Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Switzerland
Germany
Israel
Canada
PrionImmunity
Immunotherapy of familial prion diseases

Project Coordinator

University of Zurich
Zurich
Switzerland

Partners

Ehud Cohen The Hebrew University of Jerusalem Jerusalem, Israel
Luca Berdondini Istituto Italiano di Tecnologia Genova, Italy
Holger Wille University of Alberta Edmonton, Canada
Thorsten Lührs Medizinische Hochschule Hannover Hannover, Germany

Familial prion diseases are rare neurodegenerative disorders affecting individuals in the prime of their life, with no known therapy apart from palliation. Aguzzi showed that passive immunoprophylaxis can afford protection from prions in vivo (Heppner et al., Science 294, 2001). Aguzzi then discovered that monoclonal antibodies targeting the flexible tail of the cellular prion protein (PrPC) are protective, whereas those against its globular domain can be neurotoxic (Sonati et al., Nature 501, 2013), suggesting that the flexible tail mediates toxicity. Here we propose to translate the above discoveries into a preclinical pipeline for discovering immunotherapeutics against familial prion diseases. Aguzzi will execute a high-throughput screen aimed at saturation coverage of the human PrP surface, using a novel methodology combining phage display with next-generation sequencing and allowing for the discovery of rare non-immunodominant epitopes. High-affinity phages will be tested for prion neutralization using a robotized high-throughput cell-based assay. Neutralizing phages will be converted into monovalent recombinant miniantibodies and epitope-mapped by Wille, Lührs, and Aguzzi. Miniantibodies will then be tested by Berdondini for their capacity to combat prion toxicity using high-density multielectrode arrays. Cohen will test the capability of select antibodies to counteract mutant PrP toxicity in C. elegans. Complexes of the most promising antibodies with PrP will be analyzed by X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy.

E-Rare 2012 - Created by Toussaint Biger