Polyinosinic acid enhances delivery of adenovirus vectors in vivo by preventing sequestration in liver macrophages.
Adenovirus is among the preferred vectors for gene therapy because of its superior in vivo gene-transfer efficiency. However, upon systemic administration, adenovirus is preferentially sequestered by the liver, resulting in reduced adenovirus-mediated transgene expression in targeted tissues. In the liver, Kupffer cells are responsible for adenovirus degradation and contribute to the inflammatory response. As scavenger receptors present on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated the possible implication of these receptors in the clearance of the adenovirus vector. Polyinosinic acid [poly(I)], a scavenger receptor A ligand, was analysed for its capability to inhibit adenovirus uptake specifically in macrophages. In in vitro studies, the addition of poly(I) before virus infection resulted in a specific inhibition of adenovirus-induced gene expression in a J774 macrophage cell line and in primary Kupffer cells. In in vivo experiments, pre-administration of poly(I) caused a 10-fold transient increase in the number of adenovirus particles circulating in the blood. As a consequence, transgene expression levels measured in different tissues were enhanced (by 5- to 15-fold) compared with those in animals that did not receive poly(I). Finally, necrosis of Kupffer cells, which normally occurs as a consequence of systemic adenovirus administration, was prevented by the use of poly(I). No toxicity, as measured by liver-enzyme levels, was observed after poly(I) treatment. From our data, we conclude that poly(I) can prevent adenovirus sequestration by liver macrophages. These results imply that, by inhibiting adenovirus uptake by Kupffer cells, it is possible to reduce the dose of the viral vector to diminish the liver-toxicity effect and to improve the level of transgene expression in target tissues. In systemic gene-therapy applications, this will have great impact on the development of targeted adenoviral vectors.
Haisma
Hidde J
HJ
Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands.
Kamps
Jan A A M
JAAM
Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands.
Kamps
Gera K
GK
Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands.
Plantinga
Josee A
JA
Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands.
Rots
Marianne G
MG
Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands.
Bellu
Anna Rita
AR
Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands.
D000256:Adenoviridae / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D007155:Immunologic Factors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects*; D008111:Liver Function Tests; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D011069:Poly I / Q000494:pharmacology*; D051381:Rats; D051116:Receptors, Scavenger / Q000037:antagonists & inhibitors*; D010948:Viral Plaque Assay; D014766:Viremia
D007155:Immunologic Factors; D051116:Receptors, Scavenger; D011069:Poly I