A human iPSC-CM model for type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1)

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Thesis type
(Thesis) M.Sc.
Date created
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating, heritable cardiac arrhythmia and often a cause of sudden cardiac death. Greater than 50% of cases of CPVT are due to genetic variants in the cardiac ryanodine receptor (RyR2). CPVT-associated RyR2 variants often result in gain-of-function phenotypes, producing a dominantly inherited and difficult to treat disease. Human induced pluripotent stem cells (hiPSCs) have been used to generate patient-specific hiPSC-derived cardiomyocytes (hiPSC-CM) to study CPVT phenotypes and pharmacological approaches, however generating hiPSCs from patients is low through-put and lacks true isogenic controls. Therefore, this thesis aimed to use CRIPSR/Cas9 genome-editing technology to generate hiPSC cells lines harbouring a CPVT-associated variant. Genome-edited hiPSCs were differentiated into 2D tissue-like monolayers of hiPSC-CMs, and voltage and calcium dynamics were measured. This thesis indicates that CRISPR/Cas9 is a useful technology for studying CPVT in an in vitro human model, and that the R417L mutant disrupts hiPSC-CM calcium handling.
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Supervisor or Senior Supervisor
Thesis advisor: Tibbits, Glen