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Treatment of Prion Disease with Heterologous Prion Proteins
#MMPMID26134409
Skinner PJ
; Kim HO
; Bryant D
; Kinzel NJ
; Reilly C
; Priola SA
; Ward AE
; Goodman PA
; Olson K
; Seelig DM
PLoS One
2015[]; 10
(7
): e0131993
PMID26134409
show ga
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.
|Animals
[MESH]
|Cells, Cultured
[MESH]
|Cricetinae
[MESH]
|Disease Models, Animal
[MESH]
|Disease Progression
[MESH]
|Female
[MESH]
|Gliosis/physiopathology/therapy
[MESH]
|Mice
[MESH]
|Mice, Inbred C57BL
[MESH]
|PrPC Proteins/chemistry/*therapeutic use
[MESH]
|Prion Diseases/genetics/*therapy
[MESH]
|Recombinant Proteins/chemistry/*therapeutic use
[MESH]
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