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Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice

  • Author(s): Reidling, JC
  • Relaño-Ginés, A
  • Holley, SM
  • Ochaba, J
  • Moore, C
  • Fury, B
  • Lau, A
  • Tran, AH
  • Yeung, S
  • Salamati, D
  • Zhu, C
  • Hatami, A
  • Cepeda, C
  • Barry, JA
  • Kamdjou, T
  • King, A
  • Coleal-Bergum, D
  • Franich, NR
  • LaFerla, FM
  • Steffan, JS
  • Blurton-Jones, M
  • Meshul, CK
  • Bauer, G
  • Levine, MS
  • Chesselet, MF
  • Thompson, LM
  • et al.
Abstract

© 2017 The Authors Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies. Human GMP-grade neural stem cell transplantation rescues behavioral deficits and electrophysiological alterations in Huntington's disease mice, and rescue is associated with reduced accumulation of mutant Huntingtin protein.

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