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

Tanguy Demaret,Giulio G Muccioli,Etienne M Sokal,Joachim Ravau,Jonathan Evraerts,Mustapha Najimi,Martin Roumain

doi:10.3390/cells10010040

Tanguy Demaret, Giulio G Muccioli + Show 5 more

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https://doi.org/10.3390/cells10010040

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Journal: Cells	Publication Date: Dec 30, 2020
Citations: 2	License type: CC BY 4.0

Affiliation: Université Catholique de Louvain

Abstract

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.

Highlights

Zellweger spectrum disorders (ZSD) are caused by genetic alterations in PEX genes encoding peroxins [1]
Metabolites catabolized into peroxisomes (i.e., branched-chain fatty acids (BCFA: phytanic and pristanic acids), very long-chain fatty acids (VLCFA: C22, C24, C26), C27 bile acids (BA) precursors, etc.) accumulate into plasma and tissues, and compounds synthetized in the peroxisomes are deficient
Parenchymal function is often preserved in liver-based metabolic diseases making it difficult for these patients to progress on liver transplantation (LT) waiting list [12]

Summary

Introduction

Zellweger spectrum disorders (ZSD) are caused by genetic alterations in PEX genes encoding peroxins [1]. Most mild ZSD patients survive into childhood, no validated treatment is able to impact their progressive hepatic dysfunction and developmental delay [4]. In this context, we and others have obtained proof-of principle that liver-targeted therapies such as living donor liver transplantation (LT) and hepatocyte transplantation (HT) can modify disease progression in mild ZSD patients [5,6,7,8]. First pediatric HT procedure performed in Europe was for a four-year-old child affected by mild ZSD [8].

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