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Systemic PPMO-mediated dystrophin expression in the Dup2 mouse model of Duchenne muscular dystrophy

Gushchina LV, Vetter TA, Frair EC, Bradley AJ, Grounds KM, Lay JW, Huang N, Suhaiba A, Schnell FJ, Hanson G, Simmons TR, Wein N, Flanigan KM
Mol Ther Nucleic Acids. 2022 Nov 9;30:479-492. doi: 10.1016/j.omtn.2022.10.025. eCollection 2022 Dec 13.
Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease that arises due to the loss of dystrophin expression, leading to progressive loss of motor and cardiorespiratory function. Four exon-skipping approaches utilizing antisense phosphorodiamidate morpholino oligomers (PMOs) have been approved by the FDA to restore a DMD open reading frame, resulting in expression of a functional but internally-deleted dystrophin protein, but in patients with single-exon duplications, exon skipping has the potential to restore full-length dystrophin expression. Cell-penetrating peptide-conjugated PMOs (PPMOs) have demonstrated enhanced cellular uptake and more efficient dystrophin restoration than unconjugated PMOs. In the present study, we demonstrate widespread PPMO-mediated dystrophin restoration in the Dup2 mouse model of exon 2 duplication, representing the most common single-exon duplication among patients with DMD. In this proof-of-concept study, a single intravenous injection of PPMO targeting the exon 2 splice acceptor site induced 45-68% exon 2-skipped Dmd transcripts in Dup2 skeletal muscles 15 days post-injection. Muscle dystrophin restoration peaked at 77-87% average dystrophin-positive fibers and 41-51% of normal signal intensity by immunofluorescence, and 15.7-56.8% of normal by western blotting 15-30 days after treatment. These findings indicate that PPMO-mediated exon skipping is a promising therapeutic strategy for muscle dystrophin restoration in the context of exon 2 duplications.
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