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Author Notes:

Address correspondence to: Xiao-Jiang Li or Shihua Li, 347 Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, USA. Phone: 404.727.3290; Email: xli2@emory.edu (X.J. Li); Phone: 404.712.2304; Email: sli@emory.edu (S. Li).

S. Yang and R. Chang contributed equally to this work.

SY, RC, SL, and XJL designed the study.

SY, RC, HY, TZ, and YH, performed experiments and collected the data, HEK, XS, ZQ, and PJ performed whole-genome sequencing–related work.

SY, RC, SL, and XJL analyzed the data.

SY, RC, and XJL wrote the manuscript.

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

This work was supported by grants from the NIH (NS036232 and NS101701, to XJL, and NS095279, to SHL) and the National Natural Science Foundation of China (grant 91332206).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • KNOCK-IN MICE
  • MUTANT HUNTINGTIN
  • EARLY MOTOR
  • BEHAVIORAL DEFICITS
  • RNA INTERFERENCE
  • NEUROPATHOLOGY
  • ABNORMALITIES
  • DYSFUNCTION
  • NEURONS
  • VIVO
  • Neuroscience

CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease

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Journal Title:

Journal of Clinical Investigation

Volume:

Volume 127, Number 7

Publisher:

, Pages 2719-2724

Type of Work:

Article | Final Publisher PDF

Abstract:

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele-specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy. Here, we report that permanent suppression of endogenous mHTT expression in the striatum of mHTT-expressing mice (HD140Q-knockin mice) using CRISPR/Cas9-mediated inactivation effectively depleted HTT aggregates and attenuated early neuropathology. The reduction of mHTT expression in striatal neuronal cells in adult HD140Q-knockin mice did not affect viability, but alleviated motor deficits. Our studies suggest that non-allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion-mediated neuronal toxicity in the adult brain.

Copyright information:

© 2017, American Society for Clinical Investigation

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