Exon-skipping therapy can restore functional dystrophin attenuating calcium overload for DMD cardiomyopathy with mutations in actin-binding domain 1
Abstract Body: Antisense oligonucleotide (AO)-mediated exon-skipping is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), which is caused by loss-of-function mutations in the DMD gene encoding Dp427m, leading to progressive cardiomyopathy. In-frame deletion of exons 3–9 (Δ3–9) manifesting asymptomatic or very mild clinical phenotype is an ideal goal for exon-skipping by targeting actin-binding domain 1 (ABD1); however, the efficacy of this therapy for DMD cardiomyopathy remains unclear. We compared three isogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing Δ3–9, frameshifting Δ3–7, and intact DMD. RNA-seq revealed high similarity between Δ3–9 and wild-type hiPSC-CMs. Furthermore, we observed electrophysiological alterations with accelerated CaMKII activation in Δ3–7 hiPSC-CMs compared to Δ3–9 and wild-type hiPSC-CMs, while Δ3–9 Dp427m was stably expressed, maintaining substantial binding to F-actin and retention of desmin. AOs targeting exon 8 efficiently induced exons 8–9 skipping to restore functional Dp427m and electrophysiological parameters in Δ3–7 hiPSC-CMs. Exon-skipping therapy converting the reading frame to Δ3–9 might be promising for DMD cardiomyopathy.
Shiba, Naoko
( Shinshu University
, Matsumoto
, Japan
)
Yang, Xiao
( Shinshu University
, Matsumoto
, Japan
)
Agata, Masahiro
( Shinshu University
, Matsumoto
, Japan
)
Nagamine, Kohei
( Shinshu University
, Matsumoto
, Japan
)
Kadota, Shin
( Shinshu University
, Matsumoto
, Japan
)
Mitsuto, Sato
( Shinshu University
, Matsumoto
, Japan
)
Nakamura, Akinori
( Matsumoto Medical Center
, Matsumoto
, Japan
)
Shiba, Yuji
( Shinshu University
, Matsumoto
, Japan
)
Author Disclosures:
Naoko Shiba:DO NOT have relevant financial relationships
| Xiao Yang:DO NOT have relevant financial relationships
| Masahiro Agata:No Answer
| Kohei Nagamine:No Answer
| Shin Kadota:DO NOT have relevant financial relationships
| Sato Mitsuto:No Answer
| Akinori Nakamura:No Answer
| Yuji Shiba:DO NOT have relevant financial relationships