Molecular Therapy: Nucleic Acids (Dec 2023)
Efficacy of exon-skipping therapy for DMD cardiomyopathy with mutations in actin binding domain 1
Abstract
Exon-skipping therapy is a promising treatment strategy for Duchenne muscular dystrophy (DMD), which is caused by loss-of-function mutations in the DMD gene encoding dystrophin, leading to progressive cardiomyopathy. In-frame deletion of exons 3–9 (Δ3–9), manifesting a very mild clinical phenotype, is a potential targeted reading frame for exon-skipping by targeting actin-binding domain 1 (ABD1); however, the efficacy of this approach for DMD cardiomyopathy remains uncertain. In this study, we compared three isogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing Δ3–9, frameshifting Δ3–7, or intact DMD. RNA sequencing revealed a resemblance in the expression patterns of mechano-transduction-related genes between Δ3–9 and wild-type samples. Furthermore, we observed similar electrophysiological properties between Δ3–9 and wild-type hiPSC-CMs; Δ3–7 hiPSC-CMs showed electrophysiological alterations with accelerated CaMKII activation. Consistently, Δ3–9 hiPSC-CMs expressed substantial internally truncated dystrophin protein, resulting in maintaining F-actin binding and desmin retention. Antisense oligonucleotides targeting exon 8 efficiently induced skipping exons 8–9 to restore functional dystrophin and electrophysiological parameters in Δ3–7 hiPSC-CMs, bringing the cell characteristics closer to those of Δ3–9 hiPSC-CMs. Collectively, exon-skipping targeting ABD1 to convert the reading frame to Δ3–9 may become a promising therapy for DMD cardiomyopathy.
