An Inducible CRISPR-dCas9-Based Transcriptional Repression System for Cancer Therapy
An Inducible CRISPR-dCas9-Based Transcriptional Repression System for Cancer Therapy
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DOI：
10.1002/smtd.202301310
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发表时间：
2024-01-02
期刊：
影响因子：
12.4
通讯作者：
Chi，Jiadong
中科院分区：
文献类型：
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作者：
Gu，Pengfei;Zhao，Jie;Chi，Jiadong
基因治疗已被用于改善恶性肿瘤的治疗。然而，针对癌症的药物治疗仍然有限，通常不适用于罕见疾病的患者。齐墩果酸(OA)是一种植物来源的三萜类化合物，在中医中经常被用作治疗许多疾病的安全但缓慢起作用的药物。在这里，利用了OA和CRISPR-dCas9在靶向AURKA或KDM1A和改善疾病特异性预后方面的一致药理活性，并使用合成生物学启发的设计原则来设计治疗基因电路，使两种药物能够协同作用。特别是，OA触发的CRISPR-dCas9转录抑制系统迅速并同时减弱了肺癌和甲状腺癌。总而言之，这项工作表明，合理设计的合成基因电路能够通过多路传输单一疗法的靶向效率，以协同方式治疗多因素疾病。
Gene therapy has been adapted for improving malignant tumor treatment. However, pharmacotherapies targeting cancer remain limited and are generally inapplicable for rare disease patients. Oleanolic acid (OA) is a plant‐derived triterpenoid that is frequently used in Chinese medicine as a safe but slow‐acting treatment for many disorders. Here, the congruent pharmacological activities of OA and CRISPR‐dCas9 in targeting AURKA or KDM1A and improving disease‐specific prognosis and used a synthetic‐biology‐inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs are utilized. In particular, the OA‐triggered CRISPR‐dCas9 transcriptional repression system rapidly and simultaneously attenuated lung and thyroid cancer. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficiencies of single therapeutics.