FIG. 1.

Route of AONs from administration to therapeutic effects in mdx muscle. Upon dosing of M23D, it is taken up in muscle, where it induces exon 23 skipping of mouse dystrophin, resulting in production of dystrophin. The increase in dystrophin gives rise to an improvement of muscle integrity, which can be assessed by quantifying several markers of muscle leakiness and by MRI to assess hyperintense regions in muscle representing edemic damage. Ultimately, the improved muscle integrity results in an improvement of muscle performance. (A) The used methods for each step are indicated in italics below the corresponding arrow. (B) Study design. mdx mice (n = 15), 5 weeks of age at first dose, received either twice weekly SC injections or once weekly IV injections of 100 mg/kg with M23D for a total of 12 weeks. A scrambled M23D AON was taken along as a control for the SC dosing group. The total dose is indicated. Mice were subjected to MotoRater analysis at 14 weeks of age and to MRI at 15 weeks of age. AON, antisense oligonucleotide; IV, intravenous; MRI, magnetic resonance imaging; SC, subcutaneous.