Antiprion Prophylaxis by Gene Transfer of a Soluble Prion Antagonist. Commentary

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 naive 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.