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Complement inhibition rescued mice allowing observation of transgene expression following intraportal delivery of baculovirus in mice
Author(s) -
Hoare Jonathan,
Waddington Simon,
Thomas Howard C.,
Coutelle Charles,
McGarvey Michael J.
Publication year - 2005
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.671
Subject(s) - complement system , autographa californica , in vivo , transgene , alternative complement pathway , biology , gene delivery , c1 inhibitor , complement receptor , immunology , microbiology and biotechnology , antibody , recombinant dna , genetic enhancement , gene , biochemistry , spodoptera , angioedema
Abstract Background The baculovirus Autographa californica nucleo‐polyhedrosis virus (AcNPV) is an alternative to other viral vectors for hepatic gene delivery. A barrier to AcNPV being used in vivo is its susceptibility to inactivation by serum complement 1. In vivo utility has only been demonstrated using methods that avoid contact with serum 2–5. We have studied the complement pathways involved in baculovirus inactivation in vitro and the systemic administration of baculovirus vectors in vivo , with the co‐administration of the complement inhibitor, soluble complement inhibitor 1 (sCR1). Results EDTA increased baculovirus survival in human serum more than EGTA showing that both the alternative and classical pathways of complement are activated. Depleting serum of IgM increased survival, whereas reconstitution with pooled IgM restored activity against baculovirus, suggesting naturally occurring IgM antibodies with affinity for baculovirus may be partially responsible for complement activation. Intraportal administration of baculovirus led to hepatic expression when the complement inhibitor sCR1 (soluble complement receptor type 1) was co‐administered by tail vein injection; however, liver histology showed hepatic necrosis. Without co‐administration of sCR1, intraportal infusion of baculovirus was fatal within 24 h. Histology demonstrated massive hepatic necrosis. Yolk sac vein injection of baculovirus was associated with fetal death. Conclusions Transgene expression was demonstrated following intraportal infusion of recombinant baculovirus vectors in combination with sCR1; however, our experiments suggest a significant associated toxicity. Copyright © 2004 John Wiley & Sons, Ltd.