2007年,科学家们获得了人诱导性多能干细胞(induced pluripotent stem cell, iPS细胞),即对成体细胞进行基因改造使得它们返回到一种多能性干细胞状态而有潜力变成体内的任何一种细胞类型,从而源源不断地供应干细胞同时没有使用胚胎干细胞所面临的伦理争议。但是,与胚胎干细胞一样,iPS细胞具有不受控制生长和发生潜在癌变的倾向。这一点,再加上iPS细胞制备时的基因突变风险和成本,阻碍了它们的临床应用发展。
将一种细胞疗法从实验室转移到临床需要解决两个重要的问题:它是否是有效的?它是安全的吗?基于此,Nagy团队找到了一种方法来预测产生具有潜在危险的治疗性细胞的几率,并通过基因编辑来降低这些几率。经过基因编辑的细胞具有一个拼接到DNA中的自杀基因(HSV-TK),这个自杀基因直接连接到细胞分裂和存活所必需的一个基因(CDK1)上。如果检测到有害突变,那么使用一种小分子药物就能够阻止这些细胞发生分裂和造成伤害。它们也是隐形的,也就无需进行免疫抑制。
根据迄今为止的反馈结果,Nagy乐观地认为他们正朝着正确的方向前进。他们下一步计划在动物模型中进行更多测试,同时已经开始与加拿大卫生部沟通,推动开展人体临床试验。如果这种安全细胞方法能够在所有iPS细胞制备中实施,那么它很可能成为细胞治疗安全性的标准,用于提供可信的和可预测的测量,并允许经过基因编辑的iPS细胞快速推进到临床试验。
推荐阅读原文:
Linking a cell-division gene and a suicide gene to define and improve cell therapy safety.
Human pluripotent cell lines hold enormous promise for the development of cell-based therapies. Safety, however, is a crucial prerequisite condition for clinical applications. Numerous groups have attempted to eliminate potentially harmful cells through the use of suicide genes, but none has quantitatively defined the safety level of transplant therapies. Here, using genome-engineering strategies, we demonstrate the protection of a suicide system from inactivation in dividing cells. We created a transcriptional link between the suicide gene herpes simplex virus thymidine kinase (HSV-TK) and a cell-division gene (CDK1); this combination is designated the safe-cell system. Furthermore, we used a mathematical model to quantify the safety level of the cell therapy as a function of the number of cells that is needed for the therapy and the type of genome editing that is performed. Even with the highly conservative estimates described here, we anticipate that our solution will rapidly accelerate the entry of cell-based medicine into the clinic.
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