Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis

Abstract

Background and aim: Primary 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Impact and implications: 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.

Keywords: antibody therapy; biliary fibrosis; cholangiopathies; proof-of-concept; signaling.