title: IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients.
abstract: Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.
authors.affiliation: Vertex Pharmaceuticals, San Diego, CA 92121, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Stack
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.forename: Paul D
authors.initials: PD
authors.lastname: Larsen
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Straley
authors.forename: Greg W
authors.initials: GW
authors.lastname: Henkel
authors.forename: John C R
authors.initials: JC
authors.lastname: Randle
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D020170:Caspase 1 / Q000096:biosynthesis / Q000502:physiology; D061945:Caspase Inhibitors; D003080:Cold Temperature / Q000009:adverse effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011355:Prodrugs / Q000494:pharmacology; D011498:Protein Precursors / Q000096:biosynthesis; D013577:Syndrome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011355:Prodrugs; D011498:Protein Precursors; D020170:Caspase 1