Developing DMD therapeutics: a review of the effectiveness of small molecules, stop-codon readthrough, dystrophin gene replacement, and exon-skipping therapies

ABSTRACT

Introduction

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin (DMD) gene. Most patients die from respiratory failure or cardiomyopathy. There are significant unmet needs for treatments for DMD as the standard of care is principally limited to symptom relief through treatments including steroids.

Areas Covered

This review summarizes safety and efficacy in promising areas of DMD therapeutics – small molecules, stop codon readthrough, gene replacement, and exon skipping – under clinical examination from 2015–2020 as demonstrated in the NIH Clinical Trials and PubMed search engines.

Expert Opinion

Currently, steroids persist as the most accessible medicine for DMD. Stop-codon readthrough, gene replacement, and exon-skipping therapies all aim to restore dystrophin expression. Of these strategies, gene replacement therapy has recently gained momentum while exon-skipping retains great traction. The  FDA approval of three exon-skipping antisense oligonucleotides illustrate this regulatory momentum, though the effectiveness and sequence design of eteplirsen remain controversial. Cell-penetrating peptides promise to more efficaciously treat DMD-related cardiomyopathy.The recent success of antisense therapies, however, poses major regulatory challenges. To fully realize the benefits of exon-skipping, including cocktail oligonucleotide-mediated multiple exon-skipping and oligonucleotide drugs for very rare mutations, regulatory challenges need to be addressed in coordination with scientific advances.

KEYWORDS:

• Ataluren
• deflazacort
• dystrophin
• n-of-1 clinical trial
• ppmo (peptide-conjugated phosphorodiamidate morpholino oligomer)
• prednisone
• vamorolone (also known as VBP15)
• viltolarsen
• gene replacement therapy

Article highlights

• We review developments in four key areas of investigational DMD therapeutics:1. steroids and small molecules, 2. stop codon readthrough, 3. dystrophin gene replacement therapy, and 4. exon-skipping.

• Based on progress through clinical trials, momentum is concentrated within gene replacement and exon-skipping therapies.

• Currently, gene replacement therapy for DMD has demonstrated promise in Phase I/II trials, positioning therapies by Pfizer and Sarepta for Phase III trials.

• The exon-skipping therapies golodirsen and viltolarsen, which skip exon 53, have received approval in the US, highlighting the field’s progress.

• Antisense oligonucleotide delivery and sequence optimization remain key to successful exon-skipping.

• Regulatory pathways must be urgently prepared for mutation-customized therapies including cocktail antisense oligonucleotide-mediated multiple exon-skipping and oligonucleotide drugs for very rare mutations.

Acknowledgments

The authors wish to thank Stanley Woo, Kenji Lim, Rika Maruyama, and Justin Alan Middleton for feedback during the creation of this paper.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One peer reviewer is an inventor on patents covering the DMD exon skipping drugs Eteplirsen and Golodirsen described in this review. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research (CIHR), Alberta Innovates: Health Solutions (AIHS), Jesse’s Journey, Fulbright Scholarship Program, and the Women and Children’s Health Research Institute (WCHRI). The authors wish to thank Stanley Woo, Kenji Lim, Rika Maruyama, and Justin Alan Middleton for feedback during the creation of this paper.