斯坦福大学医学院的Matthew H. Porteus团队提供了一种非转基因的人类细胞控制机制。研究人员认为利用代谢工程的方法控制细胞可以为细胞疗法增加安全性。 相关论文于2020年7月13日发表在《自然—生物技术》杂志上。

研究人员旨在为人类细胞创造一种不受转基因介导的控制机制。研究人员使用基因组编辑方法，破坏了细胞、多能细胞和初级人类T细胞中嘧啶从头合成通路中的尿苷一磷酸合成酶（UMPS）。研究工作表明，这使细胞增殖依赖于外部尿苷，从而实现在异种移植模型中移植后体内和体外通过调节尿苷供应来控制细胞生长的目的。

此外，扰乱这一合成通路可以产生对5-氟乳清酸的抗性，从而实现对UMPS敲除的细胞的正向选择。该研究组人为，这种方法将提供给细胞疗法额外的安全调控，因此使开发具有更高的风险的方法成为可能，尤其是用于有限治疗时间的情况。一个新的基于膳食尿苷的安全开关可以用于控制细胞疗法。

据了解，保障机制可以改善与细胞疗法相关的潜在风险，但目前依靠引进转基因。然而免疫原性或转基因沉默限制了转基因在细胞疗法中的使用。

附：英文原文

Title: Metabolic engineering generates a transgene-free safety switch for cell therapy

Author: Volker Wiebking, James O. Patterson, Renata Martin, Monica K. Chanda, Ciaran M. Lee, Waracharee Srifa, Gang Bao, Matthew H. Porteus

Issue&Volume: 2020-07-13

Abstract: Safeguard mechanisms can ameliorate the potential risks associated with cell therapies but currently rely on the introduction of transgenes. This limits their application owing to immunogenicity or transgene silencing. We aimed to create a control mechanism for human cells that is not mediated by a transgene. Using genome editing methods, we disrupt uridine monophosphate synthetase (UMPS) in the pyrimidine de novo synthesis pathway in cell lines, pluripotent cells and primary human T cells. We show that this makes proliferation dependent on external uridine and enables us to control cell growth by modulating the uridine supply, both in vitro and in vivo after transplantation in xenograft models. Additionally, disrupting this pathway creates resistance to 5-fluoroorotic acid, which enables positive selection of UMPS-knockout cells. We envision that this approach will add an additional level of safety to cell therapies and therefore enable the development of approaches with higher risks, especially those that are intended for limited treatment durations. A new safety switch allows for control of cell therapies by dietary uridine.

DOI: 10.1038/s41587-020-0580-6

Source: https://www.nature.com/articles/s41587-020-0580-6