A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health.

ABSTRACT: Despite the proven safety of dystrophin-targeting phosphorodiamidate morpholino oligomer (PMO) therapy, poor delivery of the PMOs limit the efficacy of this dystrophin restoring gene therapy for Duchenne muscular dystrophy (DMD). Limited myogenesis and excessive fibrosis in DMD are pathological features that contribute to the poor efficacy of PMOs. We show that the severe DMD mouse model (D2-mdx) not only replicates these pathological features of DMD but also mirrors the resulting PMO-mediated dystrophin restoration deficit. High transforming growth factor β (TGF-β) activity, which is a common feature of DMD patient and D2-mdx muscles, limits myogenesis and causes fibrosis. We developed a TGF-β-targeting PO (TPMO), which when used acutely, lowered macrophage TGF-β activity an

SUBMITTER: Moon YJ 

PROVIDER: S-EPMC12398789 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature