'CRISPR-DM1': In vivo CRISPR/Cas9-mediated correction of triplet nucleotide repeat expansion in myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a genetic disorder that severely affects the skeletal muscle, diaphragm and heart, resulting in progressive muscle wasting, myotonia and severe disability.
Cardiac arrhythmia and sudden death are the major cause of mortality in DM1 patients. The disease is caused by a triplet nucleotide repeat expansion resulting in the accumulation of a pathogenic mRNA in the cell nucleus. This perturbs splicing and results in the accumulation of ribonuclear foci in the nucleus, one of the hallmarks of DM1. Unfortunately, there is currently no cure or effective
treatment available and the exact "downstream" mechanisms of this disease are not fully understood. This 'CRISPR-DM1' project focuses on the development of an innovative and effective muscle-specific gene therapy platform that relies on CRISPR/Cas9 gene editing to excise the pathogenic CTG triplet repeat expansion in vivo, in a preclinical DM1 mouse model. We expect that this would reduce the accumulation of pathogenic mRNA and thus ameliorate the DM1 phenotypes. High-throughput RNA sequencing and computational approaches will be performed to investigate the molecular, cellular and physiologic consequences of preventing pathogenic mRNA expression by CRISPR/Cas-based gene editing in vivo. Ultimately, this 'CRISPR-DM1' project may pave the way towards a potential cure for DM1, while contributing to the identification of novel DM1-associated pathways.