Abstract

Protein Knockout Mice: A Novel in vivo Validation Approach for Membrane Targets

Stefan Dübel, Full Professor and Director, Technische Universität Braunschweig

We present a novel method for drug discovery, which is broadly applicable (all membrane/secretory proteins) and allows to specifically analyse functionally relevant protein features like individual splice variants or individual posttranslational modifications in vivo, which is just not possible with the existing gene knockout methods. We demonstrated for the first time that endoplasmatic reticulum retained antibodies ("intrabodies") can induce a protein knock down phenotype in transgenic mice. This was achieved by introducing the genes for a single chain antibody fragment in transgenic mice. Linking rapid human antibody generation to gene function knock down using these antibodies will allow a new functional approach to the discovery of target/antibody drug combinations. In addition, the method allows the generation of mouse models that more closely resemble disease states than classic knockouts can do.