KLIPP - a precision CRISPR approach to target structural variant junctions in cancer.
KLIPP - a precision CRISPR approach to target structural variant junctions in cancer.
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KLIPP - 一种精确的 CRISPR 方法，用于靶向癌症中的结构变异连接。
DOI：
10.1101/2023.05.10.540176
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ljungman,Mats
中科院分区：
文献类型：
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作者：
Yang,Huibin;Hulbatte,RadhikaSuhas;Kelleher,Alan;Gratsch,Natalie;Wang,Yin;Palmbos,PhilipL;Ljungman,Mats
目前的癌症治疗方法通常会引起剂量限制的正常组织毒性。我们已经开发了Klipp，这是一种精确的癌症方法，使用CRISPR/Cas9技术专门杀死癌细胞。该方法包括以癌症特异性结构变异连接为靶点的引导RNA，使dCas9结合的核酸内切酶Fok1的两个部分成核，从而导致其激活。我们发现Klipp导致目标连接处的DNA双链断裂(DSB)和细胞死亡。当癌细胞在小鼠体内原位生长时，只在两个连接处激活Fok1导致7/11小鼠肿瘤细胞消失。这种治疗方法对肿瘤细胞具有高度的特异性，并且不依赖于肿瘤特异性驱动因素。Klipp对患者的个性化翻译将是变革性的，并导致一致和简化的癌症治疗决定。
Current cancer therapies typically give rise to dose-limiting normal tissue toxicity. We have developed KLIPP, a precision cancer approach that specifically kills cancer cells using CRISPR/Cas9 technology. The approach consists of guide RNAs that target cancer-specific structural variant junctions to nucleate two parts of a dCas9-conjugated endonuclease, Fok1, leading to its activation. We show that KLIPP causes induction of DNA double strand breaks (DSBs) at the targeted junctions and cell death. When cancer cells were grown orthotopically in mice, activation of Fok1 at only two junctions led to the disappearance of tumor cells in 7/11 mice. This therapeutic approach has high specificity for tumor cells and is independent of tumor-specific drivers. Individualized translation of KLIPP to patients would be transformative and lead to consistent and simplified cancer treatment decisions.