Inflammatory responses and their impact on beta-galactosidase transgene expression following adenovirus vector delivery to the primate caudate nucleus.
An E1, E3 deleted adenovirus vector, serotype 5, carrying the marker gene LacZ was bilaterally microinfused into the caudate nuclei of 10 St Kitts green monkeys. The location and number of cells expressing transgene and host immunologic response were evaluated at 1 week (n = 2) and 1 month (n = 8) following vector infusion. A large number of cells expressed beta-galactosidase in some monkeys, exceeding 600000 in one monkey, but no expression was seen in three of 10. All monkeys had positive adenoviral antibody titers before vector infusion, indicating the possibility of previous exposure to some adenovirus, but only one showed a significant increase in titer afterwards. Inflammatory cell markers revealed an inverse correlation between transgene expression and the extent of inflammatory response. Dexamethasone administered immediately before and for 8 days following vector delivery, however, had no effect on transgene expression. The demonstration of significant inflammatory responses in the brain of some individual primates, including demyelination, indicates the need for new generations of adenovirus vectors, or the successful suppression of inflammatory responses, before this vector is suitable for non-cytotoxic clinical applications in the CNS.
Lawrence
M S
MS
Yale University School of Medicine, Neural Transplantation and Repair Program, Department of Psychiatry, New Haven, CT 06520, USA.
Foellmer
H G
HG
Elsworth
J D
JD
Kim
J H
JH
Leranth
C
C
Kozlowski
D A
DA
Bothwell
A L
AL
Davidson
B L
BL
Bohn
M C
MC
Redmond
D E
DE
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017209:Apoptosis; D002421:Caudate Nucleus / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D002522:Chlorocebus aethiops; D004660:Encephalitis / Q000201:enzymology / Q000821:virology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D008297:Male; D019076:Transgenes / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism*
D001616:beta-Galactosidase