Published online before print March 27, 2008

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2008.070836v1 172/5/1287    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Genoud, N. Articles by Aguzzi, A. PubMed PubMed Citation Articles by Genoud, N. Articles by Aguzzi, A.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070836

Accepted for publication January 22, 2008.

Article

Antiprion Prophylaxis by Gene Transfer of a Soluble Prion Antagonist

Nicolas Genoud^*, David Ott^*, Nathalie Braun^*, Marco Prinz^*, Petra Schwarz^*, Ueli Suter, Didier Trono, and Adriano Aguzzi^*@

From the Institute of Neuropathology,* University Hospital Zurich, Zurich; the Department of Biology, Institute of Cell Biology, Swiss Federal Institute of Technology, Eidgenössische Technische Hochschule Zürich, Zürich; and the School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland

^@ To whom correspondence should be addressed. E-mail: adriano.aguzzi{at}usz.ch.

	Abstract

Prion diseases are untreatable neurodegenerative disorders characterized by accumulation of PrP^Sc, an aggregated isoform of the normal prion protein PrP^C. Here, we delivered the soluble prion antagonist PrP-Fc₂ to the brains of mice by lentiviral gene transfer. Although naïve mice developed scrapie at 175 ± 5 days postintracerebral prion inoculation (dpi), gene transfer before inoculation delayed disease onset by 72 ± 4 days. At 170 days postintracerebral prion inoculation, PrP^Sc accumulation and prion infectivity in PrPFc-treated brains were reduced by 3.6 and 4.2 logs, respectively. When PrP-Fc₂ was delivered 30 days after prion inoculation, survival of the treated animals was extended by 25 days. We then used tissue-specific recombination to express PrP-Fc₂ in the entire central nervous system, in only astrocytes, or in only oligodendrocytes. Oligodendrocyte-restricted PrP-Fc₂ expression impaired PrP^Sc deposition and delayed disease even though oligodendrocytes are completely resistant to prion infection, suggesting that PrP-Fc₂ affords protection via noncell autonomous mechanisms. These results suggest that somatic gene transfer of prion antagonists may be effective for postexposure prophylaxis of prion diseases.

This article has been cited by other articles:

				M. P. Fink Neuropeptide Modulators of High Mobility Group Box 1 Secretion as Potential Therapeutic Agents for Severe Sepsis Am. J. Pathol., May 1, 2008; 172(5): 1171 - 1173. [Abstract] [Full Text] [PDF]