Ex VivoGene Therapy Using Targeted Engraftment of NGF-Expressing Human NT2N Neurons Attenuates Cognitive Deficits Following Traumatic Brain Injury in Mice
| Autor: | John H. Wolfe, Luca Longhi, Deborah J Castelbuono, Kathryn E. Saatman, John Q. Trojanowski, Tracy K. McIntosh, Hilaire J. Thompson, Scott Fujimoto, Nicolas C. Royo, Chen Zhang, Virginia M.-Y. Lee, Deborah Watson, Nino Stocchetti, Ramesh Raghupathi |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty Traumatic brain injury Morris water navigation task Motor Activity Neuroprotection Choline O-Acetyltransferase Mice Transduction Genetic Cyclosporin a Internal medicine Nerve Growth Factor medicine Animals Humans Maze Learning Neurons Basal forebrain biology business.industry Genetic Therapy medicine.disease Mice Inbred C57BL Endocrinology Nerve growth factor nervous system Brain Injuries biology.protein Neurology (clinical) business Neuroscience Ex vivo Neurotrophin |
| Zdroj: | Journal of Neurotrauma. 21:1723-1736 |
| ISSN: | 1557-9042 0897-7151 |
| DOI: | 10.1089/neu.2004.21.1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|