AOC 1001 for Myotonic Dystrophy Type 1
Myotonic Dystrophy Type 1 (DM1) is a progressive disease that impacts skeletal and cardiac muscle. More than 40,000 people are affected in the U.S. and the condition has no approved therapies. Individuals with DM1 suffer from muscle weakness, respiratory and cardiac problems, severe gastrointestinal complications, and cognitive and behavioral impairment—resulting in significant decline in quality of life and large caregiver burden. The disease is highly variable from patient to patient and with respect to disease severity, presentation, and age of onset.
DM1 is caused by an increase in the number of CUG triplet repeats found in the myotonic dystrophy protein kinase (DMPK) gene. In a healthy individual the number of repeats is approximately 35 but in someone with DM1 there can be thousands. When there are too many CUG repeats, large hairpin loops form trapping DMPK mRNA in the nucleus, effectively sequestering muscleblind-like protein (MBNL) and reducing its activity. Specifically, mutated DMPK mRNA binds to MBNL, a critical CUG-binding protein, forming nuclear foci and preventing MBNL from performing its normal function of processing the mRNAs for many other genes. As a result, multiple mRNAs that encode key proteins are misprocessed, resulting in atypical proteins that ultimately are the cause of DM1. Our therapeutic approach is to reduce DMPK and CUG levels thereby reducing nuclear foci and relieving the sequestration of MBNL so that MBNL can perform its normal function.