Researchers studied the turnover of dystrophin and dystroglycan complex (DGC) proteins in mice with Duchenne Muscular Dystrophy (DMD) after receiving exon skipping therapy.

Exon skipping therapies, such as Eteplirsen, Golodirsen, Viltolarsen, and Casimersen, have received accelerated approvals from the FDA for DMD. However, these therapies have shown variable and often insufficient levels of restored dystrophin protein in patients, limiting their effectiveness.

To understand the dynamics of protein expression and behavior of truncated dystrophin in vivo, the researchers used a targeted and sensitive mass spectrometry approach in mdx mice (a model for DMD) compared to wild type mice. The study revealed that the restored dystrophin protein had altered stability and slower turnover in treated mdx muscle compared to wild type muscle (approximately 44 days vs. 24 days, respectively).

The researchers also looked into muscle fiber turnover in the context of persistent fiber degeneration. They observed sequestration of restored dystrophin protein after exon skipping therapy in mdx muscle, leading to a significant extension of its half-life compared to full-length dystrophin in normal muscle. In contrast, DGC proteins showed constant turnover due to muscle fiber degeneration and dysregulation of the extracellular matrix in dystrophic muscle.

Based on these results, the researchers suggest using targeted mass spectrometry to evaluate the suitability and functionality of restored dystrophin isoforms in the context of the disease. They propose its use to optimize alternative gene correction strategies in development for DMD.