Periostin Exon 17 Skipping Enhances the Efficacy of Local Adeno-Associated Viral-Microdystrophin Administration in a Fibrotic Model of Duchenne Muscular Dystrophy.

Abstract

Duchenne muscular dystrophy (DMD) is a severe, progressive genetic disorder primarily affecting boys, characterized by muscle degeneration due to mutations in the DMD gene encoding dystrophin, a crucial protein for muscle fiber integrity. The disease leads to significant muscle weakness and eventually to loss of ambulation. Adeno-associated viral (AAV)-microdystrophin (MD) gene therapy shows promise in preclinical and clinical settings. However, muscle fibrosis, a consequence of chronic inflammation and extracellular matrix remodeling, exacerbates disease progression and may hinder therapeutic efficacy. Periostin, a matricellular protein involved in fibrosis, is upregulated in DMD rodent models and correlates with collagen deposition. We previously developed an antisense oligonucleotide strategy to induce exon 17 skipping and so reduce periostin expression and collagen accumulation in the fibrotic D2.mdx mouse model of DMD. Here, we investigated the combined effects of periostin modulation and AAV-MD1 treatment. We found that systemic periostin splicing modulation significantly improved muscle function, assessed by forelimb grip strength and treadmill performance. Importantly, periostin exon skipping increased the MD protein expression. These findings suggest that targeting periostin in conjunction with MD therapy could represent a valid therapeutic strategy for DMD.