EFFECTS OF CIAS-1 MUTATIONS IN THE PATHOGENESIS OF CRYOPYRIN ASSOCIATED PERIODIC SYNDROMES (CAPS). SEARCH FOR NEW GENES AND NOVEL THERAPEUTIC STRATEGIES

The cryopyrin associated periodic syndromes (CAPS) are a group of chronic or recurrent inflammatory diseases associated to mutations of a gene coding for Cryopyrin. This protein play a pivotal role in the regulation of production and secretion of IL-1b, one of the most potent pro-inflammatory cytokines. CAPS usually present during childhood. The clinical manifestations associated with the most severe phenotype are: chronic systemic inflammation, urticarial rash, arthritis, chronic meningitis, sensorineural deafness and mental delay. Skeletal dysplasia may also be present, with variable limitation of daily activities. The beneficial effect of the recombinant IL-1 receptor antagonist (Anakinra) on the inflammatory manifestations of CAPS has been recently reported. However: i) not all CAPS-associated manifestations are controlled by Anakinra, ii) some patients may gradually present a progressive resistance to Anakinra treatment; iii) the drug is expensive and not available in all Countries. This research plan integrates the competences of doctors and geneticists that deal with these diseases with those of basic scientists with a particular knowledge on the mechanisms governing the control of inflammation. The aims are: i) to understand the pathogenic consequences related to the defect of Cryopyrin, ii) defining the mechanisms leading to bone deformities in CINCA patients iii) to identify new genes possible involved in patients presenting with a CAPS-like phenotype but negative for mutations of Cryopyrin gene.