Next steps for the optimization of exon therapy for Duchenne muscular dystrophy

ABSTRACT

Introduction

It is established that the exon-skipping approach can restore dystrophin in Duchenne muscular dystrophy (DMD) patients. However, dystrophin restoration levels are low, and the field is evolving to provide solutions for improved exon skipping. DMD is a neuromuscular disorder associated with chronic muscle tissue loss attributed to the lack of dystrophin, which causes muscle inflammation, fibrosis formation, and impaired regeneration. Currently, four antisense oligonucleotides (AONs) based on phosphorodiamidate morpholino oligomer (PMO) chemistry are approved by US Food and Drug Administration for exon skipping therapy of eligible DMD patients.

Areas covered

This review describes a preclinical and clinical experience with approved and newly developed AONs for DMD, outlines efforts that have been done to enhance AON efficiency, reviews challenges of clinical trials, and summarizes the current state of the exon skipping approach in the DMD field.

Expert opinion

The exon skipping approach for DMD is under development, and several chemical modifications with improved properties are under (pre)-clinical investigation. Despite existing advantages of these modifications, their safety and effectiveness have to be examined in clinical trials, which are planned or ongoing. Furthermore, we propose clinical settings using natural history controls to facilitate studying the functional effect of the therapy.

KEYWORDS:

• Duchenne muscular dystrophy
• neuromuscular disorder
• preclinical trial
• clinical trial
• exon skipping
• antisense oligonucleotides

Article highlights

• Duchenne muscular dystrophy (DMD) is a severe heritable muscle disorder caused by mutations in the DMD gene.

• FDA granted accelerated approval to four exon skipping compounds for DMD therapy.

• Functional effect of the approved exon skipping therapies has to be established.

• Application of natural history (NH) controls was suggested to assist in an evaluation of the functional effect.

• Additional chemical modifications of AONs showing enhanced oligonucleotides properties are being investigated in preclinical and clinical studies.

Declaration of interest

A Aartsma-Rus is an advisory board member for Sarepta Therapeutics, Silence Therapeutics, Eisai, and Hybridize Therapeutics. She is also an ad hoc consultant for PTC Therapeutics, Alpha Anomeric, BioMarin, Entrada, Takeda, Splicesense, Galapagos, and Astra Zeneca. 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.