In Vivo Evaluation of Exon 51 Skipping in hDMD/Dmd-null Mice.

Duchenne muscular dystrophy (DMD) is a fatal X-linked condition that affects 1 in 3500-6000 newborn boys a year. An out-of-frame mutation in the DMD gene typically causes the condition. Exon skipping therapy is an emerging approach that uses antisense oligonucleotides (ASOs), short synthetic DNA-like molecules that can splice out mutated or frame-disrupting mRNA fragments, to restore the reading frame. The restored reading frame will be in-frame and will produce a truncated, yet functional protein. ASOs called phosphorodiamidate morpholino oligomers (PMO), including eteplirsen, golodirsen, and viltolarsen, have recently been approved by the US Food and Drug Administration as the first ASO-based drugs for DMD. ASO-facilitated exon skipping has been extensively studied in animal models. An issue that arises with these models is that the DMD sequence differs from the human DMD sequence. A solution to this issue is to use double mutant hDMD/Dmd-null mice, which only carry the human DMD sequence and are null for the mouse Dmd sequence. Here, we describe intramuscular and intravenous injections of an ASO to skip exon 51 in hDMD/Dmd-null mice, and the evaluation of its efficacy in vivo.