Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
Bioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
Cells. 2020 Dec 30;10(1):40. doi: 10.3390/cells10010040.
Genetic alterations in 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 -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 -G844D NMRI mouse liver. The mouse model exhibited the robustness required for ZSD liver-targeted therapies evaluation.
基因的遗传改变导致过氧化物酶体生物发生障碍。在人类中，它们与 Zellweger 谱障碍（ZSD）有关。目前还没有经过验证的治疗方法可以改变 ZSD 患者的悲惨自然病史。肝移植（LT）改善了轻度 ZSD 患者的临床和生化结局。为了克服 LT 的局限性而开发的肝细胞移植（HT）在一名轻度 ZSD 4 岁儿童中进行，取得了令人鼓舞的短期结果。在这里，我们评估了通过脾内输注在 -G844D NMRI 小鼠模型中进行的低剂量（1250 万个肝细胞/kg）和高剂量（5000 万个肝细胞/kg）同种异体男性 HT，该模型重现了轻度 ZSD 表型。HT 在生长迟缓的 ZSD 小鼠中是可行且安全的。临床（体重和食物摄入）和生化参数（超长链脂肪酸、异常胆汁酸等）与 ZSD 表型一致，但 HT 并不能显著改善这些参数。正如预期的那样，HT 后 24 小时有三分之一的输注细胞被检测到在肝脏中。在 7、14 和 30 天后，未检测到肝或脾微嵌合体。需要进一步优化以提高 -G844D NMRI 小鼠肝脏中肝细胞的移植效果。该小鼠模型表现出了评估 ZSD 肝脏靶向治疗所需的稳健性。
