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通过选择增强的肝细胞移植来完全纠正小鼠基尿症

Anne Vonada^1,2, Leslie Wakefield^1,3, Michael Martinez²

¹Oregon Stem Cell Center, Oregon Health & Science University, Portland, Oregon, USA.

Hepatology (Baltimore, Md.)

|October 12, 2023

概括

移植的转基因肝细胞的乙氨基介导的选择为治疗氨酸尿症提供了一个有前途的策略. 这种方法可以选择性扩张捐赠细胞,在小鼠模型中实现血液氨酸水平的长期正常化.

科学领域:

肝病学肝病学是一种肝病学.
遗传疾病遗传疾病
细胞疗法细胞疗法

背景情况:

肝细胞移植对遗传性肝病有前途,但面临着低细胞移植效率的挑战.
移植的供体肝细胞的选择性扩张对于通过替换肝脏质量来实现治疗效益至关重要.
一种以前开发的基因疗法方法利用乙氨基 (APAP) 来选择性地扩大细胞组P450减少酶 (Cypor) 缺乏的肝细胞.

研究的目的:

应用APAP介导的选择性扩张系统来纠正使用肝细胞移植的表类尿 (PKU) 的小鼠模型.
评估这种方法在长期治疗PKU时的疗效和安全性.

主要方法:

肝细胞在实验室中被基因修改,以产生Cypor缺乏症.
这些修改后的肝细胞被移植到基尿 (PKU) 鼠标模型中.
乙氨基 (APAP) 用于诱导移植的Cypor缺乏肝细胞的选择性扩张.

主要成果:

移植的Cypor缺乏肝细胞显著扩大,从更正的PKU小鼠中的不到1%扩大到约14%.
血液中的 fenilalanine 度完全正常化,并在 APAP 停用后保持稳定.
在治疗动物的血液化学,肝脏组织学或药物代谢中没有观察到任何不良影响.

结论:

移植肝细胞的乙氨基介导选择为基尿提供了潜在的治疗策略.
这种方法在临床前模型中证明了长期的疗效和有利的安全性.
这些发现支持这种细胞疗法用于遗传性肝脏疾病的临床转化.

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