METHODS AND COMPOSITIONS FOR TREATMENT OF NLRP3 INFLAMMASOME MEDIATED IL-1BETA DEPENDENT DISORDERS

摘要

The present invention relates to a PAK-1 and/or PAK-2 inhibitor for use in the treatment of NLRP3 inflammasome mediated IL-1beta dependent disorders in a subject in need thereof. Inventors invalidated PAK-1 and/or PAK-2 in BMDM by transfecting siRNA targeting either PAK-1 and/or PAK-2 (PAK-3 is predominantly expressed in the brain). After 72 hours of siRNA expression, cells were stimulated by LPS and the CNF1 toxin for 8 hours. They observed that cells invalidated for PAK-1 had a reduced Caspase-1 activation compared to the control cells or cells invalidated for PAK-2. Similar results were observed when the IL-1ß maturation was monitored. Confirming this data, the use of PAK-1 inhibitors (IPA-3 and FRAX597) were sufficient to block the IL-1ß maturation observed in macrophages treated with LPS and CNF1 as well as Caspase-1 activation measured using FAM-FLICA.