NR AWEK
AU Eigenbrod,S.; Bertsch,U.; Al-Khadra,S.; Hofmann,A.; Moser,M.; Pfeifer,A.; Kretzschmar,H.A.
TI Lentivector mediated RNAI knock-down of prion protein expression in neuronal cells and mice aimed at a somatic gene therapy of prion diseases
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-49
PT Konferenz-Vortrag
AB RNA interference (RNAi) is a conserved mechanism by which small interfering RNAs (siRNAs) specifically silence target genes. Experimental evidence suggesting that reducing the expression of PrP could be therapeutically beneficial turns RNAi into a promising approach for the treatment of Creutzfeldt-Jakob disease. Quite recently, the therapeutic properties of RNAi directed against PrP were verified in scrapie infected cell lines. To further explore the potential of RNAi for the treatment of scrapie infected animals, we generated lentiviral vectors expressing short hairpin RNAs (shRNAs) specifically targeting the mouse PRNP gene. In neuronal cell cultures these lentivectors efficiently silenced PrPc and suppressed the accumulation of PrPsc. In vivo studies using PrP overexpressing tga20 mice revealed reduced PrPc levels after intracerebral stereotactic application of lentiviral shRNA vectors. In addition, mice chimeric for lentivector transduced embryonic stem cells were generated. These animals showed a considerable reduction of PrPc levels in those areas, where a significant proportion of cells was derived from the lentivector transduced embryonic stem cells. Importantly, scrapie-infected chimeric mice displayed a delayed onset of scrapie symptoms and a significant extension of survival times. Taken together, our data suggest that lentivector mediated RNAi could be an approach for the treatment of prion disease.
AD S. Eigenbrod, U. Bertsch, H. Kretzschmar: Center for Neuropathology and Prion Research, Ludwig Maximilians University of Munich, Feodor-Lynen-Strasse 23, Munich, Germany; S. Al-Khadra, A. Hofmann, A. Pfeifer: Department of Pharmacy, Molecular Pharmacology, Center for Drug Research, Butenandtstrasse 5 (C); M. Moser: MPI for Biochemistry, Molecular Medicine, Am Klopferspitz 18, Martinsried, Germany
SP englisch
PO Italien