Deciphering the pathogenic role of a variant with uncertain significance for short QT and Brugada syndromes using gene‐edited human‐induced pluripotent stem cell‐derived cardiomyocytes and preclinical drug screening

El‐Battrawy, Ibrahim; Liu, Huan; Cyganek, Lukas; Maywald, Lasse; Zhong, Rujia; Zhang, Feng; Xu, Qiang; Lee, Ji‐Hyun; Duperrex, Eliane; Hierlemann, Andreas; Saguner, Ardan M.; Duru, Fırat; Kovacs, Boldizsar; Huang, Mengying; Liao, Zhenxing; Albers, Sebastian; Müller, Judith; Dinkel, Hendrik; Rose, Lena; Hohn, Alyssa; Yang, Zhen; Lin, Qiao; Li, Yingrui; Lang, Siegfried; Kleinsorge, Mandy; Mügge, Andreas; Aweimer, Assem; Fan, Xuehui; Diecke, Sebastian; Akın, İbrahim; Li, Guang; Zhou, Xiaobo

doi:10.1002/ctm2.646

Cited by 14 publications

(16 citation statements)

References 10 publications

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“…[82][83][84] With the advent of CRISPR-Cas9, it is now possible to test the functional consequences of VUS in iPSC-CMs. [85][86][87][88][89] An interesting example is a VUS from the MYL3 gene (170C>A) that was identified from an asymptomatic carrier and was predicted by in silico tools to be pathogenically damaging to protein function. In contrast, the combinatorial approach of CRISPR-Cas9 and iPSC-CMs has definitively classified this VUS as a benign variant for HCM, as iPSC-CMs harboring the MYL3 170C>A mutation displayed normal cardiomyocyte morphology and function.…”

Section: Compendium On Basic Models Of Cardiovascular Diseasementioning

confidence: 99%

CRISPR Modeling and Correction of Cardiovascular Disease

Liu

Olson

2022

Circulation Research

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Cardiovascular disease remains the leading cause of morbidity and mortality in the developed world. In recent decades, extraordinary effort has been devoted to defining the molecular and pathophysiological characteristics of the diseased heart and vasculature. Mouse models have been especially powerful in illuminating the complex signaling pathways, genetic and epigenetic regulatory circuits, and multicellular interactions that underlie cardiovascular disease. The advent of CRISPR genome editing has ushered in a new era of cardiovascular research and possibilities for genetic correction of disease. Next-generation sequencing technologies have greatly accelerated the identification of disease-causing mutations, and advances in gene editing have enabled the rapid modeling of these mutations in mice and patient-derived induced pluripotent stem cells. The ability to correct the genetic drivers of cardiovascular disease through delivery of gene editing components in vivo, while still facing challenges, represents an exciting therapeutic frontier. In this review, we provide an overview of cardiovascular disease mechanisms and the potential applications of CRISPR genome editing for disease modeling and correction. We also discuss the extent to which mice can faithfully model cardiovascular disease and the opportunities and challenges that lie ahead.

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Section: Compendium On Basic Models Of Cardiovascular Diseasementioning

confidence: 99%

CRISPR Modeling and Correction of Cardiovascular Disease

Liu

Olson

2022

Circulation Research

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“…The hiPSC-CM possess a lot of advantages in modeling genetic cardiac disorders like long-QT syndrome, short QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome and familial hypertrophic cardiomyopathy (HCM) [209][210][211][212][213][214][215][216][217][218][219]. First, hiPSC-CMs possess a human gene background, avoiding possible effects resulting from the gene differences between humans and animals.…”

