Periostin exon 17 skipping enhances the efficacy of local AAV-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. AAV-microdystrophin gene therapy shows promise in preclinical and clinical settings. However, muscle fibrosis, a consequence of chronic inflammation and extracellular matrix (ECM) 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-microdystrophin (AAV-MD1) treatment. We found that systemic periostin splicing modulation with intramuscular AAV-MD1 administration significantly improved muscle function, assessed by grip strength and treadmill performance, compared to either single treatment. Importantly, periostin exon skipping increases the microdystrophin protein expression. These findings suggest that targeting periostin in conjunction with microdystrophin therapy could represent a valid therapeutic strategy for DMD.