Caspase 1-deficient humans survive into late adulthood despite dramatically lower canonical inflammasome activity

Caspase-1 (CASP1) is a key effector of the canonical inflammasome and innate immunity. Inhibitors of the canonical inflammasome pathway are in clinical development for multiple inflammatory pathologies, but efficacy and long-term safety effects of these molecules are yet to be established. Complete CASP1 deficiency in humans, which has not been described, would yield valuable insights for therapeutic inhibitor development and fundamental immunobiology.

We sought to identify and characterize individuals with ultrarare, homozygous loss-of-function variants in CASP1 using a large consanguineous biobank, the Pakistan Genome Resource, and recall-by-genotype studies.

Homozygotes of a loss-of-function CASP1 variant (Tyr153Ter) were recontacted and, along with consenting family members, clinically profiled for a wide range of phenotypes.

Eight homozygotes of Tyr153Ter, 19 heterozygotes of Tyr153Ter, and 17 homozygotes of the reference allele are described in 2 separate families. Complete CASP1 deficiency is associated with near-absence of IL-18 and lower white blood cell counts. IL-1β secretion is absent in stimulated CASP1-deficient PBMCs but is detectable at low levels in circulation, suggesting alternative IL-1β processing pathways in humans. CASP1-deficient humans have survived into advanced age and have children, both without an overt increase in infection risk.

Complete loss of CASP1 in humans dramatically reduces activity of the canonical inflammasome but does not overtly increase risk of infection observations or radically affect human reproduction and development through to late adulthood. These findings establish safety and biomarker data for ongoing clinical programs.