Abstract

Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy Using Human Induced Pluripotent Stem Cells

Faye Drawnel, Scientist, Pharma Research and Early Development, Roche

Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. Here, environmentally and genetically driven in vitro models of the condition are developed using human induced pluripotent stem cell-derived cardiomyocytes. First, diabetic clinical chemistry is mimicked to induce a phenotypic surrogate of diabetic cardiomyopathy, generating structural and functional disarray. Next, genetic effects are modelled by deriving cardiomyocytes from 2 diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs which preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, the first patient-specific iPSC model of a complex metabolic condition is presented, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.