Adenovirus-transduced human butyrylcholinesterase in mouse blood functions as a bioscavenger of chemical warfare nerve agents

Nageswararao Chilukuri, Ellen G. Duysen, Kalpana Parikh, Robert DiTargiani, Bhupendra P. Doctor, Oksana Lockridge, Ashima Saxena

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents. We have showed previously that recombinant (r) Hu BChE can be expressed at very high levels, 400 to 600 U/ml in mouse blood, by delivering the Hu BChE gene using adenovirus (Ad). Here, we report the biochemical properties of the Ad-expressed full-length and truncated rHu BChE in mouse blood. The molecular sizes of the full-length rHu BChE subunit and its oligomers were similar to those of native Hu BChE, although only a small portion of the full-length rHu BChE subunit underwent assembly into dimers and tetramers. As expected, Ad containing the truncated Hu BChE gene transduced the expression of monomeric rHu BChE only. Compared with 415 U of rHu BChE per milliliter in blood, tissues including liver, lung, heart, brain, kidney, muscle, intestine, diaphragm, salivary gland, and fat expressed <10 U/g of rHu BChE activity. Adexpressed rHu BChE in mouse blood neutralized soman and O-ethyl S-2-N,N-diisopropylaminoethyl methylphosphonothiolate at rates similar to those of native Hu BChE and rHu BChE expressed in vitro. Because the expression of rHu BChE rapidly decreased 6 days after virus administration, sera were assayed for the presence of anti-Hu BChE antibodies. Anti-Hu BChE antibodies were detected on day 7 and in increased amounts thereafter, which coincided with the loss of Hu BChE expression in sera. In conclusion, the delivery of Hu BChE gene using Ad can be a promising strategy that can provide protection against multiple lethal doses of chemical warfare nerve agents in vivo.

Original languageEnglish (US)
Pages (from-to)612-617
Number of pages6
JournalMolecular pharmacology
Volume76
Issue number3
DOIs
StatePublished - Sep 1 2009

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Chemical Warfare Agents
Butyrylcholinesterase
Human Adenoviruses
Serum
Adenoviridae
Nerve Agents
Soman
Antibodies
Diaphragm
Salivary Glands
Genes
Intestines

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Adenovirus-transduced human butyrylcholinesterase in mouse blood functions as a bioscavenger of chemical warfare nerve agents. / Chilukuri, Nageswararao; Duysen, Ellen G.; Parikh, Kalpana; DiTargiani, Robert; Doctor, Bhupendra P.; Lockridge, Oksana; Saxena, Ashima.

In: Molecular pharmacology, Vol. 76, No. 3, 01.09.2009, p. 612-617.

Research output: Contribution to journalArticle

Chilukuri, Nageswararao ; Duysen, Ellen G. ; Parikh, Kalpana ; DiTargiani, Robert ; Doctor, Bhupendra P. ; Lockridge, Oksana ; Saxena, Ashima. / Adenovirus-transduced human butyrylcholinesterase in mouse blood functions as a bioscavenger of chemical warfare nerve agents. In: Molecular pharmacology. 2009 ; Vol. 76, No. 3. pp. 612-617.
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