Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity

McKeithan, Wesley L.; Feyen, Dries; Bruyneel, Arne A.N.; Okolotowicz, Karl J.; Ryan, David L.; Sampson, Kevin J.; Potet, F; Savchenko, A. K.; Gómez-Galeno, Jorge; Vu, Michelle M.; Serrano, Ricardo; George, Alfred L.; Kass, Robert S.; Cashman, John R.; Mercola, Mark

doi:10.1016/j.stem.2020.08.003

Cited by 38 publications

(30 citation statements)

References 44 publications

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“…The use of hiPSC-CM-based models for the development of precision therapeutics is a powerful and growing tool. McKeithan and colleagues 219 recently described the use of high-throughput physiological screening for arrhythmic phenotypes in hiPSC-CMs derived from patients with LQT3. Their goal was to facilitate the rapid chemical refinement of mexiletine in order to improve its therapeutic potential and reduce toxicity.…”

Section: Novel Strategies To Study Ion Channel Dysfunction and Drug-specific Therapies In Lqt1 Lqt2 And Lqt3 Syndromesmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients. In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.

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Section: Novel Strategies To Study Ion Channel Dysfunction and Drug-specific Therapies In Lqt1 Lqt2 And Lqt3 Syndromesmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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“…However, in cases like WWS, the short lifespan along with the difficulty in obtaining tissue from patients represents major hurdles in establishing patient-specific myoblasts lines. The generation of patient-specific iPS cells circumvents the restricted patient tissue availability and the limited cell proliferation capacity seen in ex vivo expanded primary cells ( Kondo et al, 2013 ; McKeithan et al, 2020 ; Sampaziotis et al, 2015 ; Young et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

NAD+ enhances ribitol and ribose rescue of α-dystroglycan functional glycosylation in human FKRP-mutant myotubes

Ortiz-Cordero

Magli

Dhoke

et al. 2021

eLife

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Mutations in the fukutin-related protein (FKRP) cause Walker-Warburg Syndrome (WWS), a severe form of congenital muscular dystrophy. Here we established a WWS human induced pluripotent stem cell-derived myogenic model that recapitulates hallmarks of WWS pathology. We used this model to investigate the therapeutic effect of metabolites of the pentose phosphate pathway in human WWS. We show that functional recovery of WWS myotubes is promoted not only by ribitol but also its precursor ribose. Moreover, we found that the combination of each of these metabolites with NAD+ results in a synergistic effect, as demonstrated by rescue of α-dystroglycan glycosylation and laminin binding capacity. Mechanistically, we find that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analysis. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.

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“…Patient specific hiPSC line carrying the SCN5A N406K mutation was generated as previously described [60]. Human iPSC-CMs were differentiated by methods developed in the laboratory of Mark Mercola [44]. At day 20, hiPSC-CMs were placed in a metabolic maturation media and cultured for 5 weeks to improve cardiomyocyte phenotype, including more negative diastolic membrane potentials and Na + current dependent action potentials [12].…”

Section: Human Ipsc-cmsmentioning

confidence: 99%

Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors

et al. 2021

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Cardiomyocyte Na+ and Ca2+ mishandling, upregulated Ca2+/calmodulin-dependent kinase II (CaMKII), and increased reactive oxygen species (ROS) are characteristics of various heart diseases, including heart failure (HF), long QT (LQT) syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). These changes may form a vicious cycle of positive feedback to promote cardiac dysfunction and arrhythmias. In HF rabbit cardiomyocytes investigated in this study, the inhibition of CaMKII, late Na+ current (INaL), and leaky ryanodine receptors (RyRs) all attenuated the prolongation and increased short-term variability (STV) of action potential duration (APD), but in age-matched controls these inhibitors had no or minimal effects. In control cardiomyocytes, we enhanced RyR leak (by low [caffeine] plus isoproterenol mimicking CPVT) which markedly increased STV and delayed afterdepolarizations (DADs). These proarrhythmic changes were significantly attenuated by both CaMKII inhibition and mitochondrial ROS scavenging, with a slight synergy with INaL inhibition. Inducing LQT by elevating INaL (by Anemone toxin II, ATX-II) caused markedly prolonged APD, increased STV, and early afterdepolarizations (EADs). Those proarrhythmic ATX-II effects were largely attenuated by mitochondrial ROS scavenging, and partially reduced by inhibition of CaMKII and pathological leaky RyRs using dantrolene. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing LQT3 mutation SCN5A N406K, dantrolene significantly attenuated cell arrhythmias and APD prolongation. Targeting critical components of the Na+–Ca2+–CaMKII–ROS–INaL arrhythmogenic vicious cycle may exhibit important on-target and also trans-target effects (e.g., INaL and RyR inhibition can alter INaL-mediated LQT3 effects). Incorporating this vicious cycle into therapeutic strategies provides novel integrated insight for treating cardiac arrhythmias and diseases.

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Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity

Cited by 38 publications

References 44 publications

Long QT syndrome – Bench to bedside

Long QT syndrome – Bench to bedside

NAD+ enhances ribitol and ribose rescue of α-dystroglycan functional glycosylation in human FKRP-mutant myotubes

Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors

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