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From: TSS ()
Subject: Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice
Date: December 9, 2006 at 10:54 am PST

Lentivector-mediated RNAi efficiently

suppresses prion protein and prolongs

survival of scrapie-infected mice

Alexander Pfeifer,1,2 Sabina Eigenbrod,3 Saba Al-Khadra,1,2 Andreas Hofmann,1,2

Gerda Mitteregger,3 Markus Moser,4 Uwe Bertsch,3 and Hans Kretzschmar3

1Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany. 2Molecular Pharmacology, Department of Pharmacy,

and 3Center for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany.

4Max Planck Institute of Biochemistry, Molecular Medicine, Martinsried, Germany.

Prion diseases are fatal neurodegenerative diseases characterized by the accumulation of PrPSc, the infectious

and protease-resistant form of the cellular prion protein (PrPC). We generated lentivectors expressing PrPCspecific

short hairpin RNAs (shRNAs) that efficiently silenced expression of the prion protein gene (Prnp)

in primary neuronal cells. Treatment of scrapie-infected neuronal cells with these lentivectors resulted in an

efficient and stable suppression of PrPSc accumulation. After intracranial injection, lentiviral shRNA reduced

PrPC expression in transgenic mice carrying multiple copies of Prnp. To test the therapeutic potential of lentiviral

shRNA, we used what we believe to be a novel approach in which the clinical situation was mimicked. We

generated chimeric mice derived from lentivector-transduced embryonic stem cells. Depending on the degree

of chimerism, these animals carried the lentiviral shRNAs in a certain percentage of brain cells and expressed

reduced levels of PrPC. Importantly, in highly chimeric mice, survival after scrapie infection was significantly

extended. Taken together, these data suggest that lentivector-mediated RNA interference could be an approach

for the treatment of prion disease.

full text ;

http://www.tse-forum.de/tse_forum/englisch/oeffentlich/bilder/Neuer_Ansatz_JoCI_1206.pdf

TSS




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