用治疗性肝细胞移植来治疗小鼠 PKU。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Inherited Metabolic Disease Pub Date : 2024-10-24 DOI:10.1002/jimd.12802
Melanie Willimann, Hiu Man Grisch-Chan, Nicole Rimann, Tanja Rothgangl, Martina Hruzova, Gerald Schwank, Beat Thöny
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引用次数: 0

摘要

在肝脏基因治疗方面,基于腺相关病毒的体内应用是最先进的载体,尽管存在一些局限性,包括低效和外显子丢失、潜在的整合和安全问题以及高昂的生产成本。替代载体和/或递送途径备受关注。肝脏的再生能力为利用肝细胞移植进行活体外治疗提供了可能性,如果肝细胞移植具有选择性优势,可以扩增和替换现有的细胞群,从而矫正疾病。在此,我们介绍了对人类苯丙酮尿症(PKU)小鼠模型的这种治疗方法。野生型小鼠的原代肝细胞在体外进行了基因修饰(使用慢病毒载体),该载体携带的基因编辑系统(CRISPR)可抑制Cypor。Cypor失活会使肝细胞对扑热息痛(或对乙酰氨基酚)产生抗性,从而在移植(通过脾脏)和反复接触扑热息痛治疗时,具有消除原有肝细胞的生长优势。将Cypor失活的野生型肝细胞移植到近亲繁殖的年轻成年enu2(PKU)小鼠体内,然后通过服用扑热息痛进行选择性扩增,结果可替代高达5%的细胞质量,使血液中的苯丙氨酸恢复正常,并永久性纠正PKU。因此,肝细胞移植为治疗遗传性肝缺陷提供了新的治疗方案。
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Therapeutic liver cell transplantation to treat murine PKU.

For gene therapy of the liver, in vivo applications based on adeno-associated virus are the most advanced vectors despite limitations, including low efficacy and episomal loss, potential integration and safety issues, and high production costs. Alternative vectors and/or delivery routes are of high interest. The regenerative ability of the liver bears the potential for ex vivo therapy using liver cell transplantation for disease correction if provided with a selective advantage to expand and replace the existing cell mass. Here we present such treatment of a mouse model of human phenylketonuria (PKU). Primary hepatocytes from wild-type mice were gene modified in vitro (with a lentiviral vector) that carries a gene editing system (CRISPR) to inhibit Cypor. Cypor inactivation confers paracetamol (or acetaminophen) resistance to hepatocytes and thus a growth advantage to eliminate the pre-existing liver cells upon grafting (via the spleen) and exposure to repeated treatment with paracetamol. Grafting Cypor-inactivated wild-type hepatocytes into inbred young adult enu2 (PKU) mice, followed by selective expansion by paracetamol dosing, resulted in replacing up to 5% of cell mass, normalization of blood phenylalanine, and permanent correction of PKU. Hepatocyte transplantation offers thus an armamentarium of novel therapy options for genetic liver defects.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
期刊最新文献
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