Development of human models to detect cardiac arrhythmias

Development of clinically relevant models based on induced pluripotent stem cells from patients affected by catecholaminergic ventricular tachycardia and multiplexed phenotypic readouts convertible to high throughput formats

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a disease that remains silent in resting conditions and causes in some cases sudden death, triggered by emotional or physical stress. This makes the study of patients with CPVT extraordinarily difficult. Human induced pluripotent stem cell (hiPSC) technology consents the generation of diseased heart cells, allowing the study of the disease in vitro. In this project, beating cardiac cells (cardiomyocytes) derived from hiPSCs (hiPSC-CMs) of CPVT patients has been tested to identify the disease signs. The same cells can be used for testing thousand compounds with the potential to revert CPVT. Specifically, this project represents a public-private partnership that brings together the generation of patient hiPSC-CMs by LUMC and the expertise in high-throughput drug screening by Ncardia.

CPVT is a disease that, if untreated, causes cardiac arrest in 30% of patients and syncope in 80%. Therapeutic approaches include pharmacological treatments with beta-blockers and calcium channel blockers. However, patients respond differently to these treatments. The development of a high throughput screening (HTS) platform is a clear need to identify drugs using a personalised approach.

For this purpose, patient-specific hiPSC technology, combined with HTS platforms can create business value in The Netherlands by establishing the foundations for large scale drug screening for cardiovascular diseases. Testing drugs that are already FDA approved, may lead to directly introducing them into the clinics without any additional animal experiments, and finally reduce the burden of disease. This means any new treatment could be introduced to the clinic rapidly, potentially reducing the overall cost of drug development. On the other hand, the project aims in the long term to contribute to improving the quality of life of patients with CPVT.

During this project, new sets of hiPSC lines from CPVT patients was successfully generated which proven value in high-throughput screening.

Summary

Catecholaminergic Polymorphic Tachycardia is a genetic cardiovascular disease, often leading to sudden cardiac death, which is particularly difficult to study. The combination of human beating cardiac cells from patients and innovative screening assays can help identifying arrhythmia and drugs to prevent it using a personalized approach.

Technology Readiness Level (TRL)

3 - 6

Time period

24 months

Partners