1887

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 PrP propagation by passive immunotransfer into scrapie-infected mice. Here, we report the development of an 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 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 levels in the spleen most likely due to the blockage of the prion receptor LRP/LR by scFv.

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2008-08-01
2020-01-17
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