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Nat Commun. 2015 Feb 10;6:6246. doi: 10.1038/ncomms7246.

Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors.

Author information

1
Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany.
2
1] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany [2] German Center for Infection Research (DZIF), partner site Bonn-Cologne and Department I of Internal Medicine, University of Cologne, 50931 Cologne, Germany.
3
Department of Biochemistry, University of Zurich, Zurich 8057, Switzerland.
4
Institute of Medical Virology, University of Zurich, Zurich 8057, Switzerland.
5
1] Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany [2] German Cancer Consortium, 69120 Heidelberg, Germany.

Abstract

We describe receptor-targeted adeno-associated viral (AAV) vectors that allow genetic modification of rare cell types ex vivo and in vivo while showing no detectable off-targeting. Displaying designed ankyrin repeat proteins (DARPins) on the viral capsid and carefully depleting DARPin-deficient particles, AAV vectors were made specific for Her2/neu, EpCAM or CD4. A single intravenous administration of vector targeted to the tumour antigen Her2/neu was sufficient to track 75% of all tumour sites and to extend survival longer than the cytostatic antibody Herceptin. CD4-targeted AAVs hit human CD4-positive cells present in spleen of a humanized mouse model, while CD8-positive cells as well as liver or other off-target organs remained unmodified. Mimicking conditions of circulating tumour cells, EpCAM-AAV detected single tumour cells in human blood opening the avenue for tumour stem cell tracking. Thus, the approach developed here delivers genes to target cell types of choice with antibody-like specificity.

PMID:
25665714
DOI:
10.1038/ncomms7246
[Indexed for MEDLINE]

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