1887

Abstract

We examined therapeutic and 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 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 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.

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2009-01-01
2019-11-21
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References

  1. Auth, D. & Brawerman, G. ( 1992; ). A 33-kDa polypeptide with homology to the laminin receptor: component of translation machinery. Proc Natl Acad Sci U S A 89, 4368–4372.[CrossRef]
    [Google Scholar]
  2. Baloui, H., Stettler, O., Weiss, S., Nothias, F. & von Boxberg, Y. ( 2008; ). Upregulation in rat spinal cord microglia of the nonintegrin laminin receptor 37 kDa-LRP following activation by a traumatic lesion, or peripheral injury. J Neurotrauma in press
    [Google Scholar]
  3. Baloui, H., von Boxberg, Y., Vinh, J., Weiss, S., Rossier, J., Nothias, F. & Stettler, O. ( 2004; ). Cellular prion protein/laminin receptor: distribution in adult central nervous system and characterization of an isoform associated with a subtype of cortical neurons. Eur J Neurosci 20, 2605–2616.[CrossRef]
    [Google Scholar]
  4. Blomer, U., Naldini, L., Kafri, T., Trono, D., Verma, I. M. & Gage, F. H. ( 1997; ). Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. J Virol 71, 6641–6649.
    [Google Scholar]
  5. Castronovo, V. ( 1993; ). Laminin receptors and laminin-binding proteins during tumor invasion and metastasis. Invasion Metastasis 13, 1–30.
    [Google Scholar]
  6. Crozet, C., Lin, Y. L., Mettling, C., Mourton-Gilles, C., Corbeau, P., Lehmann, S. & Perrier, V. ( 2004; ). Inhibition of PrPSc formation by lentiviral gene transfer of PrP containing dominant negative mutations. J Cell Sci 117, 5591–5597.[CrossRef]
    [Google Scholar]
  7. Gauczynski, S., Hundt, C., Leucht, C. & Weiss, S. ( 2001a; ). Interaction of prion proteins with cell surface receptors, molecular chaperones, and other molecules. Adv Protein Chem 57, 229–272.
    [Google Scholar]
  8. Gauczynski, S., Peyrin, J. M., Haik, S., Leucht, C., Hundt, C., Rieger, R., Krasemann, S., Deslys, J. P., Dormont, D. & other authors ( 2001b; ). The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein. EMBO J 20, 5863–5875.[CrossRef]
    [Google Scholar]
  9. Gauczynski, S., Nikles, D., El-Gogo, S., Papy-Garcia, D., Rey, C., Alban, S., Barritault, D., Lasmezas, C. I. & Weiss, S. ( 2006; ). The 37-kDa/67-kDa laminin receptor acts as a receptor for infectious prions and is inhibited by polysulfated glycanes. J Infect Dis 194, 702–709.[CrossRef]
    [Google Scholar]
  10. Givant-Horwitz, V., Davidson, B. & Reich, R. ( 2005; ). Laminin-induced signaling in tumor cells. Cancer Lett 223, 1–10.[CrossRef]
    [Google Scholar]
  11. Kinoshita, K., Kaneda, Y., Sato, M., Saeki, Y., Wataya, K. M. & Hoffmann, A. ( 1998; ). LBP-p40 binds DNA tightly through associations with histones H2A, H2B, and H4. Biochem Biophys Res Commun 253, 277–282.[CrossRef]
    [Google Scholar]
  12. Landowski, T. H., Uthayakumar, S. & Starkey, J. R. ( 1995; ). Control pathways of the 67 kDa laminin binding protein: surface expression and activity of a new ligand binding domain. Clin Exp Metastasis 13, 357–372.
    [Google Scholar]
  13. Leucht, C., Simoneau, S., Rey, C., Vana, K., Rieger, R., Lasmezas, C. I. & Weiss, S. ( 2003; ). The 37 kDa/67 kDa laminin receptor is required for PrPSc propagation in scrapie-infected neuronal cells. EMBO Rep 4, 290–295.[CrossRef]
    [Google Scholar]
  14. Ludewigs, H., Zuber, C., Vana, K., Nikles, D., Zerr, I. & Weiss, S. ( 2007; ). Therapeutic approaches for prion disorders. Expert Rev Anti Infect Ther 5, 613–630.[CrossRef]
    [Google Scholar]
  15. Menard, S., Castronovo, V., Tagliabue, E. & Sobel, M. E. ( 1997; ). New insights into the metastasis-associated 67 kD laminin receptor. J Cell Biochem 67, 155–165.[CrossRef]
    [Google Scholar]
  16. Naldini, L., Blomer, U., Gage, F. H., Trono, D. & Verma, I. M. ( 1996a; ). Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci U S A 93, 11382–11388.[CrossRef]
    [Google Scholar]
  17. Naldini, L., Blomer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M. & Trono, D. ( 1996b; ). In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267.[CrossRef]
    [Google Scholar]
  18. Nikles, D., Vana, K., Gauczynski, S., Knetsch, H., Ludewigs, H. & Weiss, S. ( 2008; ). Subcellular localization of prion proteins and the 37 kDa/67 kDa laminin receptor fused to fluorescent proteins. Biochim Biophys Acta 1782, 335–340.[CrossRef]
    [Google Scholar]
