TABLE 2.
DMD-cardiomyopathy studies based on hiPSC-CMs: individual mutations vs. functional parameter and therapeutic attempts in vitro.
| Mutation/parameter | Membrane | Electrophysiology | Calcium handling | Sarcomere | Metabolism and oxidative stress | Therapeutic approach | References |
| Δ Exon 50 | Fragility/damage | Slower calcium transients | ↓ myofibril force, slower myofibril relaxation, ↑ myofibril calcium sensitivity | ↑ mPTP opening; unaffected mitochondrial respiration | Guan et al., 2014; Macadangdang et al., 2015; Pioner et al., 2019a | ||
| Δ Exons 49–50 | Fragility/damage | ↑Spontaneous electrical activity | ↑Intracellular diastolic calcium level | ↑cTnI release (marker of cell damage) | ONX-0914 reduced ROS level | Farini et al., 2019 | |
| DMD; nonspecified mut. | Reduced Nup153 factor (regulates cardiac remodeling) | Nanni et al., 2016 | |||||
| Δ Exons 45–52 | Fragility/damage | ↑Intracellular diastolic calcium level | ↓Sarcomere transcriptome | Mitochondrial damage, CASP3 activation, apoptosis | Poloxamer 188, reduced resting cytosolic Ca2+ level, CASP3 activation and apoptosis | Lin et al., 2015 | |
| c.263ΔG | Fragility/damage | Slower calcium transients | ↓Alignment; ↓acto-myosin turnover; cellular hypertrophy | Macadangdang et al., 2015; Pioner et al., 2019a | |||
| Δ Exons 52–54 | NOS-induced ROS release | Jelinkova et al., 2019 | |||||
| Δ Exons 43–45 | ↑Stretch-induced intracellular calcium entry | Tsurumi et al., 2019 | |||||
| Δ Exons 8–12 | ↑ICa–L density; prolonged APD | Eisen et al., 2019 | |||||
| c.5899C > T | ↑ICa–L density; prolonged APD | Eisen et al., 2019 | |||||
| Δ Exon 8-9 | ↑Spontaneous electrical activity | Slower calcium transients | ↓Force production | Rescue by CRISPR-Cas9-deletion of 3–9, 6–9, 7–11 | Kyrychenko et al., 2017 | ||
| Δ Exon 3–6 | Mitochondrial damage; ↑ROS level ↑exosome protection | Exosome protection | Gartz et al., 2018 | ||||
| Δ Exons 45–50 | ↑Spontaneous electrical activity | Caluori et al., 2019 | |||||
| Δ Exons 48–50 | CRISPR-Cas9 deletion of exons 45–55 restored DGC | Young et al., 2016 | |||||
| Δ Exons 46–55 | Fragility/damage | Cellular arrhythmias | Exon 45 skipping with PMO improved arrhythmias | Sato et al., 2019 | |||
| Δ Exon 44 | CRISPR-Cas9 restoration | Min et al., 2019 | |||||
| Exon 45, 51, 45, 53, 44, 46, 52, 50, 43, 6, 7, 8, 55 | CRISPR-Cas9 restoration | Long et al., 2018 | |||||
| Δ Exons 48–50 | ↓Force production | CRISPR-Cpf1 reframing of Exon 51 or exon skipping: restored dystrophin; enhanced contractile function. | Zhang et al., 2017 | ||||
| Δ Exons 4–43 | ↓Force production | Restoration by HAC carrying the full-length genomic dystrophin sequence | Zatti et al., 2014 | ||||
| Δ Exons 48–50, 47–50, Δ TG from exon 35, c.3217G > T | Antisense oligonucleotide-mediated skipping of exon 51 and delivery of dystrophin minigene | Dick et al., 2013 | |||||
| Δ Exon 52 | Slower calcium transients; arrhythmic events | AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and ameliorate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility | Moretti et al., 2020 |