Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Institute of Pathology, Charles University-First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
Hum Mutat. 2020 Sep;41(9):1662-1670. doi: 10.1002/humu.24072. Epub 2020 Jul 15.
Classical homocystinuria (HCU) is an inborn error of metabolism caused by loss of cystathionine β-synthase (CBS) activity with the concomitant buildup of homocysteine. In knockout (KO) mice, a mouse model of HCU, complete lack of CBS is neonatally lethal. Administration of OT-58, an enzyme therapy for HCU, during the first 5 weeks of life rescued KO mice survival by preventing liver disease. Here, we studied the impact of a long-term uninterrupted OT-58 treatment or its absence beyond the neonatal period on liver pathology and metabolism. Plasma and liver metabolites of KO mice on OT-58 treatment were substantially improved or normalized compared with those receiving vehicle. Increased plasma activities of alanine aminotransferase and aspartate aminotransferase of vehicle-injected KO mice suggested the progression of liver damage with age and lack of treatment. At 3 months of age, liver histology showed no signs of hepatopathy in both vehicle- and OT-58-treated KO mice. However, moderate to severe liver disease, characterized by steatosis, hepatocellular necroses, disorganized endoplasmic reticulum, and swollen mitochondria, developed in 6-month-old vehicle-injected KO mice. KO mice on OT-58 treatment remained asymptomatic and were indistinguishable from age-matched healthy controls. Long-term uninterrupted OT-58 treatment was essential to prevent severe liver disease in the KO mouse model of HCU.
经典同型胱氨酸尿症（HCU）是一种先天性代谢缺陷，由胱硫醚β-合酶（CBS）活性丧失引起，导致同型半胱氨酸堆积。在 knockout（KO）小鼠中，一种 HCU 的小鼠模型，CBS 的完全缺失是新生儿致命的。在生命的前 5 周内给予 OT-58（HCU 的酶替代治疗）可通过预防肝脏疾病来挽救 KO 小鼠的生存。在这里，我们研究了长期不间断的 OT-58 治疗或其在新生儿期后的缺乏对肝脏病理和代谢的影响。与接受载体的 KO 小鼠相比，接受 OT-58 治疗的 KO 小鼠的血浆和肝脏代谢物得到了显著改善或正常化。接受载体注射的 KO 小鼠的血浆丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性升高表明随着年龄的增长和缺乏治疗，肝脏损伤的进展。在 3 个月大时，肝脏组织学显示接受载体和 OT-58 治疗的 KO 小鼠均没有肝病史的迹象。然而，6 个月大的接受载体注射的 KO 小鼠出现了中度至重度肝脏疾病，其特征为脂肪变性、肝细胞坏死、内质网紊乱和肿胀的线粒体。接受 OT-58 治疗的 KO 小鼠仍然无症状，与同龄的健康对照组无法区分。长期不间断的 OT-58 治疗对于预防 HCU KO 小鼠模型中的严重肝脏疾病是必不可少的。
