PROof-of-concePt for a human hEaRt model to test patient-specific THERAPY-responsiveness

PROof-of-concePt for a human hEaRt model to test patient-specific THERAPY-responsiveness. Acronym: Proper-Therapy

Inherited cardiomyopathies such as hypertrophic cardiomyopathy (HCM) have a high prevalence worldwide. HCM is a heterogeneous disease: the severity of the disease and drug responsiveness differ greatly between patients, even when patients harbour the same mutation.

Here the project will mimic extreme HCM phenotypes in vitro with the use of induced pluripotent stem cell (iPSC) technology to create better human heart models in close collaboration with 3 companies (Ionoptix, CytoCypher and InVitroSys GmbH) that have expertise with functional readouts in heart muscle. The collaboration between clinicians (cardiology, clinical genetics, pediatricians) and experts in stem cell biology, physiology, metabolism, engineering and modeling (academia and industry), allows to build and validate a high-throughput system to test effects of acute and chronic drug exposure on human cardiac muscle.

Here the project uses the heterogeneity in clinical phenotype to make better human heart models. The project focusses on hypertrophic cardiomyopathy (HCM) as showcase to: 1) validate 2-dimensional (high-throughput) and 3-dimensional (high-complexity) human heart models by studying extreme clinical phenotypes; 2) build proof that metabolic stressors underlie clinical disease variability and drug responsiveness; 3) build proof-of-concept for effectiveness of patient-specific treatments; 4) develop a high-throughput system to study effects of stressors and drugs by applying artificial intelligence to analyse the complex functional properties of patient-derived cardiomyocytes. The validation of these human heart models is an essential first step towards clinical application of stem cell-based technologies for tailored treatment strategies in inherited cardiac disease.

The current project represents an important stepping stone in achieving the final aim of this project: the application of human heart models for choosing the optimal therapeutic strategy tailored at the individual patient.

More information can be found at https://dcvalliance.nl/our-consortia/double-dose and https://cardiomyopathie-onderzoek.nl/

Summary

The end goal of our project is an assay to test (new) drugs and design tailored and more effective therapies for patients with inherited cardiac disease. Thereto, we will validate stem cell-based heart models to ensure a high-throughput, and reproducibility of functional readouts.

Technology Readiness Level (TRL)

3 - 4

Time period

48 months

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