期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 62, 期 4, 页码 368-380出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/62.4.368
关键词
lentiviral vectors; nerve growth factor (NGF); neural progenitor cells; transplantation; traumatic brain injury
资金
- NIA NIH HHS [AG09215, AG00255] Funding Source: Medline
- NIDDK NIH HHS [DK42707, DK07748] Funding Source: Medline
- NIMH NIH HHS [MH17168] Funding Source: Medline
- NINDS NIH HHS [NS11024, NS07810, NS08803, NS40978, NS38690] Funding Source: Medline
Human Ntera-2 (NT2) cells can be differentiated in vitro into well-characterized Populations of NT2N neurons that engraft and mature when transplanted into the adult CNS of rodents and humans. Them ha e shown promise as treatments for neurologic disease, trauma, and ischemic stroke. Although these features suggest that NT2N neurons would be an excellent platform for ex vivo gene therapy in the CNS, stable gene expression has been surprisingly difficult to achieve in these cells. In this report we demonstrate stable, efficient. and nontoxic gene transfer into undifferentiated NT2 cells using a pseudotyped lentiviral vector encoding the human elongation factor 1-alpha promoter and the reporter gene eGFP, Expression of eGFP was maintained when the NT2 cells were differentiated into NT2N neurons after treatment with retinoic acid, When transplanted into the striatum of adult nude mice, transduced NT2N neurons survived, engrafted, and continued to express the reporter gene for long-term time points in vivo. Furthermore. transplantation of NT2N neurons genetically modified to express nerve growth factor significantly attenuated cognitive dysfunction following traumatic brain injure in mice. These results demonstrate that defined populations of genetically modified human NT2N neurons are a practical and effective platform for stable ex vivo gene delivery into the CNS.
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