Programme : Back to Dr Giorgia Salvagiotto

Novel iPSC-derived cellular systems for in vitro disease modeling.


A major challenge in disease research and drug discovery is modeling human biology in physiologically relevant and predictive in vitro systems. Human induced pluripotent stem cell (iPSC) technology allows for the generation of virtually any cell type of the human body in unlimited quantities from a donor. This technology also enables access to human disease models which have been shown to recapitulate the native human phenotypes in vitro. The functional relevance of human iPSC-derived cells in research and drug discovery programs is being demonstrated by a rapidly growing body of literature. Here, we present case study examples of induced, engineered, and innate disease models generated by the production of iPSC-derived cell types environmentally stimulated to elicit a disease phenotype, genetically modified to introduce a disease mutation, or from patient-derived material, respectively.
In particular, we describe the application of iPSC-derived hepatocytes in hepatitis C virus (HCV) infectivity. We present an induced model of Alzheimer’s Disease where amyloid-beta dependent toxicity is induced in iPSC-derived cortical neurons. This assay was developed for a pilot screen to identify compounds protective against Alzheimer’s Disease. We also provide data from iPSC lines genetically modified to carry point mutations in the amyloid precursor protein yielding another neuron based model of Alzheimer’s Disease. Finally, we present an iPSC-derived diabetic cardiomyopathy model, in which culture conditions were optimized to induce the disease in apparently normal iPSC-derived cardiomyocytes. This model was used in a phenotypic screen for rescue from the pathological phenotype during diabetic stress and identified candidate protective molecules for iPSC-derived cardiomyocytes generated from diabetic patient samples.
The data presented show how the iPSC technology offers reliable and predictive model systems not otherwise attainable using currently available primary and immortalized cells, thus creating new tools and opportunities in drug discovery.
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