TY - JOUR
T1 - Adenovirus-mediated gene transfer of human butyrylcholinesterase results in persistent high-level transgene expression in vivo
AU - Chilukuri, Nageswararao
AU - Duysen, Ellen G.
AU - Parikh, Kalpana
AU - Sun, Wei
AU - Doctor, Bhupendra P.
AU - Lockridge, Oksana
AU - Saxena, Ashima
PY - 2008/9/25
Y1 - 2008/9/25
N2 - Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents, pesticide intoxication, and cocaine overdose. However, its widespread application is hampered by difficulties in large-scale production of the native protein from human plasma and/or availability as a recombinant protein suitable for use in vivo. This limitation may be resolved by in vivo delivery and expression of the Hu BChE gene. In this study, recombinant (r) adenoviruses (Ads) encoding full-length and truncated rHu BChEs were tested for in vivo expression in mice. Mice injected with these rAds intraperitoneally failed to express rHu BChE. However, a single tail vein injection of both rAds resulted in persistent high serum levels of rHu BChE in BChE knockout mice, which peaked on days 4/5 at 377 ± 162 U/ml for full-length rHu BChE and 574 ± 143 U/ml for truncated rHu BChE. These activity levels are orders of magnitude higher than 1.9 U/ml of mouse BChE present in wild-type mouse serum. Thereafter, rHu BChE levels dropped rapidly and very little or no activity was detected in the serum 10 days post-virus administration. In conclusion, the present study demonstrates the potential of rAd-mediated Hu BChE gene therapy to counteract multiple lethal doses of chemical warfare nerve agent toxicity.
AB - Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents, pesticide intoxication, and cocaine overdose. However, its widespread application is hampered by difficulties in large-scale production of the native protein from human plasma and/or availability as a recombinant protein suitable for use in vivo. This limitation may be resolved by in vivo delivery and expression of the Hu BChE gene. In this study, recombinant (r) adenoviruses (Ads) encoding full-length and truncated rHu BChEs were tested for in vivo expression in mice. Mice injected with these rAds intraperitoneally failed to express rHu BChE. However, a single tail vein injection of both rAds resulted in persistent high serum levels of rHu BChE in BChE knockout mice, which peaked on days 4/5 at 377 ± 162 U/ml for full-length rHu BChE and 574 ± 143 U/ml for truncated rHu BChE. These activity levels are orders of magnitude higher than 1.9 U/ml of mouse BChE present in wild-type mouse serum. Thereafter, rHu BChE levels dropped rapidly and very little or no activity was detected in the serum 10 days post-virus administration. In conclusion, the present study demonstrates the potential of rAd-mediated Hu BChE gene therapy to counteract multiple lethal doses of chemical warfare nerve agent toxicity.
KW - Adenovirus
KW - Bioscavenger
KW - Gene therapy
KW - Human butyrylcholinesterase
KW - Organophosphorus compounds
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UR - http://www.scopus.com/inward/citedby.url?scp=50649118579&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2008.04.009
DO - 10.1016/j.cbi.2008.04.009
M3 - Article
C2 - 18499092
AN - SCOPUS:50649118579
SN - 0009-2797
VL - 175
SP - 327
EP - 331
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 1-3
ER -