High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy.
Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could significantly decrease adenoviral transduction efficiency in vivo. Here we demonstrate that mice on a high fat diet have lower transgene expression compared to mice on a regular chow. In addition, on a high fat diet, ApoE-/-mice have much higher plasma transgene levels compared to LDLR-deficient mice. We also found that specific lipoprotein receptors play an important role in adenoviral transduction. These findings suggest that high plasma lipid levels, especially apoE-containing lipoproteins, reduce efficacy of adenoviral transduction in mice, which implies that high cholesterol levels in humans could be protective against viral infections and also lead to insufficient transgene expression in clinical trials using adenoviral vectors.
University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland.
A M
AM
Kivelä
University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland.
J
J
Huusko
University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland.
E
E
Gurzeler
University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland.
A
A
Laine
University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland.
M H
MH
Dijkstra
University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland.
G
G
Dragneva
University of Aarhus, Department of Biomedicine, Ole Worms Allé 3, DK-8000, Aarhus C, Denmark.
C B F
CB
Andersen
University of Aarhus, Department of Biomedicine, Ole Worms Allé 3, DK-8000, Aarhus C, Denmark.
S K
SK
Moestrup
University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland. Seppo.Ylaherttuala@uef.fi.
S
S
Ylä-Herttuala
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D059305:Diet, High-Fat; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D008055:Lipids / Q000097:blood*; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D011973:Receptors, LDL / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000378:metabolism; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics*
D001057:Apolipoproteins E; D008055:Lipids; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse