NR ATNP
AU Vana,K.; Nikles,D.; Toepper,D.; Weiss,S.
TI Delivery of siRNAs directed against the LRP mRNA by recombinant lentiviral vectors into Mice as a therapeutic strategy for the treatment of TSEs
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Human prions, risk of blood products, and therapy HUMAN-13
PT Konferenz-Poster
AB
Prion diseases, also called transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases, which occur in most mammals. A hallmark of prion diseases is the conversion of the normal, host-encoded prion protein (PrPc) into an abnormal, pathogenic isoform, termed PrPsc. The 37/67 kDa laminin receptor (LRP/LR) was identified to act as the cell surface receptor for the cellular prion protein PrPc1 and heparan sulfate proteoglycans (HSPGs) - binding partners of the prion protein2 - were thought to be co-factors/ co-receptors for the binding of PrPc to LRP/LR3. LRP/LR is essential for PrPsc propagation in neuronal cells4. The accumulation of PrPsc in scrapie-infected neuronal cells (ScN2a) has been prevented by transfection with small interfering (si) RNAs specific for the LRP mRNA4. These results demonstrate the necessity of the laminin receptor for the PrPsc propagation in cultured cells. Vector-based application of siRNAs circumvents the transient effect of downregulation of gene expression and allows persistent suppression and therefore analysis of loss-of-function-phenotypes that develop over longer periods of time. Transduction of recombinant HIV-based lentiviral vectors expressing siRNAs directed against defined regions of the LRP mRNA resulted in reduction of both PrPres and LRP levels in scrapie-infected GT1 cells. We apply the lentiviral system for (i) siRNA delivery into mice and (ii) the generation of transgenic mice expressing anti-LRP siRNAs by subzonal injections into embryos. The lentiviral system might be a powerful tool for gene therapeutic approaches targeting LRP/LR for the treatment of TSEs.
1 Gauczynski et al., EMBO J.2001, 20, 5863-75
2 Warner et al., J.Biol.Chem., 2002, 277, 18421-18430
3 Hundt et al., EMBO J., 2001, 20, 5876-86
4 Leucht et al., EMBO reports, 2003, 4, 290-295
AD K.Vana, D.Nikles, D.Toepper, S.Weiss, Genzentrum-Institut für Biochemie der LMU Muenchen, Feodor-Lynen-Str.25, D-81377 Munich, Germany
SP englisch
PO Deutschland