Therapeutic targeting of cathepsin C::from pathophysiology to treatment

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials

Papillon-Lefevre syndrome: report of six patients and identification of a novel mutation

Papillon-Lefevre syndrome is an autosomal recessive genodermatosis typically manifesting with the constellation of palmoplantar keratoderma and progressive early-onset periodontitis. The cutaneous phenotype can be strikingly psoriasiform, possibly posing a diagnostic challenge. This rare disorder is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. We report six patients with Papillon-Lefevre syndrome from five consanguineous Turkish families, in whom genetic analysis of the CTSC gene revealed four recurrent mutations (c.415G>A; c.1015C>T; c.1019A>G; and c.103-105delCTG) and a novel missense mutation (c.117G>T) in the homozygous state