Gene therapy for Duchenne muscular dystrophy: an update on the latest clinical developments

ABSTRACT

Introduction

Duchenne muscular dystrophy (DMD) is one of the most severe and devastating neuromuscular hereditary diseases with a male newborn incidence of 20 000 cases each year. The disease caused by mutations (exon deletions, nonsense mutations, intra-exonic insertions or deletions, exon duplications, splice site defects, and deep intronic mutations) in the DMD gene, progressively leads to muscle wasting and loss of ambulation. This situation is painful for both patients and their families, calling for an emergent need for effective treatments.

Areas covered

In this review, the authors describe the state of the gene therapy approach in clinical trials for DMD. This therapeutics included gene replacement, gene substitution, RNA-based therapeutics, readthrough mutation, and the CRISPR approach.

Expert opinion

Only a few drug candidates have yet been granted conditional approval for the treatment of DMD. Most of these therapies have only a modest capability to restore the dystrophin or improve muscle function, suggesting an important unmet need in the development of DMD therapeutics. Complementary genes and cellular therapeutics need to be explored to both restore dystrophin, improve muscle function, and efficiently reconstitute the muscle fibers in the advanced stage of the disease.  

KEYWORDS:

• Gene therapy
• DMD
• dystrophin
• Asos
• snRNA
• readthrough mutation
• gene transfer
• gene substitution

Article highlights

• DMD is a severe and devastating neuromuscular hereditary disease with a male newborn incidence of 20 000 cases every year.

• The significance of gene therapy development for DMD in recent years is a great enthusiasm for the Duchenne community.

• Finding new strategies to reduce discontinuous trials may help accelerate drug development and the recovery of effective therapeutic unmet needs.

• The development of multiplex and combinatory approaches will significantly improve biological and clinical outcomes.

• The genome editing option for DMD using technologies such as the CRISPR Cas system has the advantage of permanently modifying the DMD gene but, consideration has to be taken of the capacity of the chosen system to modify muscle progenitor cells.

Declaration of interest

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

One reviewer declares clinical trial support from Astellas Gene Therapies, Sarepta Therapeutics and Novartis Gene Therapies. They also serve on the advisory board of Sarepta Therapeutics. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by grants from the Canadian Institute of Health Research (CIHR) and the The Cell network (Réseau de Thérapie Cellulaire, Tissulaire et Génique du Québec) of the Fond de Recherche du Québec en Santé (FRQS).