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

• Main Authors: DOYE, Anne, COURJON, Johan-Victor, TORRE, Cédric, LOUBATIER, Céline, DUFIES, Océane, MICHEL, Grégory, VISVIKIS, Orane, MUNRO, Patrick, BOYER, Laurent
• Format: Patent
• Language: English; French; German
• Published: 23.02.2022
• Subjects: BEER; BIOCHEMISTRY; CHEMISTRY; COMPOSITIONS THEREOF; CULTURE MEDIA; ENZYMOLOGY; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; MICROBIOLOGY; MICROORGANISMS OR ENZYMES; MUTATION OR GENETIC ENGINEERING; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; SPIRITS; VINEGAR; WINE

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-1β maturation was monitored. Confirming this data, the use of PAK-1 inhibitors (IPA-3 and FRAX597) were sufficient to block the IL-1β maturation observed in macrophages treated with LPS and CNF1 as well as Caspase-1 activation measured using FAM-FLICA.