Section: Human Cardiomyocytes Derived From Induced Pluripotent Stem C...mentioning

confidence: 99%

Takotsubo Syndrome: Translational Implications and Pathomechanisms

Fan

Yang

Kowitz

et al. 2022

IJMS

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Takotsubo syndrome (TTS) is identified as an acute severe ventricular systolic dysfunction, which is usually characterized by reversible and transient akinesia of walls of the ventricle in the absence of a significant obstructive coronary artery disease (CAD). Patients present with chest pain, ST-segment elevation or ischemia signs on ECG and increased troponin, similar to myocardial infarction. Currently, the known mechanisms associated with the development of TTS include elevated levels of circulating plasma catecholamines and their metabolites, coronary microvascular dysfunction, sympathetic hyperexcitability, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, genetic predisposition and thyroidal dysfunction. However, the real etiologic link remains unclear and seems to be multifactorial. Currently, the elusive pathogenesis of TTS and the lack of optimal treatment leads to the necessity of the application of experimental models or platforms for studying TTS. Excessive catecholamines can cause weakened ventricular wall motion at the apex and increased basal motion due to the apicobasal adrenoceptor gradient. The use of beta-blockers does not seem to impact the outcome of TTS patients, suggesting that signaling other than the beta-adrenoceptor-associated pathway is also involved and that the pathogenesis may be more complex than it was expected. Herein, we review the pathophysiological mechanisms related to TTS; preclinical TTS models and platforms such as animal models, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) models and their usefulness for TTS studies, including exploring and improving the understanding of the pathomechanism of the disease. This might be helpful to provide novel insights on the exact pathophysiological mechanisms and may offer more information for experimental and clinical research on TTS.

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“…BrS‐associated genes were also found in calcium channels and potassium channels. The calcium channel is composed of the α su 84 bunit and accessory proteins. Mutations in α1 ( CACNA1C ), β2 ( CACNB2 ), and α2/δ ( CACNA2D1 ) subunit genes of cardiac long‐lasting (L)‐type channels can cause shortened action potential duration (representing shorter QT intervals) in patients with BrS 84 , 85 .…”

Section: Experimental Models Of Brsmentioning

confidence: 99%

“…The calcium channel is composed of the α su 84 bunit and accessory proteins. Mutations in α1 ( CACNA1C ), β2 ( CACNB2 ), and α2/δ ( CACNA2D1 ) subunit genes of cardiac long‐lasting (L)‐type channels can cause shortened action potential duration (representing shorter QT intervals) in patients with BrS 84 , 85 . A previous study showed that Chinese hamster ovary K1 Chinese hamster ovary K1 cells transfected with mutations of these genes could cause a reduction in Calcium current.…”

Section: Experimental Models Of Brsmentioning

confidence: 99%

Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells

Lang

Akın

et al. 2022

JAHA

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Brugada syndrome (BrS) is an inherited and rare cardiac arrhythmogenic disease associated with an increased risk of ventricular fibrillation and sudden cardiac death. Different genes have been linked to BrS. The majority of mutations are located in the SCN5A gene, and the typical abnormal ECG is an elevation of the ST segment in the right precordial leads V1 to V3. The pathophysiological mechanisms of BrS were studied in different models, including animal models, heterologous expression systems, and human‐induced pluripotent stem cell–derived cardiomyocyte models. Currently, only a few BrS studies have used human‐induced pluripotent stem cell–derived cardiomyocytes, most of which have focused on genotype–phenotype correlations and drug screening. The combination of new technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR associated protein 9)‐mediated genome editing and 3‐dimensional engineered heart tissues, has provided novel insights into the pathophysiological mechanisms of the disease and could offer opportunities to improve the diagnosis and treatment of patients with BrS. This review aimed to compare different models of BrS for a better understanding of the roles of human‐induced pluripotent stem cell–derived cardiomyocytes in current BrS research and personalized medicine at a later stage.

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Deciphering the pathogenic role of a variant with uncertain significance for short QT and Brugada syndromes using gene‐edited human‐induced pluripotent stem cell‐derived cardiomyocytes and preclinical drug screening

Cited by 14 publications

References 10 publications

CRISPR Modeling and Correction of Cardiovascular Disease

CRISPR Modeling and Correction of Cardiovascular Disease

Takotsubo Syndrome: Translational Implications and Pathomechanisms

Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells

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