Methods for the diagnosis, treatment and analysis ofnlrp3-associated autoinflammatory diseases

Using NLRP3-deficient U937 cells reconstituted with doxycycline-inducible NLRP3 variants in response to NLRP3 induction, the present inventors have developed a novel functional cell-based assay to screen for NLRP3 variants that uncouples NLRP3 induction, priming and activation. The inventors studied and characterized 38 NLRP3 variants by assessing pyroptosis and IL-1β/18 secretion in, priming and/or activation. The results were confirmed in primary monocytes from patients carrying different variants. The present invention pertains to a method for characterizing NLRP3 mutations that allows discriminating gain-of-function mutants from polymorphism without any impact on NLRP3 activity. The invention also relates to methods for the diagnosis of NLRP3-associated autoinflammatory diseases and for predicting a response to NLRP3 inhibitors based on the detection of specific NLRP3 mutations in a sample obtained from a patient. The invention also relates to new NLRP3 inhibitors.

Keywords: NLRP3, mutation, Autoinflammatory diseases, Cryopyrin-associated autoinflammatory syndromes (CAPS), prognosis, sequencing
Patent Application number: EP23 306 463.3 on 04/09/23 and PCT/EP2024/074525 on 03/09/2024
Inventors:
PY Bénédicte
Publications:
J Exp Med 2024 May 6;221(5):e20231200. Cosson et al. Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation; doi: 10.1084/jem.20231200. Epub 2024 Mar 26.

Reference:

BIO23231-D1

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Patent filling date: 2023-09-04

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