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

Robert C. Münch, Anke Muth, Alexander Muik, Thorsten Friedel, Julia Schmatz, Birgit Dreier, Alexandra Trkola, Andreas Plückthun, Hildegard Büning and Christian J. Buchholz ()
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Robert C. Münch: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut
Anke Muth: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut
Alexander Muik: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut
Thorsten Friedel: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut
Julia Schmatz: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Birgit Dreier: University of Zurich
Alexandra Trkola: Institute of Medical Virology, University of Zurich
Andreas Plückthun: University of Zurich
Hildegard Büning: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Christian J. Buchholz: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7246

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