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000304086 041__ $$aEnglish
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000304086 1001_ $$aDel Zompo, Fabio$$b0
000304086 245__ $$aClaudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis.
000304086 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2025
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000304086 520__ $$aPrimary sclerosing cholangitis (PSC) is a cholangiopathy associated with high risk of development into end-stage liver disease and hepatobiliary cancer. The pathogenesis is poorly understood, and current clinical care offers limited therapeutic options, primarily relying on liver transplantation. Claudin-1 (CLDN1), a transmembrane protein highly expressed in liver epithelial cells, plays a crucial role in cell-cell communication and signaling. Here we aimed to investigate the functional role of CLDN1 as a mediator and therapeutic target for PSC using patient cohorts combined with murine and patient-derived intervention models.CLDN1 expression patterns and cell phenotypes were analyzed in liver tissues of five PSC patient cohorts using scRNAseq, spatial transcriptomics and multi-plex proteomics. Proof-of-concept studies using CLDN1-specific monoclonal antibodies (mAbs) and genetic loss-of-function were performed in state-of-the-art mouse models for PSC and cholangiopathies. Perturbation studies in human cell-based models were applied for mechanistic studies.In liver tissues of patients with PSC, CLDN1 expression was highly up-regulated and associated with disease progression. Spatial transcriptomics and proteomics uncovered high expression of CLDN1 in diseased cholangiocytes and cholestatic periportal hepatocytes with concomitant upregulation of pro-inflammatory and profibrotic signaling pathways. Therapeutic administration of CLDN1-specific mAbs or genetic knock-out improved liver function in PSC mouse models by reducing hepatobiliary fibrosis and cholestasis. Mechanistic studies revealed that mAb treatment inhibited pro-inflammatory and pro-fibrotic signaling in cholangiocytes and hepatocytes perturbed in liver tissues of patients with PSC.Our results uncover a functional role of CLDN1 in the pathogenesis of PSC and biliary fibrosis. Completed in vivo proof-of-concept studies combined with expression analyses in PSC patients pave the way for the clinical development of CLDN1-specific mAbs to treat PSC.Primary sclerosing cholangitis (PSC) is a chronic fibrosing cholangiopathy with limited therapeutic options. Here, we identified the cell surface protein Claudin-1 as a mediator and therapeutic target for PSC. Claudin-1 expression in patients is associated with disease stage and outcome. A conditional liver epithelial-specific Claudin-1 knockout in mice resulted in reduced liver injury, fibrosis and cholestasis. Monoclonal antibodies targeting Claudin-1 inhibit fibrosis and cholestasis across state-of-the-art mouse models of PSC by inhibiting pro-inflammatory and fibrogenic signaling and the ductular reaction. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of PSC. It is therefore of impact for physicians, scientists and drug developers in the field of biliary disease.
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000304086 650_7 $$2Other$$aantibody therapy
000304086 650_7 $$2Other$$abiliary fibrosis
000304086 650_7 $$2Other$$acholangiopathies
000304086 650_7 $$2Other$$aproof-of-concept
000304086 650_7 $$2Other$$asignaling
000304086 7001_ $$aCrouchet, Emilie$$b1
000304086 7001_ $$aOstyn, Tessa$$b2
000304086 7001_ $$aNehme, Zeina$$b3
000304086 7001_ $$aMessé, Mélissa$$b4
000304086 7001_ $$aJuehling, Frank$$b5
000304086 7001_ $$aDésert, Romain$$b6
000304086 7001_ $$aVieira, Angelica T$$b7
000304086 7001_ $$aMoehlin, Julien$$b8
000304086 7001_ $$aNakib, Diana$$b9
000304086 7001_ $$aAndrews, Tallulah$$b10
000304086 7001_ $$aPerciani, Catia$$b11
000304086 7001_ $$aChung, Sai$$b12
000304086 7001_ $$aBader, Gary$$b13
000304086 7001_ $$aMcGilvray, Ian$$b14
000304086 7001_ $$aCaime, Chiara$$b15
000304086 7001_ $$aScaravaglio, Miki$$b16
000304086 7001_ $$aCarbone, Marco$$b17
000304086 7001_ $$aInvernizzi, Pietro$$b18
000304086 7001_ $$aYaqub, Sheraz$$b19
000304086 7001_ $$aFolseraas, Trine$$b20
000304086 7001_ $$aKarlsen, Tom H$$b21
000304086 7001_ $$aShankar, Gautam$$b22
000304086 7001_ $$aPrimeaux, Mark$$b23
000304086 7001_ $$aDhawan, Punita$$b24
000304086 7001_ $$aBanales, Jesus M$$b25
000304086 7001_ $$aRoehlen, Natascha$$b26
000304086 7001_ $$aIacone, Roberto$$b27
000304086 7001_ $$aTeixeira, Geoffrey$$b28
000304086 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b29$$udkfz
000304086 7001_ $$aMailly, Laurent$$b30
000304086 7001_ $$aMacParland, Sonya$$b31
000304086 7001_ $$aRoskams, Tania$$b32
000304086 7001_ $$aGovaere, Olivier$$b33
000304086 7001_ $$aSchuster, Catherine$$b34
000304086 7001_ $$aBaumert, Thomas F$$b35
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