Pannexin1 nanobodies for the clinical treatment of liver disease

ended

Pannexin1 (Panx1) channels mediate the exchange of biochemical messengers between the cytosol of a cell and its extracellular environment. This type of cellular communication underlies cell death and inflammation, both which are associated with a plethora of diseases. Closing pannexin channels therefore seems an interesting therapeutic strategy. In this respect, the ERC Starting Grant project CONNECT has demonstrated that peptide-based inhibition of Panx1 channels counteracts the manifestation of acute and chronic liver disease. However, these peptides cope with stability issues thus impeding clinical application. No other types of appropriate Panx1 channel inhibitors are available today despite their promising therapeutic potential. The present CONNECT-2-CLINIC project will meet this urgent need by generating specific and in vivo-applicable Panx1 channel inhibitors. For this purpose, nanobodies targeted towards Panx1 will be produced using unprecedented protocols that combine DNA immunization with new nanodisc technology. Panx1 nanobodies will be tested in vitro for their capacity to inhibit Panx1 channels and to reduce cell death and inflammation. They will be subsequently tested in a human-relevant mouse model of cholestatic liver disease. This technology track will be aligned by a 3-phase business track in order to analyze and create market value. By doing so, the CONNECT-2-CLINIC project will provide solid proof-of-concept for further pharmaceutical development and clinical application.