  19. Pfeifer, A., Eigenbrod, S., Al-Khadra, S., Hofmann, A., Mitteregger, G., Moser, M., Bertsch, U. & Kretzschmar, H. ( 2006; ). Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice. J Clin Invest 116, 3204–3210.[CrossRef]
    [Google Scholar]
  20. Prusiner, S. B., Scott, M., Foster, D., Pan, K. M., Groth, D., Mirenda, C., Torchia, M., Yang, S. L., Serban, D. & other authors ( 1990; ). Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63, 673–686.[CrossRef]
    [Google Scholar]
  21. Prusiner, S. B., Scott, M. R., DeArmond, S. J. & Cohen, F. E. ( 1998; ). Prion protein biology. Cell 93, 337–348.[CrossRef]
    [Google Scholar]
  22. Rieger, R., Edenhofer, F., Lasmezas, C. I. & Weiss, S. ( 1997; ). The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med 3, 1383–1388.[CrossRef]
    [Google Scholar]
  23. Rieger, R., Lasmezas, C. I. & Weiss, S. ( 1999; ). Role of the 37 kDa laminin receptor precursor in the life cycle of prions. Transfus Clin Biol 6, 7–16.[CrossRef]
    [Google Scholar]
  24. Sethi, S., Lipford, G., Wagner, H. & Kretzschmar, H. ( 2002; ). Postexposure prophylaxis against prion disease with a stimulator of innate immunity. Lancet 360, 229–230.[CrossRef]
    [Google Scholar]
  25. Simoneau, S., Haik, S., Leucht, C., Dormont, D., Deslys, J. P., Weiss, S. & Lasmezas, C. ( 2003; ). Different isoforms of the non-integrin laminin receptor are present in mouse brain and bind PrP. Biol Chem 384, 243–246.
    [Google Scholar]
  26. Susantad, T. & Smith, D. R. ( 2008; ). siRNA-mediated silencing of the 37/67-kDa high affinity laminin receptor in Hep3B cells induces apoptosis. Cell Mol Biol Lett 13, 452–464.
    [Google Scholar]
  27. Tanaka, M., Narumi, K., Isemura, M., Abe, M., Sato, Y., Abe, T., Saijo, Y., Nukiwa, T. & Satoh, K. ( 2000; ). Expression of the 37-kDa laminin binding protein in murine lung tumor cell correlates with tumor angiogenesis. Cancer Lett 153, 161–168.[CrossRef]
    [Google Scholar]
  28. Trevitt, C. R. & Collinge, J. ( 2006; ). A systematic review of prion therapeutics in experimental models. Brain 129, 2241–2265.[CrossRef]
    [Google Scholar]
  29. Tuschl, T., Zamore, P. D., Lehmann, R., Bartel, D. P. & Sharp, P. A. ( 1999; ). Targeted mRNA degradation by double-stranded RNA in vitro. Genes Dev 13, 3191–3197.[CrossRef]
    [Google Scholar]
  30. Vana, K. & Weiss, S. ( 2006; ). A trans-dominant negative 37kDa/67kDa laminin receptor mutant impairs PrPSc propagation in scrapie-infected neuronal cells. J Mol Biol 358, 57–66.[CrossRef]
    [Google Scholar]
  31. Vana, K., Zuber, C., Nikles, D. & Weiss, S. ( 2007; ). Novel aspects of prions, their receptor molecules, and innovative approaches for TSE therapy. Cell Mol Neurobiol 27, 107–128.[CrossRef]
    [Google Scholar]
  32. Vana, K., Zuber, C., Pflanz, H., Kolodziejczak, D., Zemora, G., Bergmann, A.-K. & Weiss, S. ( 2008; ). LRP/LR as an alternative promising target in therapy of prion diseases. Infect Disord Drug Targets in press
    [Google Scholar]
  33. Weissmann, C. & Aguzzi, A. ( 2005; ). Approaches to therapy of prion diseases. Annu Rev Med 56, 321–344.[CrossRef]
    [Google Scholar]
  34. Zuber, C., Ludewigs, H. & Weiss, S. ( 2007a; ). Therapeutic approaches targeting the prion receptor LRP/LR. Vet Microbiol 123, 387–393.[CrossRef]
    [Google Scholar]
  35. Zuber, C., Mitteregger, G., Pace, C., Zerr, I., Kretzschmar, H. A. & Weiss, S. ( 2007b; ). Anti-LRP/LR antibody W3 hampers peripheral PrPSc propagation in scrapie infected mice. Prion 1, 207–212.[CrossRef]
    [Google Scholar]
  36. Zuber, C., Knackmuss, S., Rey, C., Reusch, U., Rottgen, P., Frohlich, T., Arnold, G. J., Pace, C., Mitteregger, G. & other authors ( 2008a; ). Single chain Fv antibodies directed against the 37 kDa/67 kDa laminin receptor as therapeutic tools in prion diseases. Mol Immunol 45, 144–151.[CrossRef]
    [Google Scholar]
  37. Zuber, C., Knackmuss, S., Zemora, G., Reusch, U., Vlasova, E., Diehl, D., Mick, V., Hoffmann, K., Nikles, D. & other authors ( 2008b; ). Invasion of tumorigenic HT1080 cells is impeded by blocking or downregulating the 37-kDa/67-kDa laminin receptor. J Mol Biol 378, 530–539.[CrossRef]
    [Google Scholar]
  38. Zuber, C., Mitteregger, G., Schuhmann, N., Rey, C., Knackmuss, S., Rupprecht, W., Reusch, U., Pace, C., Little, M. & other authors ( 2008c; ). 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. J Gen Virol 89, 2055–2061.[CrossRef]
    [Google Scholar]
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mRNA sequence of the murine laminin receptor precursor [PDF](122 KB)



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