Ex vivo gene therapy using targeted engraftment of NGF-expressing human NT2N neurons attenuates cognitive deficits following traumatic brain injury in mice

Luca Longhi, Deborah J. Watson, Kathryn E. Saatman, Hilaire J. Thompson, Chen Zhang, Scott Fujimoto, Nicolas Royo, Deborah Castelbuono, Ramesh Raghupathi, John Q. Trojanowski, Virginia M Y Lee, John H. Wolfe, Nino Stocchetti, Tracy K. McIntosh

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Infusion of nerve growth factor (NGF) has been shown to be neuroprotective following traumatic brain injury (TBI). In this study, we tested the hypothesis that NGF-expressing human NT2N neurons transplanted into the basal forebrain of brain-injured mice can attenuate long-term cognitive dysfunction associated with TBI. Undifferentiated NT2 cells were transduced in vitro with a lentiviral vector to release NGF, differentiated into NT2N neurons by exposure to retinoic acid and transplanted into the medial septum of mice 24 h following controlled cortical impact (CCI) brain injury or sham injury. Adult mice (n = 78) were randomly assigned to one of four groups: (1) sham-injured and vehicle (serum-free medium)-treated, (2) brain-injured and vehicle-treated, (3) brain-injured engrafted with untransduced NT2N neurons, and (4) brain-injured engrafted with transduced NGF-NT2N neurons. All groups were immunosuppressed daily with cyclosporin A (CsA) for 4 weeks. At 1 month post-transplantation, animals engrafted with NGF-expressing NT2N neurons showed significantly improved learning ability (evaluated with the Morris water maze) compared to brain-injured mice receiving either vehicle (p <0.05) or untransduced NT2N neurons (p <0.01). No effect of NGF-secreting NT2N cells on motor function deficits at 1-4 weeks post-transplantation was observed. These data suggest that NGF gene therapy using transduced NT2N neurons (as a source of delivery) may selectively improve cognitive function following TBI.

Original languageEnglish
Pages (from-to)1723-1736
Number of pages14
JournalJournal of Neurotrauma
Volume21
Issue number12
DOIs
Publication statusPublished - Dec 2004

Fingerprint

Nerve Growth Factor
Genetic Therapy
Neurons
Brain
Transplantation
Aptitude
Serum-Free Culture Media
Tretinoin
Traumatic Brain Injury
Brain Injuries
Cognition
Cyclosporine
Learning
Water
Wounds and Injuries

Keywords

  • Brain injury
  • Cognition
  • Gene therapy
  • Nerve growth factor
  • Neurotrophins

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Ex vivo gene therapy using targeted engraftment of NGF-expressing human NT2N neurons attenuates cognitive deficits following traumatic brain injury in mice. / Longhi, Luca; Watson, Deborah J.; Saatman, Kathryn E.; Thompson, Hilaire J.; Zhang, Chen; Fujimoto, Scott; Royo, Nicolas; Castelbuono, Deborah; Raghupathi, Ramesh; Trojanowski, John Q.; Lee, Virginia M Y; Wolfe, John H.; Stocchetti, Nino; McIntosh, Tracy K.

In: Journal of Neurotrauma, Vol. 21, No. 12, 12.2004, p. 1723-1736.

Research output: Contribution to journalArticle

Longhi, L, Watson, DJ, Saatman, KE, Thompson, HJ, Zhang, C, Fujimoto, S, Royo, N, Castelbuono, D, Raghupathi, R, Trojanowski, JQ, Lee, VMY, Wolfe, JH, Stocchetti, N & McIntosh, TK 2004, 'Ex vivo gene therapy using targeted engraftment of NGF-expressing human NT2N neurons attenuates cognitive deficits following traumatic brain injury in mice', Journal of Neurotrauma, vol. 21, no. 12, pp. 1723-1736. https://doi.org/10.1089/0897715042664876
Longhi, Luca ; Watson, Deborah J. ; Saatman, Kathryn E. ; Thompson, Hilaire J. ; Zhang, Chen ; Fujimoto, Scott ; Royo, Nicolas ; Castelbuono, Deborah ; Raghupathi, Ramesh ; Trojanowski, John Q. ; Lee, Virginia M Y ; Wolfe, John H. ; Stocchetti, Nino ; McIntosh, Tracy K. / Ex vivo gene therapy using targeted engraftment of NGF-expressing human NT2N neurons attenuates cognitive deficits following traumatic brain injury in mice. In: Journal of Neurotrauma. 2004 ; Vol. 21, No. 12. pp. 1723-1736.
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