The immunosuppressant FK506 prolongs transgene expression in brain following adenovirus-mediated gene transfer.
First generation, replication-defective adenoviral vectors are highly effective for gene transfer into the central nervous system, but the host's immune response limits the utility of this vector for possible therapy of neurological disease or long-term gene transfer studies in experimental animals. We have demonstrated the effectiveness of FK506 (tacrolimus), a powerful immunosuppressant that readily crosses the blood-brain barrier, in maintaining adenovirus-mediated reporter gene transfer following stereotaxic injection of the recombinant (AdCMVlacZ) into mouse striatum. After 28 days, beta-galactosidase expression was reduced by 75% relative to day 10 in immunocompetent animals, accompanied by an inflammatory reaction in the region of transduced cells; however, in mice receiving daily s.c. injections of FK506, beta-galactosidase activity was maintained at the 10 days post-injection level.
Durham
H D
HD
Montreal Neurological Institute, McGill University, Quebec, Canada.
Alonso-Vanegas
M A
MA
Sadikot
A F
AF
Zhu
L
L
Lochmüller
H
H
Massie
B
B
Nalbantoglu
J
J
Karpati
G
G
D000256:Adenoviridae; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D018014:Gene Transfer Techniques; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016559:Tacrolimus / Q000494:pharmacology*; D013997:Time Factors; D019076:Transgenes / Q000235:genetics*; D001616:beta-Galactosidase / Q000378:metabolism
D007166:Immunosuppressive Agents; D001616:beta-Galactosidase; D016559:Tacrolimus