HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zuber, C. Articles by Weiss, S. Search for Related Content PubMed PubMed Citation Articles by Zuber, C. Articles by Weiss, S. Agricola Articles by Zuber, C. Articles by Weiss, S.

Delivery of single-chain antibodies (scFvs) directed against the 37/67 kDa laminin receptor into mice via recombinant adeno-associated viral vectors for prion disease gene therapy

Chantal Zuber^1,

Gerda Mitteregger^2,

¹ Laboratorium für Molekulare Biologie - Genzentrum - Institut für Biochemie der LMU München, Feodor-Lynen-Str. 25, D-81377 München, Germany
² Zentrum für Neuropathologie und Prionforschung der LMU München, Feodor-Lynen-Str. 23, 81377 München, Germany
³ Universität zu Köln, Klinik I für Innere Medizin, Kerpener Str. 62, 50937 Köln, Germany
⁴ Affimed Therapeutics AG, Technologiepark, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany
⁵ Zentrum für Molekulare Medizin Köln, Universität zu Köln, Joseph-Stelzmann-Str. 52, 50931 Köln, Germany

Correspondence
Stefan Weiss
weiss{at}lmb.uni-muenchen.de

The 37/67 kDa laminin receptor (LRP/LR) acts as a receptor for prions providing a promising target for the treatment of prion diseases. Recently, we selected anti-LRP/LR single-chain antibodies (scFvs) and proved a reduction of the peripheral PrP^Sc propagation by passive immunotransfer into scrapie-infected mice. Here, we report the development of an in vivo gene delivery system based on adeno-associated virus (AAV) vectors expressing scFvs-S18 and -N3 directed against LRP/LR. Transduction of neuronal and non-neuronal cells with recombinant (r)AAV serotype 2 vectors encoding scFv-S18, -N3 and -C9 verified the efficient secretion of the antibodies. These vectors were administered via stereotactic intracerebral microinjection into the hippocampus of C57BL/6 mice, followed by intracerebral inoculation with 10 % RML at the same site 2 weeks post-injection of rAAV. After 90 days post-infection, scFv-S18 and -N3 expression resulted in the reduction of peripheral PrP^Sc propagation by approximately 60 and 32 %, respectively, without a significant prolongation of incubation times and survival. Proof of rAAV vector DNA in spleen samples by real-time PCR strongly suggests a transport or trafficking of rAAV from the brain to the spleen, resulting in rAAV-mediated expression of scFv followed by reduced PrP^Sc levels in the spleen most likely due to the blockage of the prion receptor LRP/LR by scFv.

These authors contributed equally to this work.

This article has been cited by other articles:

				M. Tayebi, W. A. Taylor, D. R. Jones, C. Bate, and M. David PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein J. Gen. Virol., August 1, 2010; 91(8): 2121 - 2131. [Abstract] [Full Text] [PDF]

				N. G. Tassew, J. Charish, L. Chestopalova, and P. P. Monnier Sustained In Vivo Inhibition of Protein Domains Using Single-Chain Fv Recombinant Antibodies and Its Application to Dissect RGMa Activity on Axonal Outgrowth J. Neurosci., January 28, 2009; 29(4): 1126 - 1131. [Abstract] [Full Text] [PDF]

				H. Pflanz, K. Vana, G. Mitteregger, C. Pace, D. Messow, C. Sedlaczek, D. Nikles, H. A. Kretzschmar, and S. F. T. Weiss Microinjection of lentiviral vectors expressing small interfering RNAs directed against laminin receptor precursor mRNA prolongs the pre-clinical phase in scrapie-infected mice J. Gen. Virol., January 1, 2009; 90(1): 269 - 274. [Abstract] [Full Text] [PDF]