The 37 kDa/67 kDa laminin receptor (LRP/LR) represents a key player for cell adhesion, is associated with the metastatic potential of solid tumors and is required for maintenance of cell viability by preventing apoptosis. LRP/LR acts as a receptor for viruses such as Sindbis virus, Venezuelean Equine Encephalitis (VEE) virus, Adeno-associated-viruses (AAV) and Dengue Virus, the latter causing 50 to 100 million infections in humans per year. LRP/LR acts further as a receptor for prions and represents a multifunctional protein subcellularly located to the nucleus, the cytoplasm and the cell surface. The receptor represents an alternative target for therapy of viral infections, cancer and prion disorders and might play additional roles in further neurodegenerative diseases such as Alzheimer's disease. The species barrier in prion disorders might be at least in part determined by the presence of LRP/LR in enterocytes of the intestinal epithelium. Anti-LRP/LR antibodies, siRNAs directed against LRP mRNA, polysulfated glycanes such as pentosan polysulfate and heparan mimetics and LRP decoy mutants are promising tools for blocking or downregulating the receptor and may represent alternative therapeutics for the treatment of prion disorders, Alzheimer's Disease and metastatic cancer.

We examined therapeutic in vitro and in vivo approaches using lentivirus-based packaging of small interfering RNAs (siRNAs) targeting the non-integrin laminin receptor mRNA for treatment and prevention of prion disorders. Transfection of N2aSc + cells with recombinant plasmids expressing three different siRNAs, significantly reduced both the LRP (laminin receptor precursor) and PrP Sc levels by approximately 40-60 %. Stereotactic intracerebral microinjection of recombinant lentiviral vectors LVsiRNA-LRP 7 and 9 into the cortex of C57BL/6 wild-type mice resulted in a significant reduction of the LR levels in the cortex 15 days post-injection by 62 and 82 %, respectively. Intracerebral RML inoculation of C57BL/6 mice after microinjection with recombinant lentiviral vector LVsiRNA-LRP 7 into the hippocampus resulted in a significant reduction of both LRP and PrP Sc levels by 36 and 41 %, respectively, concomitant with a significant prolongation of the pre-clinical phase. Lentiviral vectors expressing siRNAs targeting LRP mRNA represent a novel delivery system for the treatment of transmissible spongiform encephalopathies.Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders affecting animals and humans. TSEs are characterized by the accumulation of an 'abnormal' pathogenic isoform (PrP Sc ) of the host-encoded cellular prion protein (PrP c ) in the brain of affected individuals (Prusiner et al., 1998). According to the 'protein-only' hypothesis, the conversion of PrP c to PrP Sc is the pivotal event in the aetiology of TSEs (Prusiner et al., 1990). Since prion diseases are lethal disorders, great endeavours have been undertaken to develop an efficient anti-prion therapy (for reviews see Ludewigs et al., 2007;Trevitt & Collinge, 2006;Weissmann & Aguzzi, 2005).The 37/67 kDa laminin receptor (LRP/LR) was identified as the receptor for prions (Gauczynski et al., 2006(Gauczynski et al., , 2001b and is localized on the cell surface, in the cytoplasm and the nucleus, respectively (for reviews see Gauczynski et al., 2001a;Ludewigs et al., 2007;Vana et al., 2007, Zuber et al., 2007a. Furthermore, LRP/LR colocalizes with PrP on the cell surface (Gauczynski et al., 2001b) and in the perinuclear compartment (Nikles et al., 2008). LRP/LR binding to laminin, elastin and carbohydrates accounts for its fundamental role in cell adhesion, cell movement and growth (for review see Gauczynski et al., 2001a;Rieger et al., 1999). LRP/LR plays an important role in the invasive and metastatic potential of neoplastic cells (Givant-Horwitz et al., 2005;Landowski et al., 1995) and tumour angiogenesis (Tanaka et al., 2000) (for reviews see Castronovo, 1993;Menard et al., 1997;Vana et al., 2008). Blocking or downregulating LRP/LR hampers the invasive potential of tumorigenic fibrosarcoma cells, by blocking the laminin-1-LRP/LR interaction on the cell surface (Zuber et al., 2008b). LRP/LR further supports maintenance of nuclear structures (Kinoshita et al., 1998), supports the translation process in the cytosol (...

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