title: Treatment of Prion Disease with Heterologous Prion Proteins.
abstract: Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for which there is no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrPC) into a protease resistant infectious form (PrPsc or PrPres). Both in vitro (cell culture and cell free conversion assays) and in vivo (animal) studies have demonstrated the strong dependence of this conversion process on protein sequence homology between the initial prion inoculum and the host's own cellular prion protein. The presence of non-homologous (heterologous) proteins is often inhibitory to this conversion process. We hypothesize that the presence of heterologous prion proteins from one species might therefore constitute an effective treatment for prion disease in another species. To test this hypothesis, we infected mice intracerebrally with murine adapted RML-Chandler scrapie and treated them with heterologous prion protein (purified bacterially expressed recombinant hamster prion protein) or vehicle alone. Treated animals demonstrated reduced disease associated pathology, decreased accumulation of protease-resistant disease-associated prion protein, with delayed onset of clinical symptoms and motor deficits. This was concomitant with significantly increased survival times relative to mock-treated animals. These results provide proof of principle that recombinant hamster prion proteins can effectively and safely inhibit prion disease in mice, and suggest that hamster or other non-human prion proteins may be a viable treatment for prion diseases in humans.
authors.affiliation: University of Minnesota, Veterinary and Biomedical Sciences Department, Saint Paul, MN 55108, United States of America.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Skinner
authors.affiliation: University of Minnesota, Veterinary and Biomedical Sciences Department, Saint Paul, MN 55108, United States of America.
authors.forename: Hyeon O
authors.initials: HO
authors.lastname: Kim
authors.affiliation: University of Minnesota, Veterinary Clinical Sciences Department, Saint Paul, MN 55108, United States of America.
authors.forename: Damani
authors.initials: D
authors.lastname: Bryant
authors.affiliation: University of Minnesota, Veterinary and Biomedical Sciences Department, Saint Paul, MN 55108, United States of America.
authors.forename: Nikilyn J
authors.initials: NJ
authors.lastname: Kinzel
authors.affiliation: University of Minnesota, School of Public Health, Division of Biostatistics, Minneapolis, MN, 55455, United States of America.
authors.forename: Cavan
authors.initials: C
authors.lastname: Reilly
authors.affiliation: Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, Montana 59840, United States of America.
authors.forename: Suzette A
authors.initials: SA
authors.lastname: Priola
authors.affiliation: Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, Montana 59840, United States of America.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Ward
authors.affiliation: University of Minnesota, Veterinary and Biomedical Sciences Department, Saint Paul, MN 55108, United States of America.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Goodman
authors.affiliation: University of Minnesota, Veterinary and Biomedical Sciences Department, Saint Paul, MN 55108, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Olson
authors.affiliation: University of Minnesota, Veterinary Clinical Sciences Department, Saint Paul, MN 55108, United States of America.
authors.forename: Davis M
authors.initials: DM
authors.lastname: Seelig
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005911:Gliosis / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018621:PrPC Proteins / Q000737:chemistry / Q000627:therapeutic use*; D017096:Prion Diseases / Q000235:genetics / Q000628:therapy*; D011994:Recombinant Proteins / Q000737:chemistry / Q000627:therapeutic use*; D012608:Scrapie / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D018621:PrPC Proteins; D011994:Recombinant Proteins