Exon skipping: a first in class strategy for Duchenne muscular dystrophy

ABSTRACT

Introduction: Exon skipping is a therapeutic approach for Duchenne muscular dystrophy (DMD) that has been in development for close to two decades. This approach uses antisense oligonucleotides (AONs) to modulate pre-mRNA splicing of dystrophin transcripts to restore the disrupted DMD reading frame. The approach has moved from in vitro proof of concept studies to the clinical trial phase and marketing authorization applications with regulators. The first AON (eteplirsen) has recently received accelerated approval by the Food and Drug Administration in the US.

Areas covered: In this review the authors explain the antisense-mediated exon skipping approach, outline how it needs be tailored for different DMD mutation types and describe the challenges and opportunities for each mutation type. The authors summarize the clinical development of antisense-mediated exon 51 skipping, and discuss methods to improve efficiency. Finally, the authors provide their opinion on current developments and identify topics for future prioritization.

Expert opinion: Exon skipping development has been a learning experience for all those involved. Aside from an approved therapy, its development has yielded side benefits including the development of tools for clinical trials and has increased collaboration between academics, patients, industry and regulators.

KEYWORDS:

• DMD
• dystrophin
• antisense oligonucleotide
• splicing
• therapy

Article highlights

• Duchenne muscular dystrophy is a severe, progressive muscle wasting disease with unmet medical need

• Antisense-mediated exon skipping is a therapeutic approach that aims to increase production of partially functional dystrophin proteins

• Antisense-mediated exon skipping is a mutation specific approach

• Clinical development of exon skipping compounds has been challenging due to the lack of natural history data and clinical trial tools

• Stakeholder collaboration in the DMD field has generated new tools for clinical trials that hopefully will facilitate future therapy development for DMD

This box summarizes key points contained in the article.

Declaration of interest

A Aartsma-Rus reports grant from the Duchenne Parent Project, ZonMw, an EU FP7 grant, AFM (The French Muscular Dystrophy Association), the Parent Project Muscular Dystrophy (PPM) and the Prinses Beatrix Spierfonds. She is also employed by the Leiden University Medical Center (LUMC), which has patents on exon skipping technology. As co-inventor of some patents, she is entitled to royalties. She also serves as an ad hoc consultant for several companies (BioClinica, Grunenthal, BioMarin, Summit, PTC Therapeutics, Global Guidepoint, GLC Consulting and Deerfield Consulting. Renumeration for these activities and speaker honoraria go to Leiden University Medical Center. EH Niks reports grants from the Duchenne Parent Project, ZonMW and the French Muscular Dystrophy Association and has received trial support from BioMarin, GlaxoSmithKline, Eli Lilly & Company and Santhera. He also reports acting as a consultant for BioMarin and Summit. Again, all reimbursements were received by the LUMC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are employees of and therefore funded by the Leiden University Medical Center.