Liver disease predominates in a mouse model for mild human Zellweger spectrum disorder

Berendse, Kevin; Boek, Maxim; Gijbels, Marion; Wel, Nicole N. van der; Klouwer, Femke C. C.; Bergh-Weerman, Marius A. van den; Shinde, Abhijit Babaji; Ofman, Rob; Poll-Thé, Bwee Tien; Houten, Sander M.; Baes, Myriam; Wanders, Ronald J. A.; Waterham, Hans R.

doi:10.1016/j.bbadis.2019.06.013

Cited by 13 publications

(10 citation statements)

References 46 publications

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“…This model exhibits multisystemic involvement, and its other primary phenotypes include growth retardation and fatty liver disease with histological evidence of a bile acid defect associated with intestinal fat malabsorption and cholestasis. 23 , 37 , 38 Animals that survive past weaning have a normal lifespan and no overt CNS manifestations. Most importantly, they display degenerative retinal phenotypes corresponding to those found in patients with milder ZSD and thus are a robust model for evaluating targeted therapeutic interventions to slow or prevent vision loss in this patient population.…”

Section: Discussionmentioning

confidence: 99%

AAV-mediated PEX1 gene augmentation improves visual function in the PEX1-Gly844Asp mouse model for mild Zellweger spectrum disorder

Argyriou

Polosa²,

Song³

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Patients with Zellweger spectrum disorder (ZSD) commonly present with vision loss due to mutations in PEX genes required for peroxisome assembly and function. Here, we evaluate PEX1 retinal gene augmentation therapy in a mouse model of mild ZSD bearing the murine equivalent (PEX1-p[Gly844Asp]) of the most common human mutation. Experimental adeno-associated virus 8.cytomegalovirus.human PEX1.hemagglutinin (AAV8.CMV. HsPEX1.HA ) and control AAV8.CMV. EGFP vectors were administered by subretinal injection in contralateral eyes of early (5-week-old)- or later (9-week-old)-stage retinopathy cohorts. HsPEX1.HA protein was expressed in the retina with no gross histologic side effects. Peroxisomal metabolic functions, assessed by retinal C26:0 lysophosphatidylcholine (lyso-PC) levels, were partially normalized after therapeutic vector treatment. Full-field flash electroretinogram (ffERG) analyses at 8 weeks post-injection showed a 2-fold improved retinal response in the therapeutic relative to control vector-injected eyes. ffERG improved by 1.6- to 2.5-fold in the therapeutic vector-injected eyes when each cohort reached 25 weeks of age. At 32 weeks of age, the average ffERG response was double in the therapeutic relative to control vector-injected eyes in both cohorts. Optomotor reflex analyses trended toward improvement. These proof-of-concept studies represent the first application of gene augmentation therapy to treat peroxisome biogenesis disorders and support the potential for retinal gene delivery to improve vision in these patients.

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Section: Discussionmentioning

confidence: 99%

AAV-mediated PEX1 gene augmentation improves visual function in the PEX1-Gly844Asp mouse model for mild Zellweger spectrum disorder

Argyriou

Polosa²,

Song³

et al. 2021

Molecular Therapy - Methods & Clinical Development

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“…Since then, successful HT protocols were reported in patients affected by chronic liver disease [ 28 ]. ZSD mouse models and patients exhibit chronic liver disease [ 18 , 29 , 30 ], and our team reported the safety of HT in a 4-year-old ZSD patient [ 8 ]. Our ZSD mouse model express a severe disease phenotype with growth retardation along with chronic liver injury and fibrosis [ 18 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…ZSD mouse models and patients exhibit chronic liver disease [ 18 , 29 , 30 ], and our team reported the safety of HT in a 4-year-old ZSD patient [ 8 ]. Our ZSD mouse model express a severe disease phenotype with growth retardation along with chronic liver injury and fibrosis [ 18 , 29 ]. Yet, this phenotype did not impede the feasibility of HT.…”

Section: Discussionmentioning

confidence: 99%

High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in Pex1-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment

Demaret

Evraerts

Ravau

et al. 2020

Cells

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Genetic alterations in PEX genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has been shown to modify the dismal natural history of ZSD. Liver transplantation (LT) improved clinical and biochemical outcomes in mild ZSD patients. Hepatocyte transplantation (HT), developed to overcome LT limitations, was performed in a mild ZSD 4-year-old child with encouraging short-term results. Here, we evaluated low dose (12.5 million hepatocytes/kg) and high dose (50 million hepatocytes/kg) syngeneic male HT via intrasplenic infusion in the Pex1-G844D NMRI mouse model which recapitulates a mild ZSD phenotype. HT was feasible and safe in growth retarded ZSD mice. Clinical (weight and food intake) and biochemical parameters (very long-chain fatty acids, abnormal bile acids, etc.) were in accordance with ZSD phenotype but they were not robustly modified by HT. As expected, one third of the infused cells were detected in the liver 24 h post-HT. No liver nor spleen microchimerism was detected after 7, 14 and 30 days. Future optimizations are required to improve hepatocyte engraftment in Pex1-G844D NMRI mouse liver. The mouse model exhibited the robustness required for ZSD liver-targeted therapies evaluation.

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“…This mouse model recapitulates many of the hepatic features and retinopathy present in these patients (Hiebler et al 2014 ). First, presented by Lingxiao Chen , came an assessment of the efficacy of colic acid therapy in preventing/treating liver disease caused, in part, by bile acid synthesis defects that result from a disrupted peroxisomal matrix protein import (Berendse et al 2019 ). They found that diet supplementation with cholic acid reduced levels of toxic C27-bile acid precursors and led to elevated levels of mature C24-bile acids in a dose dependent manner.…”

Section: Session 4: Chair: Tony Rodrigues Universidade Do Porto Portugalmentioning

confidence: 99%

Current advances in the function and biogenesis of peroxisomes and their roles in health and disease

Dahan

Francisco

Falter³

et al. 2021

Histochem Cell Biol

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Liver disease predominates in a mouse model for mild human Zellweger spectrum disorder

Cited by 13 publications

References 46 publications

AAV-mediated PEX1 gene augmentation improves visual function in the PEX1-Gly844Asp mouse model for mild Zellweger spectrum disorder

AAV-mediated PEX1 gene augmentation improves visual function in the PEX1-Gly844Asp mouse model for mild Zellweger spectrum disorder

High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in Pex1-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment

Current advances in the function and biogenesis of peroxisomes and their roles in health and disease

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