{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:08:50Z","timestamp":1791234530430,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Celiac disease is a chronic, immune\u2010mediated enteropathy with symptoms triggered by exposure to dietary gluten in genetically predisposed individuals. The only available management option is lifelong adherence to a gluten\u2010free diet. This randomized, double\u2010blind, placebo\u2010controlled, parallel\u2010group, single\u2010center study tested the effects of the cathepsin S inhibitor RO5459072 on the immune response to a 13\u2010day gluten challenge in 19 participants with celiac disease (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>: NCT02679014). Nine participants in the RO5459072 arm received 100\u2009mg study drug b.i.d. (200\u2009mg daily); 10 received a placebo. The primary end point was the number of responders to the gluten challenge (defined as individuals with an increase in the number of gliadin\u2010specific, IFN\u03b3\u2010secreting T cells detected using an ELISPOT assay). However, there was a weak response to the gluten challenge across both arms. Few participants had an increase in gliadin\u2010specific, IFN\u03b3\u2010secreting T cells, and the antigen\u2010specific responses (anti\u2010tTG and anti\u2010DGP antibodies) were weaker than expected in both arms. Therefore, the primary end point was not met, although the study was underpowered to detect a treatment effect under these circumstances. Pharmacodynamic findings suggested that RO5459072 had some beneficial effects. Fewer participants in the RO5459072 arm exhibited gliadin\u2010specific IFN\u03b3\u2010secreting T cells after 6\u2009days' gluten intake. Participants in the RO5459072 arm also showed decreased intestinal permeability, and a decrease in the number of circulating B cells, CD4+ and CD8+ T cells compared to baseline. Nevertheless, the absence of clear effects on the response to a gluten challenge indicates that inhibition of cathepsin S may not be an effective treatment strategy for celiac disease.<\/jats:p>","DOI":"10.1111\/cts.13901","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T10:44:56Z","timestamp":1735641896000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A randomized, double\u2010blind, placebo\u2010controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2136-9264","authenticated-orcid":false,"given":"Darren","family":"Bentley","sequence":"first","affiliation":[{"name":"Certara UK Ltd.  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Mannino","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Lawrence Township New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Manchester","sequence":"additional","affiliation":[{"name":"F. Hoffmann\u2010La Roche  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscila Camillo","family":"Teixeira","sequence":"additional","affiliation":[{"name":"F. Hoffmann\u2010La Roche  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-8222","authenticated-orcid":false,"given":"Bernhard","family":"Reis","sequence":"additional","affiliation":[{"name":"F. Hoffmann\u2010La Roche  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8807-612X","authenticated-orcid":false,"given":"Malcolm","family":"Boyce","sequence":"additional","affiliation":[{"name":"Hammersmith Medicines Research  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Nagel","sequence":"additional","affiliation":[{"name":"F. 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