Translating drug efficacy and safety findings from healthy to diseased states remains a significant challenge in drug development. Traditional animal models or healthy human cells often fall short in accurately predicting clinical outcomes, necessitating the development of patient-centric models.

The advent of induced pluripotent stem cell (iPSC) technology has revolutionized this field, offering a means to model diseases and test drugs in vitro using patient-derived cells.

One critical area of focus is the disruption of calcium handling, a common issue in cardiomyopathies and drug-induced cardiotoxicity, often linked to decreased expression of the ryanodine receptor 2 (RYR2).

In a recent study, researchers from AstraZeneca leveraged CRISPR/Cas9 gene-editing technology to create a heterozygous RYR2 knockout (Het KO) model using human iPSCs. This model aimed to replicate the reduced RYR2 expression observed in certain forms of heart disease.

RYR2 Het KO hiPSCs efficiently differentiated into cardiomyocytes expressing approximately 50% of the RYR2 protein compared to wild-type (WT) cells. No significant changes in the expression of other major calcium-handling proteins were noted.

The RYR2 Het KO cardiomyocytes showed notable disruptions in calcium handling, with increased calcium amplitude and slower calcium re-uptake.

Proteomics analysis revealed altered expression in proteins associated with the pentose phosphate pathway, indicating metabolic dysfunction and increased sensitivity to redox alterations.

Additionally, RYR2 Het KO cardiomyocytes exhibited differential pharmacological responses compared to WT cells. This was particularly evident in their increased beat amplitude (as measured by the CardioExcite 96 system) and altered sensitivity to calcium channel blockers like verapamil.

Overall, this study presents a robust human iPSC-based model that mimics key aspects of heart failure, including calcium handling and metabolic dysfunctions. The model provides valuable insights into the molecular mechanisms underlying these dysfunctions and highlights the importance of considering these differences in pharmacological testing.

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Find the full article here: RYR2 deficient human model identifies calcium handling and metabolic dysfunction impacting pharmacological responses

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