Affiliation:
1. Department of Molecular Biology and Biochemical Engineering Universidad Pablo de Olavide Seville Spain
2. Department of Immunology Puerta del Mar Hospital Cádiz Spain
3. Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA Hospital Universitario Puerta del Mar Cádiz Spain
4. Departamento de Química Orgánica, Facultad de Ciencias, Campus Universitario Río San Pedro s/n, Torre Sur, 4a Planta University of Cádiz Cádiz Spain
5. School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences University of Glasgow Glasgow UK
Abstract
AbstractThe role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24−/− mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans. Nevertheless, inhibition of the inflammasomes would be a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile), other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fibroblasts and a LmnaG609G/G609G mouse model. In both cases dapansutrile reduced progerin accumulation, NLRP3‐inflammasome activation and secretory phenotype of senescence, extended the lifespan of progeroid animals, preserved bodyweight, and reduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile further improved the effect of lonafarnib, the only FDA‐approved drug for the progeria. The combination of both drugs reduced the inflammation and senescence, extended survival and ameliorated various progeroid defects both in vitro and in vivo, compared with treatment using lonafarnib alone. These findings and the safety of dapansutrile demonstrated in several clinical trials proposes it as a possible co‐adjuvant treatment with lonafarnid in HGPS.
Funder
Progeria Research Foundation