The major challenge of exon skipping therapy in Duchenne muscular dystrophy is to effectively deliver the antisense oligonucleotides to the targeted tissues, in this case the muscles. After obtaining encouraging results over four weeks, a French team assessed the benefits of combining valproic acid with antisense oligonucleotides designed to skip exon 23 of the DMD gene in an mdx mouse model over a longer period of 12 weeks.
- Valproic acid significantly increased the accumulation of antisense oligonucleotides in skeletal and cardiac muscle tissue, resulting in high levels of targeted exon skipping.
- This results in a significant increase in dystrophin expression in various muscle tissues (+70% on average compared with exon skipping alone), with a 1.8-fold increase in the heart.
- A significant improvement in muscle function, assessed using various tests, was also observed.
- The overall safety profile was favourable, although early signs of nephrotoxicity and minimal adverse effects were observed on histopathology.
Evaluation in larger animal models will provide new data on this approach in a more relevant clinical context.
