{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:14:17Z","timestamp":1781104457424,"version":"3.54.1"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"15","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["222153\/Z\/20\/Z"],"award-info":[{"award-number":["222153\/Z\/20\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["MR\/W013568\/1"],"award-info":[{"award-number":["MR\/W013568\/1"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,14]]},"abstract":"<jats:p>\n                    Control of schistosomiasis, a neglected tropical disease caused by infection with\n                    <jats:italic toggle=\"yes\">Schistosoma spp<\/jats:italic>\n                    ., remains reliant on a single chemotherapy, praziquantel (PZQ). This strategy presents a risk to global health should PZQ-resistant schistosomes establish in endemic areas and justifies the search for new drugs. However, species-specific metabolic differences between humans and preclinical models hinder the optimization of next-generation anti-schistosomal therapeutics. Here, to bypass these species-specific limitations, we exploited a humanized mouse model, 8HUM, engineered to express the principal human Phase I cytochrome P450 enzymes (CYP1A1\/2, CYP2C9, CYP2D6, CYP3A4\/7) as well as the transcription factors constitutive androstane receptor and pregnane X receptor in place of 35 murine orthologs. We characterized\n                    <jats:italic toggle=\"yes\">Schistosoma mansoni<\/jats:italic>\n                    development, immunopathology, hepatic transcriptomic responses, intestinal microbiome changes, and PZQ metabolism as well as PZQ efficacy in 8HUM vs. wild-type (WT) mice. 8HUM mice supported normal\n                    <jats:italic toggle=\"yes\">S. mansoni<\/jats:italic>\n                    maturation, infection-associated microbiome dysbiosis, Th2-dominant immune responses, and characteristic hepatic pathology. PZQ intrinsic clearance in 8HUM hepatic microsomes mirrored human levels and was &gt;10-fold lower than that found for WT microsomes. Oral dosing revealed human-like PZQ exposures of (\n                    <jats:italic toggle=\"yes\">R<\/jats:italic>\n                    )-PZQ and 4OH-PZQ in 8HUM mice at 25 mg\/kg bodyweight and &gt;90% reductions in worm burdens at 100 mg\/kg bodyweight (equivalent to that seen in WT mice administered PZQ at 400 mg\/kg bodyweight). Our results revealed that 8HUM mice recapitulate key features of murine schistosomiasis while exhibiting human-relevant drug metabolism. These findings establish 8HUM as a refined translational platform for anti-schistosomal drug development, improving predictive accuracy and accelerating therapeutic discovery.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2600197123","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:34:22Z","timestamp":1775842462000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Use of a cytochrome P450 humanized mouse model to refine schistosomiasis drug discovery"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-7330","authenticated-orcid":false,"given":"Sarah D.","family":"Davey","sequence":"first","affiliation":[{"name":"Department of Life Sciences, Aberystwyth University","place":["Wales, Aberystwyth, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7202-3565","authenticated-orcid":false,"given":"Josephine E.","family":"Forde-Thomas","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Aberystwyth University","place":["Wales, Aberystwyth, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5638-6323","authenticated-orcid":false,"given":"Benjamin J.","family":"Hulme","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Aberystwyth University","place":["Wales, Aberystwyth, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9783-1227","authenticated-orcid":false,"given":"Kristin","family":"Lees","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Aberystwyth University","place":["Wales, Aberystwyth, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice H.","family":"Costain","sequence":"additional","affiliation":[{"name":"Lydia Becker Institute of Immunology and Inflammation, Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester","place":["England, Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Aberystwyth University","place":["Wales, Aberystwyth, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7767-4922","authenticated-orcid":false,"given":"Gabriel","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Aberystwyth University","place":["Wales, Aberystwyth, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Frame","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee","place":["Scotland, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laste","family":"Stojanovski","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee","place":["Scotland, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4987-1742","authenticated-orcid":false,"given":"Frederick R. 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D. Davey et al. Use of a cytochrome P450 humanised mouse model to refine schistosomiasis drug discovery. European Nucleotide Archive. https:\/\/www.ebi.ac.uk\/ena\/browser\/view\/PRJEB94950. 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