The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice

Abstract

The role of the inflammasomes in aging and progeroid syndromes remain understud-ied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24−/− mice to amelio-rate the phenotypes. However, the safety of MCC950 was questioned due to livertoxicity observed in humans. Nevertheless, inhibition of the inflammasomes wouldbe a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile),other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fi-broblasts and a Lmna G609G/G609G mouse model. In both cases dapansutrile reducedprogerin accumulation, NLRP3-inflammasome activation and secretory phenotype ofsenescence, extended the lifespan of progeroid animals, preserved bodyweight, andreduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile furtherimproved the effect of lonafarnib, the only FDA-approved drug for the progeria. Thecombination of both drugs reduced the inflammation and senescence, extended sur-vival and ameliorated various progeroid defects both in vitro and in vivo, comparedwith treatment using lonafarnib alone. These findings and the safety of dapansutriledemonstrated in several clinical trials proposes it as a possible co-adjuvant treatmentwith lonafarnid in HGPS