Antisense oligonucleotides as personalized medicine for Duchenne muscular dystrophy

• Antisense-induced exon skipping is an investigational, molecular, mutation-specific therapy for Duchenne muscular dystrophy (DMD).
• Two clinical drug candidates, drisapersen and eteplirsen, address mutations found in 13% of patients with DMD.
• Additional oligonucleotides need to be developed for subsequent, smaller subpopulations of mutations.
• This will require a nonstandard, orphan drug-tailored design of the (clinical) development program.
• To achieve this, extrapolation between clinical study data on antisense oligonucleotides and patient groups will be essential.

In recent years, the use of antisense oligonucleotides (AONs) as RNA-modulating therapeutics has made significant progress. For the treatment of Duchenne muscular dystrophy (DMD), two chemically distinct oligonucleotides inducing specific exon 51 skipping from the DMD gene's pre-messenger RNA are currently being studied in phase II and III clinical trials. Depending on their efficacy, safety profile and approval by regulators, oligonucleotides targeting additional exons to address other mutations need to follow, through more tailor-made, shorter, development programs. This review provides an overview of the current developmental status of AONs for DMD and summarizes the challenges and discussions for such personalized mutation-specific therapeutics progressing through the development pipeline.