Application of Patient-Specific iPSCs for Modelling and Treatment of X-Linked Cardiomyopathies

Abstract

Inherited cardiomyopathies are among the major causes of heart failure and associated with significant mortality and morbidity. Currently, over 70 genes have been linked to the etiology of various forms of cardiomyopathy, some of which are X-linked. Due to the lack of appropriate cell and animal models, it has been difficult to model these X-linked cardiomyopathies. With the advancement of induced pluripotent stem cell (iPSC) technology, the ability to generate iPSC lines from patients with X-linked cardiomyopathy has facilitated in vitro modelling and drug testing for the condition. Nonetheless, due to the mosaicism of the X-chromosome inactivation, disease phenotypes of X-linked cardiomyopathy in heterozygous females are also usually more heterogeneous, with a broad spectrum of presentation. Recent advancements in iPSC procedures have enabled the isolation of cells with different lyonisation to generate isogenic disease and control cell lines. In this review, we will summarise the current strategies and examples of using an iPSC-based model to study different types of X-linked cardiomyopathy. The potential application of isogenic iPSC lines derived from a female patient with heterozygous Danon disease and drug screening will be demonstrated by our preliminary data. The limitations of an iPSC-derived cardiomyocyte-based platform will also be addressed.

Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models

“…Contractile dysfunction was observed in these mutant hiPSC-CMs as was a significant decrease in CDH2 expression [86]. In contrast to the findings of Zhang et al (2021), no changes in the localization or expression of actin or a-actinin were reported in cells harboring either one or two truncated copies of the PKP2 protein. Instead, desmosome cadherins in the outer dense plaque appeared to be prone to instability, which could lead to disrupted cell-cell adhesions.…”

“…The in vitro differentiated cells generated from hiPSCs have the same DNA as the patient from whom they were derived, and advances in hiPSC technologies have led to improved understanding of the genetic factors that contribute to arrhythmic syndromes [157][158][159][160][161], valvular and vascular disorders [162,163], and metabolic risk factors that contribute to CMPs and ischemic heart disease [164][165][166][167]. With gene-editing techniques like CRISPR-Cas9, iPSCs with gene variants can be corrected to obtain isogenic controls, which are useful to remove confounding effects arising from the presence of unknown silent pathological mutations in unrelated control cell lines [168][169][170][171]. Similarly, a specific mutation of interest can be artificially introduced via CRISPR-Cas9 into iPSCs from healthy patients [172].…”

Danon Disease: Entire LAMP2 Gene Deletion with Unusual Clinical Presentation—Case Report and Review of the Literature

“…In Danon disease, like in many other genetic disorders, disease penetrance and phenotype expressivity are variable [ 7 , 11 , 31 , 35 , 37 ]. This can be reflected by variable clinical presentation in individuals and familial cases having the same genetic variant [ 35 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

“…Moreover, the genotype–phenotype correlation is well established in some genetic disorders, but no such correlation exists in others [ 38 , 39 , 40 , 41 , 42 , 43 ]. In Danon disease, there is controversy regarding the genotype–phenotype correlation [ 7 , 11 , 31 , 37 ].…”

Verification of the Efficacy of Mexiletine Treatment for the A1656D Mutation on Downgrading Reentrant Tachycardia Using a 3D Cardiac Electrophysiological Model

“…As a result, special care should be taken when modeling cardiomyopathies caused by gene mutations that impact calcium transients, such as DMD [ 40 ]. Additionally, the immature nature of iPSC-CMs may lead to different electrophysiology, cell morphology, and metabolism [ 41 , 42 ].…”