midi-dystrophin

**Midi-dystrophin** is a truncated, engineered version of the full-length 427 kDa dystrophin protein, approximately 291 kDa in size, designed for gene therapy in Duchenne muscular dystrophy (DMD). It retains key structural domains—including N-terminal, rod (with fewer spectrin-like repeats), cysteine-rich, and C-terminal regions—to protect muscle cells from contraction-induced damage and mediate signal transduction, addressing the root cause of DMD caused by *DMD* gene mutations. Delivered via dual-AAV vectors with split-intein trans-splicing for packaging within AAV capacity limits, preclinical studies in mdx4cv and DBA2/mdx mice demonstrate superior phenotypic correction, muscle protection, reduced biomarkers (e.g., creatine kinase, myomesin 3), improved heart function, decreased inflammation, and lowered expression of DMD progression genes (*Tmem8c*, *TGF-β*, *Pdgfr-α*) compared to micro-dystrophin, positioning it as a promising next-generation DMD therapy larger than micro- but smaller than full-length dystrophin.