Grant: Operating Grant - E-Rare-2: Innovative Therapeutic Approaches

A group of rare, neurodegenerative diseases, which include Creutzfeldt-Jakob diseases (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS), are caused by mutations in the gene for the prion protein. These diseases are invariably fatal and to date no treatments or cures exit. Antibodies that are directed against the prion protein have shown promise as potential treatment options in rodent models. Additional studies have demonstrated that antibodies recognizing a flexible region in the prion protein protect nerve cells, while antibodies that bind a folded (i.e. non-flexible) part of the prion protein are toxic. In this project an international consortium of researchers aims to translate these discoveries into immunotherapies against CJD and GSS. The Aguzzi lab (University Hospital of Zurich, Switzerland) will generate an extensive library of antibodies against the prion protein using novel high-throughput methods. A special emphasis will be placed on the discovery of rare antibodies that recognize previously inaccessible parts of the prion protein. Novel antibodies that prove to be effective in a cell culture model will be produced in substantial quantities by the Wille lab (University of Alberta, Canada) and then characterized with regard to their binding properties by the Wille lab, the Lührs lab (Medical University of Hannover, Germany), and Aguzzi's team. The Wille and the Lührs labs are also going to study the molecular details of these antibodies and how they bind to the prion protein in the normal and the disease-causing state. Furthermore, these antibodies will be evaluated for their toxicity and effectiveness in different cell culture and animal models by the Berdondini lab (Italian Institute for Technology, Genoa, Italy) and the Cohen lab (Hebrew University of Jerusalem, Israel).