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

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.

Cell therapy in end-stage liver disease: replace and remodel

“…3 ). The transplanted cells should be delivered to the hepatic sinusoids, where they need to subsequently integrate with the liver parenchyma [ 184 ]. The most frequent clinical technique is cell infusion via the portal vein.…”

The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

“…The PEX1G843D mutation affects PEX1 folding and attenuates the physical interaction between PEX1 and PEX6 necessary for peroxisomal import by 70% ( Geisbrecht et al, 1998 ; Zhang et al, 2010 ). Although the variability in disease severity of patients homozygous for the PEX1G843D mutation ( Poll-The et al, 2004 ) makes it difficult to predict outcomes solely from genotype, the overall milder phenotype of the homozygous PEX1G843D mutation ( Berendse et al, 2016 ) makes it amenable to liver or hepatocyte transplantation ( Demaret et al, 2018 , 2021 ) and pharmaceutical therapy to improve quality of life and lifespan for patients carrying this mutation ( Zhang et al, 2010 ).…”