Format

Send to

Choose Destination
Methods Mol Biol. 2018;1687:171-183. doi: 10.1007/978-1-4939-7374-3_12.

The Use of Antisense Oligonucleotides for the Treatment of Duchenne Muscular Dystrophy.

Author information

1
U1179 INSERM, UFR des Sciences de la Santé-LIA BAHN CSM, Université de Versailles St-Quentin en Yvelines, 2 Avenue de la Source de la Bievre, 78180, Montigny le Bretonneux, France.
2
SQY Therapeutics, UFR des Sciences de la Santé, Université de Versailles Saint-Quentin en Yvelines, Montigny-le-Bretonneux, France.
3
U1179 INSERM, UFR des Sciences de la Santé-LIA BAHN CSM, Université de Versailles St-Quentin en Yvelines, 2 Avenue de la Source de la Bievre, 78180, Montigny le Bretonneux, France. aurelie.goyenvalle@uvsq.fr.

Abstract

Antisense oligonucleotides (AONs) hold great promise for therapeutic splice-switching correction in many genetic diseases and in particular for Duchenne muscular dystrophy (DMD), where AONs can be used to reframe the dystrophin transcript and give rise to a partially deleted but yet functional dystrophin protein. Many different chemistries of AONs can be used for splice switching modulation, and some of them have been evaluated in clinical trials for DMD. However, despite advances in AON chemistry and design, systemic use of AONs is limited due to poor tissue uptake, and sufficient therapeutic efficacy is difficult to achieve. Therefore, there is still a critical need to develop efficient AONs able to restore the expression of dystrophin in all relevant tissues and international efforts are currently on going to develop new compounds or alternative chemistries with higher therapeutic potential. Here, we describe the methods to evaluate the potency of antisense oligonucleotides, and in particular of tricyclo-DNA (tcDNA)-AONs, a novel class of AONs which displays unique pharmacological properties and unprecedented uptake in many tissues after systemic administration. We focus on the most widely used mouse model for DMD, the mdx mouse and detail methods to analyze the skipping of the mouse exon 23 both in vitro in H2K mdx cells and in vivo in the mdx mouse model.

KEYWORDS:

Antisense oligonucleotides (AONs); Duchenne muscular dystrophy; Exon skipping; Splice-switching approaches; Tricyclo-DNA

PMID:
29067663
DOI:
10.1007/978-1-4939-7374-3_12
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center