Myotonic dystrophy type 1 (DM1) is a form of muscular dystrophy and a genetic neuromuscular disease affecting at least 1 in 8,000 people worldwide, or approximately 45,000 people in the United States. It is a multi-system disease, affecting the skeletal muscle, heart, diaphragm, central nervous system, and gastrointestinal tract. DM1 is caused by a trinucleotide (CUG) repeat expansion in the mRNA encoding myotonic dystrophy protein kinase (DMPK) that results in the formation of nuclear aggregates that bind and sequester splicing factors such as Muscleblind-Like Splicing Regulator 1 (MBNL1). Depletion of critical splicing factors leads to global splicing abnormalities and widespread pathology. There are no approved disease-modifying treatments for DM1, but several muscle-targeted oligonucleotide therapies are in clinical development. These therapies show evidence of addressing skeletal muscle defects in patients but are unlikely to fully address systemic manifestations of the disease.
Here we present preclinical data on RNA-targeted small molecules (rSMs) that selectively bind the pathogenic CUG repeat RNA and release MBNL1 from nuclear aggregates. In DM1 donor cells with 2,600 CTG repeats, rSMs reduce nuclear aggregates by 90% and correct splicing defects in a dose-dependent manner. rSMs also modulate splicing in skeletal muscle and completely reverse myotonia in the HSALR mouse model. The compounds are orally bioavailable and broadly biodistributed to multiple impacted tissues.
Although muscle pathology is a significant component of DM1, an orally bioavailable, broadly biodistributed rSM has the potential to address systemic manifestations of the disease beyond skeletal muscle and establish that rSMs represent a new class of small-molecule genetic medicines that directly address the genetic basis of disease.