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
Zuber, Chantal and Mitteregger, Gerda and Schuhmann, Natascha and Rey, Clémence and Knackmuss, Stefan and Rupprecht, Wolfgang and Reusch, Uwe and Pace, Claudia and Little, Melvyn and Kretzschmar, Hans A. and Hallek, Michael and Büning, Hildegard and Weiss, Stefan,, 89, 2055-2061 (2008),
doi = https://doi.org/10.1099/vir.0.83670-0,
publicationName = Microbiology Society,
issn = 0022-1317,
abstract= 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 PrPSc 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 PrPSc 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 PrPSc levels in the spleen most likely due to the blockage of the prion receptor LRP/LR by scFv.,
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