Treatment with a Non-toxic, Self-replicating Anti-prion Delays or Prevents Prion Disease In vivo

SUMMARY

Transmissible Spongiform Encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrP ^Sc) that self-propagates in the brain of infected individuals by converting the normal prion protein (PrP ^C) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self-replicating, but innocuous PrP ^Sc-like form, termed anti-prion, which can compete with the replication of pathogenic prions. Our results show that a prophylactic inoculation of prion-infected animals with an anti-prion delays the onset of the disease and in some animals completely prevents the development of clinical symptoms and brain damage. The data indicate that a single injection of the anti-prion eliminated ~99% of the infectivity associated to pathogenic prions. Furthermore, this treatment caused significant changes in the profile of regional PrP ^Sc deposition in the brains of animals that were treated, but still succumbed to the disease. Our findings provide new insights for a mechanistic understanding of prion replication and support the concept that prion replication can be separated from toxicity, providing a novel target for therapeutic intervention.