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.

Zellweger谱系疾病（ZSD）是由先天性PEX基因突变引起的新陈代谢错误，导致过氧化物酶体生物生成障碍（PBD）。没有经过验证的治疗方法能够改变疾病的恶化进程。用于开发治疗方法的ZSD小鼠模型受到不良生存和繁殖限制的限制。为了克服这些限制，我们回交了亚型的Pex1p.G844D等位基因为NMRI背景。NMRI小鼠繁殖恢复了常染色体隐性孟德尔遗传模式，并提供了两倍大的产仔。对小鼠进行纵向表型分析，直到6个月大时才使该模型适合治疗干预。ZSD小鼠表现出生长迟缓和与进行性肝细胞肥大相关的相对肝肿大。与RNA测序相关的生化研究破译了ZSD肝糖原代谢改变。受影响的成纤维细胞表现出经典的免疫荧光模式和与PBD相关的生化改变。血浆和肝脏在ZSD小鼠体内显示出很长的脂肪酸，特定的氧固醇和C ₂₇胆汁酸中间产物，以及特定的尿液有机酸谱。随着年龄的增长，C ₂₆如成年患者所述，ZSD小鼠中的脂肪酸和植酸水平趋于正常。总之，我们的小鼠模型概括了轻度的ZSD表型，适用于肝靶向治疗评估。