Grant: CIHR Fellowship

Duchenne muscular dystrophy is a severe muscle disease caused by mutations in the DMD gene, which produces a protein called dystrophin. This gene is located on the X chromosome, and thus almost exclusively affects boys. This is the most common childhood- onset muscular dystrophy, affecting 1 in 5000 male newborns. The disease causes progressive muscle weakness, and most boys lose the ability to walk by age 12. The heat and respiratory muscles are also affected, and these complications frequently lead to death in the 20s and 30s. Although some medications can slow progression of the disease, there is currently no curative treatment for Duchenne muscular dystrophy. In this project, we aim to develop a new method to correct a very common DMD mutation using CRISPR/Cas9 genome editing. This method makes use of a process called homology-independent targeted integration (HITI), which is a more efficient way of introducing DNA into muscle cells. Unlike previously described genome editing methods, this also allows production of the complete dystrophin protein, rather than a shortened version. Although we are planning to initially develop this method for correction of one particular DMD mutation, we anticipate that it can be adapted to correct a broader range of mutations in the same region. We have already collected data showing that HITI can be used to correct a different set of DMD mutations. Based on this experience, we will conduct experiments in cells obtained from DMD patients, in order to develop the new methodology. After optimising several aspects of the design in these cells, we will test the system in a mouse carrying the same mutation. We hope that this will represent the first step towards bringing genome editing for DMD into clinical use.