Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model

Mehta, Ashish; Ramachandra, Chrishan J A; Singh, Pritpal; Chitre, Anuja; Lua, Chong Hui; Mura, Manuela; Crotti, Lia; Wong, Philip; Schwartz, Peter J.; Gnecchi, Massimiliano; Shim, Winston

doi:10.1093/eurheartj/ehx394

Cited by 107 publications

(73 citation statements)

References 34 publications

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“…In particular, iPSCs are not burdened by ethical issues and have been shown to differentiate into cardiac-like cells both in vitro and in vivo [15]. The characteristics of these cardiac cells are similar, but not identical, to human cardiomyocytes also in their ion channel apparatus, as demonstrated by disease-modeling studies [17,18]. Efforts to obtain standardized protocols to produce iPSC lines possibly committed toward cardiac lineage and to induce the maturation of iPSC-derived cardiomyocytes are needed.…”

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confidence: 99%

Cell therapy trials for heart regeneration — lessons learned and future directions

2018

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The effects of cell therapy on heart regeneration in patients with chronic cardiomyopathy have been assessed in several clinical trials. These trials can be categorized as those using noncardiac stem cells, including mesenchymal stem cells, and those using cardiac-committed cells, including KIT cardiac stem cells, cardiosphere-derived cells, and cardiovascular progenitor cells derived from embryonic stem cells. Although the safety of cell therapies has been consistently reported, their efficacy remains more elusive. Nevertheless, several lessons have been learned that provide useful clues for future studies. This Review summarizes the main outcomes of these studies and draws some perspectives for future cell-based regenerative trials, which are largely based on the primary therapeutic target: remuscularization of chronic myocardial scars by exogenous cells or predominant use of these cells to activate host-associated repair pathways though paracrine signalling. In the first case, the study design should entail delivery of large numbers of cardiac-committed cells, supply of supportive noncardiac cells, and promotion of cell survival and appropriate coupling with endogenous cardiomyocytes. If the primary objective is to harness endogenous repair pathways, then the flexibility of cell type is greater. As the premise is that the transplanted cells need to engraft only transiently, the priority is to optimize their early retention and possibly to switch towards the sole administration of their secretome.

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confidence: 99%

Cell therapy trials for heart regeneration — lessons learned and future directions

2018

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“…Additionally, molecular characterization of the LQT2 hiPSC‐CM models has confirmed that many KCNH2 missense mutations result in a trafficking defect of the ion channel . Recently, Lumacaftor, a drug known to act on channel trafficking and approved for treating cystic fibrosis, was shown to restore trafficking of the ion channel in LQT2 hiPSC‐CMs but only for certain mutations . Excitingly, the first attempt to validate these findings in two of the patients whose hiPSC‐CMs had shown a response, indicated a significant shortening of their QTc interval when they were also treated with the corresponding clinically approved compound .…”

Section: Hpsc Models Of Inherited Cardiac Diseasesmentioning

confidence: 92%

“…23,24 Recently, Lumacaftor, a drug known to act on channel trafficking and approved for treating cystic fibrosis, was shown to restore trafficking of the ion channel in LQT2 hiPSC-CMs but only for certain mutations. 25 Excitingly, the first attempt to validate these findings in two of the patients whose hiPSC-CMs had shown a response, indicated a significant shortening of their QTc interval when they were also treated with the corresponding clinically approved compound. 26 These findings emphasize the importance of understanding the complex interplay between an aberrant genotype and molecular phenotype to pave the way for more personalized medicine.…”

Section: Significance Statementmentioning

confidence: 94%

Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

et al. 2019

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Research on mechanisms underlying monogenic cardiac diseases such as primary arrhythmias and cardiomyopathies has until recently been hampered by inherent limitations of heterologous cell systems, where mutant genes are expressed in noncardiac cells, and physiological differences between humans and experimental animals. Human-induced pluripotent stem cells (hiPSCs) have proven to be a game changer by providing new opportunities for studying the disease in the specific cell type affected, namely the cardiomyocyte. hiPSCs are particularly valuable because not only can they be differentiated into unlimited numbers of these cells, but they also genetically match the individual from whom they were derived. The decade following their discovery showed the potential of hiPSCs for advancing our understanding of cardiovascular diseases, with key pathophysiological features of the patient being reflected in their corresponding hiPSC-derived cardiomyocytes (the past). Now, recent advances in genome editing for repairing or introducing genetic mutations efficiently have enabled the disease etiology and pathogenesis of a particular genotype to be investigated (the present). Finally, we are beginning to witness the promise of hiPSC in personalized therapies for individual patients, as well as their application in identifying genetic variants responsible for or modifying the disease phenotype (the future). In this review, we discuss how hiPSCs could contribute to improving the diagnosis, prognosis, and treatment of an individual with a suspected genetic cardiac disease, thereby developing better risk stratification and clinical management strategies for these potentially lethal but treatable disorders.

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“…Cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) are now wellestablished as models for LQT2 [15][16][17][18] . Indeed, a number of hiPSC lines have been derived from both symptomatic and asymptomatic patients with mutations in various regions of hERG 19 .…”

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confidence: 99%

Isogenic sets of hiPSC-CMs harboringKCNH2mutations capture location-related phenotypic differences

Brandão

Brink

Miller

et al. 2019

Preprint

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AimsLong QT syndrome type 2 (LQT2) is caused by mutations in the gene KCNH2, encoding the hERG ion channel. Clinically, mild and severe phenotypes are associated with this cardiac channelopathy, complicating efforts to predict patient risk. The location of the mutation within KCNH2 contributes to this variable disease manifestation. Here we determined whether such phenotypic differences could be detected in cardiomyocytes derived from isogenic human induced pluripotent stem cells (hiPSCs) genetically edited to harbour a range of KCNH2 mutations. Methods and ResultsThe hiPSC lines heterozygous for missense mutations either within the pore or tail region of the ion channel were generated using CRISPR-Cas9 editing and subsequently differentiated to cardiomyocytes (hiPSC-CMs) for functional assessment. Electrophysiological analysis confirmed the mutations prolonged the action potentials and field potentials of the hiPSC-CMs, with differences detected between the pore and tail region mutations when measured as paced 2D monolayers. This was also reflected in the cytosolic Ca 2+ transients and contraction kinetics of the different lines. Pharmacological blocking of the hERG channel in the hiPSC-CMs also revealed that mutations in the pore-loop region conferred a greater susceptibility to arrhythmic events. ConclusionThese findings establish that subtle phenotypic differences related to the location of the KCNH2 mutation in LQT2 patients are reflected in hiPSC-CMs under genetically controlled conditions. Moreover, the results validate hiPSC-CMs as a strong candidate for evaluating the underlying severity of individual KCNH2 mutations in humans which could ultimately facilitate patient risk stratification.

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Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model

Cited by 107 publications

References 34 publications

Cell therapy trials for heart regeneration — lessons learned and future directions

Cell therapy trials for heart regeneration — lessons learned and future directions

Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

Isogenic sets of hiPSC-CMs harboringKCNH2mutations capture location-related phenotypic differences

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