ジストロフィン遺伝子変異マウスにおけるアンチセンスオリゴヌクレオチド反復投与による行動改善

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the DMD gene that disrupt the production of functional dystrophin proteins. Intellectual disability and neurobehavioral complications including autism spectrum disorder, attention-deficit disorders, and anxiety cumulatively occur in 33%-43% of the patients due to deficiency of multiple dystrophin isoforms produced in brain. Previous work also identified behavioral abnormalities in the mdx23 mouse model of DMD. In this work we mapped the expression of the different dystrophin isoforms in different areas of the mouse brain. Next, we determined the behavioral phenotypes that best differentiate mdx23 (lacking the Dp427 isoform) and wild-type mice. Finally, we investigated the response to intracisternal magna (ICM) injection of exon-skipping phosphorodiamidate morpholino oligomer (PMO) antisense oligonucleotides, which induces skipping of exon 23 and restores the reading frame on these phenotypes. PMO administration led to low, detectable, restoration of dystrophin protein and DMD exon skipping in different brain regions. Treated mdx23 male mice exhibited a small but significant rescue of their enhanced fear response. We conclude that ICM delivery of PMO leads to low levels of dystrophin restoration, but these levels are sufficient to elicit a modest behavioral phenotype in mdx23 mice.