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Non-human adenovirus vectors have attractive immunological properties for gene therapy but are frequently restricted by inefficient transduction of human target cells. Using chicken embryo lethal orphan (CELO) virus, we employed a nongenetic mechanism of polymer coating and retargeting with basic fibroblast growth factor (bFGF-pc-CELOluc), a strategy that permits efficient tropism modification of human adenovirus. bFGF-pc-CELOluc showed efficient uptake and transgene expression in chick embryo fibroblasts (CEF), and increased levels of binding and internalization in a variety of human cell lines. Transgene expression was also greater than unmodified CELOluc in PC-3 human prostate cells, although the specific activity (RLU per internalized viral genome) was decreased. In CEF, the specific activity of bFGF-pc-CELOluc was considerably higher than in the human prostate cell line PC-3. Retargeted virus was fully resistant to inhibition by human serum with known adenovirus-neutralizing activity in vitro, while in mice CELOluc was cleared less rapidly from the blood than Adluc following i.v. administration in the presence of adenovirus neutralizing serum. Polymer coating and retargeting with bFGF further reduced rates of clearance for both viruses, suggesting protection against both neutralizing and opsonizing factors. The data indicate that CELO virus may be retargeted to infect human cells via alternative, potentially disease-specific, receptors and resist the effects of pre-existing humoral immunity.

Original publication

DOI

10.1038/sj.gt.3302655

Type

Journal article

Journal

Gene Ther

Publication Date

02/2006

Volume

13

Pages

356 - 368

Keywords

Animals, Cell Adhesion Molecules, Cell Line, Cells, Cultured, Chick Embryo, Fibroblast Growth Factor 2, Fibroblasts, Fowl adenovirus A, Gene Expression, Gene Targeting, Genetic Therapy, Genetic Vectors, Humans, Immune Sera, Immunohistochemistry, Male, Metalloendopeptidases, Mice, Neutralization Tests, Polymers, Prostate, Protein Engineering, Transduction, Genetic, Transgenes