Development of 3D-cardiac organoids as new experimental model to study (rare) cardiac diseases

Partnership & Approach: In this collaborative project, Maastricht University will team up with Innoser, a preclinical CRO with laboratories in the Netherlands and Belgium. At Maastricht University, an engineered heart muscle platform using stem cell technology was recently established. 2D cultured stem-cell derived cardiac muscle cells have been developed from skin fibroblasts from a patients carrying a PKP2 p.Arg79X mutation, a known pathogenic mutation for arrhythmogenic cardiomyopathy (ACM). Together with a unique ACM mouse model that harbors the same mutation, unique 2D in vitro and in vivo models have been established that strongly mimic the ACM phenotype. Based on these foundations, the CARDIOIDS collaborative project was defined with the aim to generate 3D cardiac organoids and evaluate their functionality and predictive behaviour in comparison with the existing models carrying the same PKP2 p.Arg79X mutation and clinical data. These 3D cardiac organoids are expected to become a superior drug screening tool supporting the development of new treatments for ACM.

Expected impact & Results: ACM has devastating psychosocial and economic consequences, as many patients succumbing to sudden death are relatively young adults in their productive years of life. Due to a fundamental lack of understanding disease mechanisms, current standard of care of ACM patients aims to primarily reduce mortality. It is clear that in ACM, novel (molecular) targets need to be translated into clinical therapies to tackle this high impact orphan disease. Therefore, novel in vitro and in vivo disease models such as 3D engineered heart muscle as cardiac organoids are needed to accelerate drug discovery and development. The application of these models will also advance precision medicine that seeks to exploit patient-specific individualised therapeutic strategies. The CARDIOIDS project is designed to take up this challenge.