NR AUQM
AU Weiss,S.
TI Therapeutic Strategies for the treatment of TSEs targeting the 37 kDa/67 kDa Laminin Receptor
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Vortrag V-05
PT Konferenz-Vortrag
AB
The 37-kDa/67-kDa laminin receptor (LRP/LR) acts as the receptor for the cellular prion protein (PrPc) (1) and as a receptor for bovine prions on human enterocytes (2). HSPGs act as co-factors/co-receptors for PrPc (3). Knock-down of LRP/LR in scrapie infected neuronal cells by antisense LRP RNA, siRNAs directed against LRP mRNA and a LRP/LR specific polyclonal antibody (W3) resulted in ablation of PrPsc propagation (4). Secretion of the mutant LRP102-295::FLAG impaired as a decoy in a transdominant negative manner PrPsc propagation in N2aSc+ cells (5). Heparan mimetics (HMs) inhibit PrPsc propagation in cultured cells and prolong the incubation times in rodents. We show, that the HMs interfere more efficiently with moPrP27-30 binding to LRP::FLAG hyperexpressing BHK cells compared to other polysulfated glycanes such as pentosan polysulfate.
We established a series of in vivo systems for the delivery of single chain antibodies (scFvs) directed against LRP/LR and siRNAs directed against LRP mRNA into mice. Selected scFvs directed against LRP/LR have been delivered to animals by injection of recombinant Adeno-Associated Viruses (AAVs). anti-LRP/LR antibodies (scFvs and W3) have been delivered by i.p. injections for passive immuno-therapy. scFv secreting myotubes have been generated for continuous antibody secretion after grafting into defined brain regions. Recombinant lentiviral vectors expressing siRNAs directed against LRP mRNA have been generated for delivery of siRNAs into mice.
Transgenic animals have been generated ectopically expressing (i) antisense LRP RNA and (ii) the LRP102-295::FLAG mutant in the brain.
Anti-LRP antibodies, anti-LRP mRNA siRNAs, the LRP102-295::FLAG mutant and heparan mimetics represent alternative promising tools in therapy of prion diseases.
(1) Gauczynski et al. (2001) EMBO J. 20, 5863-5875.
(2) Morel et al. (2005) Am J Path, 167, 1033-1042.
(3) Hundt et al. (2001) EMBO J. 20, 5876-5886.
(4) Leucht et al. (2003) EMBO rep 4, 290-295.
(5) Vana and Weiss (2006) J Mol Biol. 358, 57-66.
AD Stefan Weiss, Laboratorium für Molekulare Biologie - Genzentrum-Institut für Biochemie der LMU München, Feodor-Lynen-Str. 25, 81377 München, Germany
SP englisch
PO Deutschland
OR Tagungsband