Human PSC-based disease modeling to study X-linked Dystonia-Parkinsonism

The isolation of human embryonic stem cells (hESCs) and the discovery of human induced pluripotent stem cell (hiPSC) reprogramming have sparked a renaissance in stem cell biology, in vitro disease modeling, and drug discovery. In general, hPSC-based disease models are well-suited to study genetic variation. Studies commonly compare patient-derived hiPSCs, e.g., with a disease-causing genetic mutation, and (age-matched) control subject-derived hiPSCs, typically differentiated to the disease-affected cell type, e.g., neurons. A major caveat of this disease-modeling strategy is the variability of differentiation propensities and phenotypic characteristics, even in hPSCs derived from the same donor. Still, even if the cellular phenotype of a given mutation is strong and highly penetrant, it may be lost due to confounding effects of differences in genetic background of unrelated hPSC lines. A very powerful approach to overcome this hurdle is to use custom-engineered endonucleases, such as CRISPR/Cas9 that enable precise and programmable modification of endogenous hPSC genomic sequences. In our lab we use hPSC-based disease modeling to study the neurological movement disorder dystonia, in particular X-linked Dystonia Parkinsonism (XDP). In this talk I will show how we use hPSC-based disease modeling in combination with CRISPR/Cas9 gene editing, to elucidate the underlying molecular pathogenesis of XDP. I will also discuss some of the potential problems one might face using hPSC-based disease modeling in combination with gene editing.