Projects per year
Abstract
Interactions of gene therapy vectors with human blood components upon intravenous administration have a significant effect on vector efficacy and patient safety. Here we describe methods to evaluate these interactions and their effects in whole human blood, using baculovirus vectors as a model. Opsonisation of baculovirus particles by binding of IgM and Ob was demonstrated, which is likely to be the cause of the significant blood cell-associated virus that was detected. Preventing formation of the complement C5b-9 (membrane attack) complex maintained infectivity of baculovirus particles as shown by studying the effects of two specific complement inhibitors, Compstatin and a C5a receptor antagonist. Formation of macroscopic blood clots after 4 h was prevented by both complement inhibitors. Pro- and anti-inflammatory cytokines Il-1 beta, IL-6, IL-8 and TNF-alpha were produced at variable levels between volunteers and complement inhibitors showed patient-specific effects on cytokine levels. Whilst both complement inhibitors could play a role in protecting patients from aggressive inflammatory reactions, only Compstatin maintained virus infectivity. We conclude that this ex vivo model, used here for the first time with infectious agents, is a valuable tool in evaluating human innate immune responses to gene therapy vectors or to predict the response of individual patients as part of a clinical trial or treatment. The use of complement inhibitors for therapeutic viruses should be considered on a patient-specific basis. (C) 2009 Elsevier Ltd. All rights reserved.
Original language | English |
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Pages (from-to) | 2911-2917 |
Number of pages | 7 |
Journal | Molecular immunology |
Volume | 46 |
Issue number | 15 |
DOIs | |
Publication status | Published - Sep 2009 |
Keywords
- Baculoviridae
- Complement C3b
- Complement C5a
- Complement Membrane Attack Complex
- Cytokines
- Gene Therapy
- Genetic Vectors
- Humans
- Immunity, Innate
- Immunoassay
- Immunoglobulin M
- Peptides, Cyclic
Projects
- 1 Finished
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Use of Baculovirus as a vector for gene therapy
1/01/07 → 31/03/10
Project: Research project (funded) › Research