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Ornithine transcarbamylase (OTC) deficiency (OTCD) is X\u2010linked and the most common and often fatal UCD. In male hemizygous patients, disease severity primarily depends on the pathogenic sequence variant, while in heterozygous females, disease severity also depends on the X\u2010chromosomal inactivation (XCI) pattern. Females with unfavorable XCI predominantly expressing the mutant OTC protein may be severely affected. Here, we investigated a novel treatment strategy for OTCD since there is an unmet need for better therapies. In the first step, we performed a high throughput screening (HTS) using a diversity library with 10\u2009000 chemical compounds to identify pharmacological chaperone (PC) candidates that stabilize purified wild\u2010type OTC. Stratification of our HTS results revealed five potential PCs, which were selected for further experimentation in cellular systems using primary human hepatocytes (PHHs) and human induced pluripotent stem cell (hiPSC)\u2010derived hepatocytes (hiPSC\u2010Heps) from healthy controls and OTCD patients. Two PCs\u2014PC1 and PC4\u2014increased OTC protein stability and activity in control hiPSC\u2010Heps, while PC4 in addition increased OTC activity in patient\u2010derived PHHs from a female OTCD patient with unfavorable XCI. Finally, PC1 and PC4 both significantly increased ureagenesis in patient\u2010derived PHHs. To conclude, we identified two PCs that stabilized wild\u2010type OTC and enhanced enzyme activity and ureagenesis. Our work suggests that PCs could provide a novel treatment strategy for OTCD specifically in females with unfavorable XCI.<\/jats:p>","DOI":"10.1002\/jimd.70043","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T06:17:31Z","timestamp":1748326651000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel Treatment Strategy for Patients With Urea Cycle Disorders: Pharmacological Chaperones Enhance Enzyme Stability and Activity in Patient\u2010Derived Liver Disease Models"],"prefix":"10.1002","volume":"48","author":[{"given":"Adhuresa","family":"Ramosaj","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital University of Bern  Bern Switzerland"},{"name":"University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern  Bern 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Inselspital, Bern University Hospital University of Bern  Bern Switzerland"},{"name":"Department of Biomedical Research University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Gougeard","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Valencia (IBV\u2010CSIC) and Group 739 of CIBER de Enfermedades Raras (CIBERER\u2010ISCIII)  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Rubio","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Valencia (IBV\u2010CSIC) and Group 739 of CIBER de Enfermedades Raras (CIBERER\u2010ISCIII)  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Biomedicine University of Bergen  Bergen 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