Experimental treatment with RAP of TSE infection in cell cultures and sCJD infection in HuTg mice
2010: 1 year / Grant: 22 000 euros
Project: The project “RAP experimental treatment” aimed to evaluate a therapeutic strategy in TSEs based on the use of recombinant human low densitylipoprotein (LDL) receptor-related proteinassociated protein 1 (Lrpap1 or RAP). The rational was that RAP a small protein (39–44kDa) found in endoplasmic reticulum and serving as a chaperon for the LDL receptor family member proteins, which have been previously shown to be dysregulated in numerous neurodegenerative disorders, may affect the formation or degradation of PrPTSE. Moreover, preliminary data obtained with prion infected cells,showed an inhibitory effect of recombinant full-length RAP (rRAP) on PrPTSE replication and encouraging results were obtained in in vivo studies when transgenic mice carrying human prion protein 129M gene (TgRM) were infected with sporadic CJD and treated with rRAP.
Main results and related published data: To understand the role of RAP in TSEs , mice knockout forLRPAP1 gene (RAP/KO) and wild-type (WT)controls were infected with prions byintracerebral injection. RAP/KO mice exhibited disease after a shorter incubation period than WT mice, therefore suggesting a role of RAP in the disease. In pilotstudies, different groups of mice, that have received a 10-3 to 10-6 dilution of mouse-dapted vCJD (mo-vCJD) strain, were treated with RAP before, or 100 days after prion inoculation. An increase of the incubation time, as well as a therapeutic effect, were observed in some mice injected with the most diluted prion and treated with RAP.