A French team evaluated the efficacy of small molecules (UNC7938) in mdx mice to increase the availability of antisense oligonucleotides in the cell, by facilitating their escape from the cellular endosomes in which they are trapped.
The mdx mice were injected intravenously with a therapeutic treatment combining tricyclo-DNA antisense targeting mutated exon 23 and UNC7938. The results showed :
- a significant improvement in exon skipping levels, particularly in the early stages of treatment, with up to a 4. 4x increase in the heart 72 hours after injection;
- significantly higher levels of restored dystrophin, two weeks after the end of treatment, with 2.7 times more protein in the heart compared with mice treated with oligonucleotides alone;
- normalisation of cardiac function three months after the end of treatment, comparable to the group of non-diseased mice.
These results suggest that these compounds, which facilitate endosomal escape, can considerably improve the therapeutic potential of exon skipping approaches.
