title: Ex vivo gene therapy using targeted engraftment of NGF-expressing human NT2N neurons attenuates cognitive deficits following traumatic brain injury in mice.
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.
authors.affiliation: Veterans Administration Medical Center, Philadelphia, Pennsylvania, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Longhi
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Watson
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Saatman
authors.forename: Hilaire J
authors.initials: HJ
authors.lastname: Thompson
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Scott
authors.initials: S
authors.lastname: Fujimoto
authors.forename: Nicolas
authors.initials: N
authors.lastname: Royo
authors.forename: Deborah
authors.initials: D
authors.lastname: Castelbuono
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John H
authors.initials: JH
authors.lastname: Wolfe
authors.forename: Nino
authors.initials: N
authors.lastname: Stocchetti
authors.forename: Tracy K
authors.initials: TK
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000208:ethnology / Q000473:pathology / Q000628:therapy*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology*; D020932:Nerve Growth Factor / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D014161:Transduction, Genetic
chemical_list: D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase