Interleukins 4 and 13 Induce Exon Skipping of MutantDystrophinPre-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 1 , which encodes Dystrophin 2,3 . 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 4 . 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 5,6 , we recommend IL4 as an agent of immediate consideration for treating Duchenne muscular dystrophy.