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Longitudinal study of Pex1-G844D NMRI mouse model: A robust pre-clinical model for mild Zellweger spectrum disorder
Tanguy Demaret1, Martin Roumain2, Jérôme Ambroise3
1Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
Abstract:
Zellweger spectrum disorders (ZSD) are inborn errors of metabolism caused by mutations in PEX genes that lead to peroxisomal biogenesis disorder (PBD). No validated treatment is able to modify the dismal progression of the disease. ZSD mouse models used to develop therapeutic approaches are limited by poor survival and breeding restrictions. To overcome these limitations, we backcrossed the hypomorphic Pex1 p.G844D allele to NMRI background. NMRI mouse breeding restored an autosomal recessive Mendelian inheritance pattern and delivered twice larger litters. Mice were longitudinally phenotyped up to 6 months of age to make this model suitable for therapeutic interventions. ZSD mice exhibited growth retardation and relative hepatomegaly associated to progressive hepatocyte hypertrophy. Biochemical studies associated with RNA sequencing deciphered ZSD liver glycogen metabolism alterations. Affected fibroblasts displayed classical immunofluorescence pattern and biochemical alterations associated with PBD. Plasma and liver showed very long-chain fatty acids, specific oxysterols and C27 bile acids intermediates elevation in ZSD mice along with a specific urine organic acid profile. With ageing, C26 fatty acid and phytanic acid levels tended to normalize in ZSD mice, as described in patients reaching adulthood. In conclusion, our mouse model recapitulates a mild ZSD phenotype and is suitable for liver-targeted therapies evaluation.
Insights
A new mouse model for Zellweger spectrum disorders (ZSD), a metabolic disease, shows improved breeding and recapitulates key disease features. This model is suitable for evaluating liver-targeted therapies for PBD.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Zellweger spectrum disorders (ZSD) are severe inborn errors of metabolism due to PEX gene mutations, leading to peroxisomal biogenesis disorder (PBD).
- Current ZSD mouse models have limitations including poor survival and breeding difficulties, hindering therapeutic development.
- There is a critical need for improved animal models to test potential treatments for ZSD.
Purpose of the Study:
- To develop and characterize a novel mouse model of Zellweger spectrum disorders (ZSD) with improved breeding characteristics.
- To assess the suitability of this new model for evaluating liver-targeted therapeutic interventions.
- To investigate the biochemical and phenotypic manifestations of ZSD in the developed mouse model.
Main Methods:
- Backcrossing a hypomorphic Pex1 p.G844D allele to the NMRI background to establish a new ZSD mouse model.
- Longitudinal phenotyping of ZSD mice up to 6 months of age.
- Biochemical analyses including RNA sequencing, fibroblast studies, and analysis of plasma, liver, and urine for metabolic markers.
Main Results:
- The NMRI-backcrossed ZSD mouse model exhibits improved breeding efficiency and litter size.
- ZSD mice display characteristic phenotypes such as growth retardation, hepatomegaly, and progressive hepatocyte hypertrophy.
- Metabolic alterations including changes in liver glycogen metabolism, very long-chain fatty acids, oxysterols, bile acids, and urine organic acids were identified.
- Fibroblast studies confirmed classical PBD-associated immunofluorescence and biochemical changes.
- Age-dependent normalization of certain fatty acid levels was observed, mirroring human patient progression.
Conclusions:
- A novel ZSD mouse model with enhanced breeding capacity has been successfully generated.
- This model effectively recapitulates key biochemical and phenotypic features of mild ZSD.
- The developed mouse model is suitable for preclinical evaluation of liver-targeted therapies for peroxisomal biogenesis disorders.
