MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK.
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
Molecules. 2021 Oct 28;26(21):6530. doi: 10.3390/molecules26216530.
RNA activation (RNAa) is a mechanism whereby RNA oligos complementary to genomic sequences around the promoter region of genes increase the transcription output of their target gene. Small activating RNA (saRNA) mediate RNAa through interaction with protein co-factors to facilitate RNA polymerase II activity and nucleosome remodeling. As saRNA are small, versatile and safe, they represent a new class of therapeutics that can rescue the downregulation of critical genes in disease settings. This review highlights our current understanding of saRNA biology and describes various examples of how saRNA are successfully used to treat various oncological, neurological and monogenic diseases. MTL-CEBPA, a first-in-class compound that reverses CEBPA downregulation in oncogenic processes using CEBPA-51 saRNA has entered clinical trial for the treatment of hepatocellular carcinoma (HCC). Preclinical models demonstrate that MTL-CEBPA reverses the immunosuppressive effects of myeloid cells and allows for the synergistic enhancement of other anticancer drugs. Encouraging results led to the initiation of a clinical trial combining MTL-CEBPA with a PD-1 inhibitor for treatment of solid tumors.
RNA 激活（RNAa）是一种机制，其中与基因启动子区域周围基因组序列互补的 RNA 寡核苷酸增加其靶基因的转录产量。小激活 RNA（saRNA）通过与蛋白辅因子相互作用介导 RNAa，以促进 RNA 聚合酶 II 活性和核小体重塑。由于 saRNA 体积小、多功能且安全，它们代表了一类新的治疗药物，可以在疾病环境中挽救关键基因的下调。本文综述了 saRNA 生物学的最新认识，并描述了 saRNA 成功用于治疗各种肿瘤、神经和单基因疾病的各种实例。MTL-CEBPA 是一种首创的化合物，它使用 CEBPA-51 saRNA 逆转致癌过程中 CEBPA 的下调，已进入肝细胞癌（HCC）治疗的临床试验。临床前模型表明，MTL-CEBPA 逆转了髓样细胞的免疫抑制作用，并允许与其他抗癌药物协同增强。令人鼓舞的结果促使启动了一项临床试验，将 MTL-CEBPA 与 PD-1 抑制剂联合用于治疗实体瘤。
