小柯机器人

合成内含子实现对癌细胞的剪接因子突变依赖性靶向
2022-03-06 18:08
来源：小柯机器人

美国华盛顿大学Robert K. Bradley、纪念斯隆•凯特琳癌症中心Omar Abdel-Wahab等研究人员合作发现，合成内含子实现对癌细胞的剪接因子突变依赖性靶向。该研究于2022年3月3日在线发表于国际一流学术期刊《自然—生物技术》。

研究人员描述了一种方法，利用异常的剪接活动来驱动剪接因子突变依赖的基因表达，从而选择性地消除肿瘤细胞。研究人员设计了合成内含子，这些内含子在带有SF3B1突变的癌细胞中被有效地剪接，但在其他同源的野生型细胞中未被剪接，从而产生突变依赖性的蛋白质生产。对8,878个内含子的大规模平行筛选划定了理想的内含子大小，并绘制了突变依赖性拼接的基本元素。合成内含子使单纯疱疹病毒-胸苷激酶（HSV-TK）的突变依赖性表达和随后的更昔洛韦（GCV）介导的体外杀伤SF3B1突变的白血病、乳腺癌、葡萄膜黑色素瘤和胰腺癌细胞，而使野生型细胞不受影响。
 
将含有合成内含子的HSV-TK构建体传递给白血病、乳腺癌和葡萄膜黑色素瘤细胞，并在体内进行GCV处理，可显著抑制这些原本致命的异种移植的生长，并改善小鼠宿主的生存。合成内含子为利用肿瘤特异性的RNA剪接变化进行癌症基因治疗提供了一种手段。
 
据悉，许多癌症带有影响RNA剪接因子的复发性、功能改变的突变。
 
附：英文原文

Title: Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells

Author: North, Khrystyna, Benbarche, Salima, Liu, Bo, Pangallo, Joseph, Chen, Sisi, Stahl, Maximilian, Bewersdorf, Jan Philipp, Stanley, Robert F., Erickson, Caroline, Cho, Hana, Pineda, Jose Mario Bello, Thomas, James D., Polaski, Jacob T., Belleville, Andrea E., Gabel, Austin M., Udy, Dylan B., Humbert, Olivier, Kiem, Hans-Peter, Abdel-Wahab, Omar, Bradley, Robert K.

Issue&Volume: 2022-03-03

Abstract: Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors. Here, we describe a method to harness this abnormal splicing activity to drive splicing factor mutation-dependent gene expression to selectively eliminate tumor cells. We engineered synthetic introns that were efficiently spliced in cancer cells bearing SF3B1 mutations, but unspliced in otherwise isogenic wild-type cells, to yield mutation-dependent protein production. A massively parallel screen of 8,878 introns delineated ideal intronic size and mapped elements underlying mutation-dependent splicing. Synthetic introns enabled mutation-dependent expression of herpes simplex virus–thymidine kinase (HSV–TK) and subsequent ganciclovir (GCV)-mediated killing of SF3B1-mutant leukemia, breast cancer, uveal melanoma and pancreatic cancer cells in vitro, while leaving wild-type cells unaffected. Delivery of synthetic intron-containing HSV–TK constructs to leukemia, breast cancer and uveal melanoma cells and GCV treatment in vivo significantly suppressed the growth of these otherwise lethal xenografts and improved mouse host survival. Synthetic introns provide a means to exploit tumor-specific changes in RNA splicing for cancer gene therapy.

DOI: 10.1038/s41587-022-01224-2

Source: https://www.nature.com/articles/s41587-022-01224-2

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章：《自然—生物技术》：Online/在线发表

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