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Modelling adverse drug reactions using induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) Christidi, Effimia

Abstract

Adverse drug reactions (ADRs) constitute the fourth leading cause of death and their incidence is steadily increasing. Cardiovascular toxicity is one of the most common and serious ADR and is the leading cause of drug discontinuation. The overarching goal of this thesis is to investigate cardiac ADRs using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs). Doxorubicin is a chemotherapy drug administered to adult and pediatric patients for the treatment of hematological and solid tumors, however, it can cause doxorubicin induced cardiotoxicity (DIC). We generated induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients who received doxorubicin as part of their chemotherapy regimen. iPSC-CMs from individuals who developed DIC displayed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from patients who did not experience DIC. Several variants associated with DIC have been identified, with RARG –S427L having the strongest genetic evidence. iPSC-CMs together with genome editing, provide a powerful platform to establish causal relationships between genetic variants and ADRs. We used CRISPR/Cas9 to investigate the functional impact of RARG-S427L on DIC in isogenic patient derived iPSC-CMs that differed only at the RARG locus. Genetic correction of RARG-S427L decreased susceptibility to in vitro DIC, whereas introduction of RARG-S427L had the opposite effect. We also used this platform to identify novel cardioprotectants that can be used clinically to prevent DIC. Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, is an FDA-approved medication for the treatment of diabetes that shows cardiovascular benefits. iPSC-CMs treated with empagliflozin exhibited reduced doxorubicin induced cell death. Finally, we showed that enriched cardiomyocyte subtype populations are necessary for accurate drug screening and disease modelling. Ibrutinib is an anticancer drug indicated for the treatment of B cell malignancies; however, it can cause atrial fibrillation. We used atrial and ventricular hPSC-CMs to study ibrutinib induced atrial fibrillation. Ibrutinib had an arrhythmogenic impact on hPSC atrial derived cardiomyocytes, while ventricular hPSC remained unaffected. Collectively, our findings demonstrate that hPSC-CMs represent a powerful platform for disease modelling and drug screening that is amenable to personalized risk prediction for the prevention of adverse drug reactions.

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