Enhanced nigrostriatal neuron-specific,long-term expression by using neural-specific promoters in combination with targeted gene transfer by modified helper virus-free HSV-1 vector particles |
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Authors: | Haiyan Cao Guo-rong Zhang Xiaodan Wang Lingxin Kong Alfred I Geller |
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Institution: | (1) Department of Neurology, West Roxbury VA Hospital/Harvard Medical School, W. Roxbury, MA 02132, USA |
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Abstract: | Background Direct gene transfer into neurons has potential for developing gene therapy treatments for specific neurological conditions,
and for elucidating neuronal physiology. Due to the complex cellular composition of specific brain areas, neuronal type-specific
recombinant gene expression is required for many potential applications of neuronal gene transfer. One approach is to target
gene transfer to a specific type of neuron. We developed modified Herpes Simplex Virus (HSV-1) particles that contain chimeric
glycoprotein C (gC) – glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) proteins.
HSV-1 vector particles containing either gC – GDNF or gC – BDNF target gene transfer to nigrostriatal neurons, which contain
specific receptors for GDNF or BDNF. A second approach to achieve neuronal type-specific expression is to use a cell type-specific
promoter, and we have used the tyrosine hydroxylase (TH) promoter to restrict expression to catecholaminergic neurons or a
modified neurofilament heavy gene promoter to restrict expression to neurons, and both of these promoters support long-term
expression from HSV-1 vectors. To both improve nigrostriatal-neuron specific expression, and to establish that targeted gene
transfer can be followed by long-term expression, we performed targeted gene transfer with vectors that support long-term,
neuronal-specific expression. |
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Keywords: | |
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