Proof-of-concept for a human heart model to test patient-specific therapy responsiveness

Within the research programme Human Measurement Models 2.0 a grant has been awarded to the PROPER-THERAPY team, led by Jolanda van der Velden (Amsterdam UMC). The PROPER-THERAPY team involves a collaboration between 4 academic (Amsterdam UMC, Erasmus MC, UMC Maastricht, UMC Utrecht) and 3 industrial (CytoCypher, Ionoptix, InVitroSys GmbH) partners, and aims to build proof that the metabolic state of the heart underlies drug responsiveness in inherited cardiomyopathies.

Clinical problem: Pathogenic mutations in muscle components cause cardiac disease. Inherited cardiomyopathies have the unique characteristic that the gene defect is identified at young age, which allows timely application of preventive and curative therapies. However, inherited cardiomyopathies are clinically heterogeneous: disease-severity and drug responsiveness differ greatly between patients with the exact same gene mutation and thereby limits targeted treatment strategies.

Human heart models: The PROPER-THERAPY team uses hypertrophic cardiomyopathy, caused by mutations in structural (sarcomere) proteins and mitochondrial enzymes, as showcase to create better human heart models. Our model will be subjected to metabolic stressors and drugs to showcase the effectiveness of stem cell-based models in patient-specific treatment strategies. Artificial intelligence will be applied to build a high-throughput system for future drug screening. We use our well-phenotyped patient cohorts to select extreme clinical phenotypes (mild versus severe disease) for production of patient-derived cardiomyocytes and a unique set of cardiac tissue samples. The latter patient material is key for the validation of stem cell-derived human cardiac muscles. Freshly cultured multicellular cardiac tissue slices (InVitroSys) from cardiac biopsies that are obtained during open heart surgery represent a unique opportunity to compare patient cardiac tissue with stem cell-derived heart tissues. The current project will shed light on the role of metabolism in maturity of human stem cell-derived heart models, and represents an important stepping stone in achieving our final aim: the application of human heart models for choosing the optimal therapeutic strategy tailored at the individual patient.

Team members: Jolanda van der Velden, Riekelt Houtkooper, Michiel Helmes, Andreas Dendorfer, Daphne Merkus, Magdalena Harakalova, Miranda Nabben, Diederik Kuster, Frank van Steenbeek.

Funding scheme: Human Measurement Models 2.0: for health research on diseases and prevention; NWO Domain Applied and Engineering Sciences (AES), the Association of Collaborating Health Foundations (SGF), ZonMw and Top Sector Life Sciences & Health (LSH; Health~Holland)

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