Efficacy of exon-skipping therapy for DMD cardiomyopathy with mutations in actin binding domain 1.

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. © 2023 The Authors.

Citation

Naoko Shiba, Xiao Yang, Mitsuto Sato, Shin Kadota, Yota Suzuki, Masahiro Agata, Kohei Nagamine, Masaki Izumi, Yusuke Honda, Tomoya Koganehira, Hideki Kobayashi, Hajime Ichimura, Shinichiro Chuma, Junichi Nakai, Shugo Tohyama, Keiichi Fukuda, Daigo Miyazaki, Akinori Nakamura, Yuji Shiba. Efficacy of exon-skipping therapy for DMD cardiomyopathy with mutations in actin binding domain 1. Molecular therapy. Nucleic acids. 2023 Dec 12;34:102060

PMID: 38028197

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