devices to assist with sleep apnea and medications to increase daytime wakefulness can be useful, although for some patients, these aspects are severe and intractable. Assistive technology can help with ambulation. There is no treatment that addresses the root cause of the disease.
Myotonic Dystrophy type 1 (DM1) is a multi-system disorder affecting many tissues in the body. It is caused by an expansion mutation in the DMPK gene. A related disorder, DM2, is caused by a similar repeat expansion in the CNBP gene.