This research will be done primarily in Uruguay at the University of Uruguay in collaboration with Drs. Jose A. Chabalgoity and Fernando Goni, as an extension of NIH grant #NS047433. Currently, there is not effective form of treatment for prion disease or other conformational disorders, such as Alzheimer's disease (AD). The pathogenesis of prion disease is related to a conformational change of the normal prion protein, PrPC, to a form with a high beta-sheet content, PrPSc. Recently vaccination has been shown to be an effective therapy in both AD and prion model mice by us and others. In the parent grant R01NS047433, we are focused on a variety of novel therapeutic approaches for prion disease, including vaccination in transgenic prion mouse models and metal chelation, along with imaging studies to correlate with a potential treatment effect. A significant problem with immunization for prion disease or other conformational disorders is toxicity. A human Phase II trail of active immunization for AD was terminated due to the development of toxicity in 6% of patients. However, patients without toxicity improved suggesting that the vaccination approach is effective. The toxicity of this vaccine has been linked to cell mediated immunity, while the efficacy of the vaccine approach is thought to be related to antibody mediated clearance of the disease associated protein. In this collaborative grant we plan to develop methods for inducing mucosal immunity in prion model mice. These studies are an extension of the work proposed in the parent grant. We have extensive new preliminary data showing the effectiveness of this approach, done in collaboration with the foreign scientists. Our vaccination approach will expression the prion protein in a Salmonella vaccine strain or coupling it to cholera toxin. These immunization approaches will primarily induce systemic and mucosal antibody responses. This immunization approach should be less likely to be associated with cell mediated toxicity. Induction of mucosal immunity may also be particularly effective for prion related disease, since the gastro-intestinal tract is thought to be the primary source of entry of the infectious agent. The proposed studies may lead to a mucosal prion vaccine that could be used for humans at risk to develop new variant Creutzfeldt-Jakob disease or animals at risk for prion diseases such as chronic wasting disease. These studies will build research capabilities in the foreign site by expanding their studies to include neurogenerative disorders and prion model animals.
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|Goni, F; Prelli, F; Schreiber, F et al. (2008) High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience 153:679-86|
|Wisniewski, T; Chabalgoity, J A; Goni, F (2007) Is vaccination against transmissible spongiform encephalopathy feasible? Rev Sci Tech 26:243-51|
|Pankiewicz, Joanna; Prelli, Frances; Sy, Man-Sun et al. (2006) Clearance and prevention of prion infection in cell culture by anti-PrP antibodies. Eur J Neurosci 23:2635-47|