title: Antiprion prophylaxis by gene transfer of a soluble prion antagonist.
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-Fc(2) 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-Fc(2) 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-Fc(2) in the entire central nervous system, in only astrocytes, or in only oligodendrocytes. Oligodendrocyte-restricted PrP-Fc(2) expression impaired PrP(Sc) deposition and delayed disease even though oligodendrocytes are completely resistant to prion infection, suggesting that PrP-Fc(2) 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.
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Nicolas
authors: N
authors: Genoud
authors: David
authors: D
authors: Ott
authors: Nathalie
authors: N
authors: Braun
authors: Marco
authors: M
authors: Prinz
authors: Petra
authors: P
authors: Schwarz
authors: Ueli
authors: U
authors: Suter
authors: Didier
authors: D
authors: Trono
authors: Adriano
authors: A
authors: Aguzzi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D019281:Dimerization; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D018621:PrPC Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012608:Scrapie / Q000628:therapy*
chemical_list: D018621:PrPC Proteins