Use of a cytochrome P450 humanized mouse model to refine schistosomiasis drug discovery
Abstract
Control of schistosomiasis, a neglected tropical disease caused by infection with Schistosoma spp ., 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 Schistosoma mansoni 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 S. mansoni 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 >10-fold lower than that found for WT microsomes. Oral dosing revealed human-like PZQ exposures of ( R )-PZQ and 4OH-PZQ in 8HUM mice at 25 mg/kg bodyweight and >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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (28)
Sarah D. Davey
Department of Life Sciences, Aberystwyth University
Josephine E. Forde-Thomas
Department of Life Sciences, Aberystwyth University
Benjamin J. Hulme
Department of Life Sciences, Aberystwyth University
Kristin Lees
Department of Life Sciences, Aberystwyth University
Alice H. Costain
Lydia Becker Institute of Immunology and Inflammation, Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester
Mary Evans
Department of Life Sciences, Aberystwyth University
Gabriel Rinaldi
Department of Life Sciences, Aberystwyth University
Laura Frame
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Laste Stojanovski
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Frederick R. C. Simeons
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Amy Tavendale
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
A. Kenneth MacLeod
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Remi Pichon
Department of Life Sciences, Aberystwyth University
Yi-Hsuan Lee
Department of Life Sciences, Aberystwyth University
Oktawia Polak
Department of Life Sciences, Aberystwyth University
Iain W. Chalmers
Department of Life Sciences, Aberystwyth University
Bismark Dankwa
Department of Life Sciences, Aberystwyth University
Brenda Kisia Odhiambo
Department of Life Sciences, Aberystwyth University
Victor Hugo Guimaraes
Laboratory of Inflammation and Infectious Diseases, Department of Morphology and Pathology, Federal University of São Carlos
Matthew Hegarty
Department of Life Sciences, Aberystwyth University
Martin T. Swain
Department of Life Sciences, Aberystwyth University
Wayne Aubrey
Department of Computer Science, Aberystwyth University
Nicola Caldwell
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Andrew S. MacDonald
Lydia Becker Institute of Immunology and Inflammation, Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester
Ian H. Gilbert
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Beatriz Baragaña
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Kevin D. Read
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee
Karl F. Hoffmann
Department of Life Sciences, Aberystwyth University