AUG 30, 2016 08:00 AM PDT

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

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  • Instructor in Neurology, Harvard Medical School
      After receiving his PhD in Neuroscience at the VU University Amsterdam in the Netherlands in 2008, Dr. Hendriks joined the lab of Dr. Paola Arlotta at the Center for Regenerative Medicine of Massachusetts General Hospital (MGH) in Boston to study neuronal development focusing on neuronal differentiation of human pluripotent stem cells. In 2011, Dr. Hendriks joined the Harvard Stem Cell Institute (HSCI) iPS Core facility with Dr. Chad Cowan at Harvard University in Cambridge, where initially he worked on developing and implementing foot-print free somatic cell iPSC reprogramming methods. Dr. Hendriks also initiated and managed the hPSC genome editing service for 2 years at HSCI before moving to his current position as a Harvard Medical School Instructor in Neurology at the MGH Collaborative Center for X-Linked Dystonia Parkinsonism in 2014.

    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. 

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