OLT1177 (Dapansutrile), a Selective NLRP3 Inflammasome Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis Pathogenesis
Sánchez Fernández, Alba (Universitat Autònoma de Barcelona. Institut de Neurociències)
Skouras, Damaris B. (Olatec Therapeutics LLC)
Dinarello, Charles A. (Department of Medicine. Radboud University Medical Center)
López Vales, Rubèn (Universitat Autònoma de Barcelona. Institut de Neurociències)

Data:	2019
Resum:	IL-1β and IL-18 are pro-inflammatory cytokines that are linked to inflammation. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is involved in the maturation and secretion of IL-1β and IL-18 and, thus, plays a key role in the pathogenesis of many inflammatory conditions, including multiple sclerosis (MS). OLT1177™ (Dapansutrile) is a newly developed drug that is safe in humans and inhibits specifically the NLRP3 inflammasome. In the present study, we investigated whether OLT1177 exerts therapeutic effects in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that EAE mice fed an OLT1177-enriched diet prophylactically were significantly protected against functional deficits and demyelination in the spinal cord. We also demonstrated that prophylactic oral administration of OLT1177 led to marked reduction (~2- to 3-fold) in the protein levels of IL-1β and IL-18, as well as, IL-6 and TNFα, in the spinal cord of EAE mice. Moreover, prophylactic oral administration of OLT1177 significantly attenuated the infiltration of CD4 T cells and macrophages in the spinal cord. We also demonstrated that oral administration of OLT1177, starting at disease onset, resulted in significant amelioration of the clinical signs of EAE. Overall, these first data suggest that OLT1177 could have clinical benefit for the treatment of MS in humans.
Ajuts:	Ministerio de Economía y Competitividad SAF2016-79774-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Experimental autoimmune encephalomyelitis ; OLT1177 ; NLRP3 ; Inflammation ; Cytokines
Publicat a:	Frontiers in immunology, Vol. 10 (january 2019) , p. 2578, ISSN 1664-3224

DOI: 10.3389/fimmu.2019.02578
PMID: 31736980

10 p, 2.3 MB

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