Interleukins 4 and 13 Induce Exon Skipping of Mutant Dystrophin Pre-mRNA to Restore Dystrophin Production

Duchenne muscular dystrophy is (DMD) a lethal muscle degenerative disease caused by nonsense or out of frame deletion mutations in the DMD gene, which encodes Dystrophin. While multiple therapeutic strategies to ameliorate the disease symptoms are under development, there is currently no cure. Here we report an unexpected finding that intramuscular injections of the anti-inflammatory interleukin 4 or 13 (IL4/13) not only reduce inflammation but also restore Dystrophin protein production in the mdx mouse model. IL4/13 restores Dystrophin production by inducing changes in the Dmd pre-mRNA splicing pattern that exclude the mutated exon and restore the reading frame. We further show that systemic delivery of IL4-Fc can restore Dystrophin in multiple muscle groups and increase muscle endurance and strength in mdx mice. Importantly, IL4/13 treatment of mdx myoblasts is sufficient to induce exon skipping and restore Dmd reading frame in vitro. Moreover, IL4-treated DMD patient myoblasts produce Dystrophin-positive myofibers after transplantation. In light of the established clinical safety of IL4 treatment, we recommend IL4 as an agent of immediate consideration for treating Duchenne muscular dystrophy.