Lesion-dependent regulation of transgene expression in the rat brain using a human glial fibrillary acidic protein-lentiviral vector.
The ability to regulate transgene expression will be crucial for development of gene therapy to the brain. The most commonly used systems are based on a transactivator in combination with a drug, e.g. the tetracycline-regulated system. Here we describe a different method of transgene regulation by the use of the human glial fibrillary acidic protein (GFAP) promoter. We constructed a lentiviral vector that directs transgene expression to astrocytes. Using toxin-induced lesions we investigated to what extent transgene expression could be regulated in accordance with the activation of the endogenous GFAP gene. In animals receiving excitotoxic lesions of the striatum we detected an eightfold increase of green fluorescent protein (GFP)-expressing cells. The vast majority of these cells did not divide, suggesting that the transgene was indeed regulated in a similar fashion as the endogenous GFAP gene. This finding will lead to the development of lentiviral vectors with autoregulatory capacities that may be very useful for gene therapy to the brain.
Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, BMC A11, 221 84 Lund, Sweden.
Johan
J
Jakobsson
Biljana
B
Georgievska
Cecilia
C
Ericson
Cecilia
C
Lundberg
D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002452:Cell Count; D004797:Enzyme-Linked Immunosorbent Assay; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006801:Humans; D006892:Hydroxydopamines / Q000633:toxicity; D007051:Ibotenic Acid / Q000633:toxicity; D016086:Lentivirus / Q000235:genetics; D008164:Luminescent Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019076:Transgenes
D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D006892:Hydroxydopamines; D008164:Luminescent Proteins; D018809:Proliferating Cell Nuclear Antigen; D049452:Green Fluorescent Proteins; D007051:Ibotenic Acid; D010751:Phosphopyruvate Hydratase