Utrophin Overexpression by Precise Base Editing of miRNA Binding Sites as a Universal Therapeutic Strategy for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a devastating muscular dystrophy that affects ~1:5,000 boys. Patients with DMD succumb to loss of mobility early in life, culminating in premature death from cardiac and respiratory failure. DMD is caused by mutations in the dystrophin gene and more than 7,000 mutations have been identified in DMD patients so far. Dystrophin acts like a shock absorber in the muscle cells reducing the mechanical stress induced by muscle contraction. Another protein, utrophin, can perform the same function, but it is lowly expressed in cardiac and skeletal muscles. Its low expression in muscle cells is partially due to the translational silencing mediated by small RNA molecules called miRNAs. The new gene editing technology of base editing has the potential to permanently introduce a precise modification in the utrophin gene to destroy the target sites of the miRNAs, therefore inhibiting the translational silencing of utrophin. This will result in the increase of utrophin protein in the dystrophic muscle cells with a consequent amelioration of the function of cardiac and skeletal muscles. Importantly, this project will develop a new universal treatment to enhance quality of life and extend the life span of all DMD patients, independently of the type of mutation.