小柯机器人

美国加州大学桑福德干细胞研究所Catriona H.M. Jamieson课题组发现瑞贝西尼逆转恶性作用于RNA1（ADAR1）的腺苷脱氨酶剪接亚型转换。2023年2月16日出版的《细胞—干细胞》杂志发表了这项最新研究成果。

他们开发了慢病毒ADAR1和剪接报告基因，用于非侵入性检测剪接介导的ADAR1腺苷-肌苷（A-to-I）RNA编辑激活;定量ADAR1p150细胞内流式细胞术测定；剪接介导的ADAR1激活的选择性小分子抑制剂Rebecsinib，其抑制白血病干细胞（LSC）自我更新并延长人源化LSC小鼠模型存活，其剂量可保留正常造血干细胞和祖细胞（HSPC）; IND前研究显示有利的瑞贝西尼毒代动力学和药效学（TK / PD）特性。总之，这些结果为开发瑞贝西尼作为临床ADAR1p150拮抗剂奠定了基础，旨在避免恶性微环境驱动的LSC生成。

研究人员表示，ADAR1通过在应激反应期间阻止逆转录病毒整合和逆转录转位来保持基因组完整性。然而，炎症微环境诱导的ADAR1p110至p150剪接亚型转换驱动了20种恶性肿瘤的癌症干细胞（CSC）生成和治疗耐药性。以前，预测和预防ADAR1p150介导的恶性RNA编辑是一项重大挑战。

附：英文原文

Title: Reversal of malignant ADAR1 splice isoform switching with Rebecsinib

Author: Leslie A. Crews, Wenxue Ma, Luisa Ladel, Jessica Pham, Larisa Balaian, S. Kathleen Steel, Phoebe K. Mondala, Raymond H. Diep, Christina N. Wu, Cayla N. Mason, Inge van der Werf, Isabelle Oliver, Eduardo Reynoso, Gabriel Pineda, Thomas C. Whisenant, Peggy Wentworth, James J. La Clair, Qingfei Jiang, Michael D. Burkart, Catriona H.M. Jamieson

Issue&Volume: 2023-02-16

Abstract: Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation and therapeutic resistance in 20 malignancies. Previously, predicting and preventing ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 and splicing reporters for non-invasive detection of splicing-mediated ADAR1 adenosine-to-inosine (A-to-I) RNA editing activation; a quantitative ADAR1p150 intracellular flow cytometric assay; a selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib, which inhibits leukemia stem cell (LSC) self-renewal and prolongs humanized LSC mouse model survival at doses that spare normal hematopoietic stem and progenitor cells (HSPCs); and pre-IND studies showing favorable Rebecsinib toxicokinetic and pharmacodynamic (TK/PD) properties. Together, these results lay the foundation for developing Rebecsinib as a clinical ADAR1p150 antagonist aimed at obviating malignant microenvironment-driven LSC generation.

DOI: 10.1016/j.stem.2023.01.008

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00008-5

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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