Biological and genetic therapies for the treatment of Duchenne muscular dystrophy

ABSTRACT

Introduction

Duchenne muscular dystrophy is a lethal genetic disease which currently has no cure, and poor standard treatment options largely focused on symptom relief. The development of multiple biological and genetic therapies is underway across various stages of clinical progress which could markedly affect how DMD patients are treated in the future.

Areas covered

The purpose of this review is to provide an introduction to the different therapeutic modalities currently being studied, as well as a brief description of their progress to date and relative advantages and disadvantages for the treatment of DMD. This review discusses exon skipping therapy, microdystrophin therapy, stop codon readthrough therapy, CRISPR-based gene editing, cell-based therapy, and utrophin upregulation. Secondary therapies addressing nonspecific symptoms of DMD were excluded.

Expert opinion

Despite the vast potential held by gene replacement therapy options such as microdystrophin production and utrophin upregulation, safety risks inherent to the adeno-associated virus delivery vector might hamper the clinical viability of these approaches until further improvements can be made. Of the mutation-specific therapies, exon skipping therapy remains the most extensively validated and explored option, and the cell-based CAP-1002 therapy may prove to be a suitable adjunct therapy filling the urgent need for cardiac-specific therapies.

KEYWORDS:

• Cardiosphere-derived cells (CDC)
• CRISPR-Cas9
• Duchenne muscular dystrophy (DMD)
• exon skipping therapy
• microdystrophin
• stop codon readthrough
• utrophin

Article highlights

• Exon skipping therapy remains among the most clinically advanced DMD therapeutics, with four candidates having received conditional FDA approval

• Two candidates for microdystrophin therapy are currently in phase III clinical trials, although safety concerns have caused delays

• Ataluren, the lead readthrough therapy candidate, is in longitudinal phase III trials following FDA rejection but acceptance in the EMA for the treatment of DMD arising from nonsense mutations

• Cell-based therapy could serve as a valuable cardiac-specific therapeutic, with a candidate in phase III trials

• Utrophin therapy remains in its early stages and warrants more studies before its clinical utility can truly be ascertained

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank Ahad Shah for verbal feedback.

Declaration of interest

T Yokota is a founder and shareholder of OligomicsTx, which aims to commercialize

antisense oligonucleotide technology. 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 supported by grants to T Yokota from Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Alberta Innovates: Health Solutions (AIHS), Jesse’s Journey, and the Women and Children’s Health Research Institute (WCHRI).