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Originally published online as doi:10.2353/ajpath.2008.070836 on March 27, 2008

Published online before print March 27, 2008
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(American Journal of Pathology. 2008;172:1287-1296.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070836

Antiprion Prophylaxis by Gene Transfer of a Soluble Prion Antagonist

Nicolas Genoud*, David Ott*, Nathalie Braun*, Marco Prinz*, Petra Schwarz*, Ueli Suter{dagger}, Didier Trono{ddagger} and Adriano Aguzzi*

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

Prion diseases are untreatable neurodegenerative disorders characterized by accumulation of PrPSc, an aggregated isoform of the normal prion protein PrPC. 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, PrPSc 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 PrPSc 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.




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