Development of Multiexon Skipping Antisense Oligonucleotide Therapy for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an incurable, X-linked progressive muscle degenerative disorder that results from the absence of dystrophin protein and leads to premature death in affected individuals due to respiratory and/or cardiac failure typically by age of 30. Very recently the exciting prospect of an effective oligonucleotide therapy has emerged which restores dystrophin protein expression to affected tissues in DMD patients with highly promising data from a series of clinical trials. This therapeutic approach is highly mutation specific and thus is personalised. Therefore DMD has emerged as a model genetic disorder for understanding and overcoming of the challenges of developing personalised genetic medicines. One of the greatest weaknesses of the current oligonucleotide approach is that it is a mutation-specific therapy. To address this limitation, we have recently demonstrated that exons 45–55 skipping therapy has the potential to treat clusters of mutations that cause DMD, which could significantly reduce the number of compounds that would need to be developed in order to successfully treat all DMD patients. Here we discuss and review the latest preclinical work in this area as well as a variety of accompanying issues, including efficacy and potential toxicity of antisense oligonucleotides, prior to human clinical trials.

Translational and Regulatory Challenges for Exon Skipping Therapies

“…Multiexon skipping (skipping of more than 2 exons) has been proposed as a method to reduce the mutation specificity of DMD exon skipping (Aartsma-Rus et al, 2004;Aoki et al, 2013).…”

Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy

“…BMD patients have a shortened, but functional, dystrophin protein that maintains both termini 3,6,18 . Exon skipping, in theory, can restore the reading frame, resulting in shortenedbut-functional dystrophin proteins similar to those seen in BMD 3,19 .…”

“…Skipping exons 51 and 53 using these AONs has been examined and while results are promising, single-exon skipping has limited applicability, as it is mutation-specific 3,19,20,21,[22][23][24][25][26] . Questions also remain about the stability of the resulting shortened dystrophin proteins produced from single-exon skipping 22,23 .…”

“…Compared with single-exon skipping, multi-exon skipping is applicable to a much larger proportion of patients. Among the three most common mutation types (deletions, nonsense, and duplications), 80 -98% of patients could be treated through multi-exon skipping 14,32,33 , while 45% of all DMD patients could benefit from specifically skipping exons 45 -55 3,19,22,34 .…”

Non-invasive assessment of skeletal muscle pathology and treatment for Duchenne muscular dystrophy

“…Considerable promising research is currently being conducted to treat DMD. These areas of research include viral (and other) delivery of mini or microdystrophin variants 1,2 , stem/ progenitor cell transplantation 3 , exon skipping 4 and analog (eg. utrophin) upregulation 5 .…”