Reversal of phenotypic abnormalities by CRISPR/Cas9-mediated gene correction in Huntington disease patient-derived induced pluripotent stem cells
Author(s)
Type
Journal Article
Abstract
Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs.
Date Issued
2017-03-14
Date Acceptance
2017-01-21
Citation
Stem Cell Reports, 2017, 8 (3), pp.619-633
ISSN
2213-6711
Publisher
Elsevier (Cell Press)
Start Page
619
End Page
633
Journal / Book Title
Stem Cell Reports
Volume
8
Issue
3
Copyright Statement
© 2017 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Cell Biology
STRIATAL PROJECTION NEURONS
TRANSGENIC MICE
DIFFERENTIATION
INHIBITION
MUTATIONS
DEFECTS
MODELS
CAS9
Publication Status
Published
Date Publish Online
2017-02-23