Repositioning of a novel GABA-B receptor agonist, AZD3355 (Lesogaberan), for the treatment of non-alcoholic steatohepatitis.
Repositioning of a novel GABA-B receptor agonist, AZD3355 (Lesogaberan), for the treatment of non-alcoholic steatohepatitis.
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DOI：
10.1038/s41598-021-99008-2
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发表时间：
2021-10-21
影响因子：
4.6
通讯作者：
Friedman SL
中科院分区：
文献类型：
--
作者：
Bhattacharya D;Becker C;Readhead B;Goossens N;Novik J;Fiel MI;Cousens LP;Magnusson B;Backmark A;Hicks R;Dudley JT;Friedman SL
非酒精性脂肪性肝炎（NASH）是一个日益严重的健康挑战，没有批准的药物。我们使用计算药物重新定位策略来发现NASH的新疗法，确定了GABA-B受体激动剂AZD 3355（Lesogaberan），该激动剂先前被评估为食管反流疗法。在人星状细胞、人精密切割肝脏切片（hPCLS）和经过充分验证的NASH小鼠模型中，检测了AZD 3355在NASH中的潜在疗效。在人星状细胞中，AZD 3355显著下调促纤维化基因和蛋白的表达。这些反应的转录组学分析确定了受AZD 3355影响的关键调控节点，包括Myc以及MAP和ERK激酶。在PCLS中，AZD 3355下调胶原1 α1、αSMA和TNF-α mRNA以及分泌的胶原1 α1。在体内，该药物显着改善了组织学，促纤维化基因表达和肿瘤发展，这与奥贝胆酸在NASH的稳健小鼠模型中的活性相当，但仍有待进一步测试以确定其在患者中的相对疗效。这些数据通过其保肝、抗炎和抗纤维化作用机制，确定了耐受性良好的临床阶段资产作为人NASH的新型候选疗法。该方法验证了计算方法，以确定NASH的新疗法，发现疾病发展的新途径，可以迅速转化为临床试验。
Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (Lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, αSMA and TNF-α mRNAs as well as secreted collagen1α1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development, which was comparable to activity of obeticholic acid in a robust mouse model of NASH, but awaits further testing to determine its relative efficacy in patients. These data identify a well-tolerated clinical stage asset as a novel candidate therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
24.5
作者：
Boeckxstaens, Guy E.;Beaumont, Hanneke;Denison, Hans
通讯作者：
Denison, Hans
影响因子：
5
作者：
Branden, Lena;Fredriksson, Anita;Lehmann, Anders
通讯作者：
Lehmann, Anders
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM
影响因子：
6.2
作者：
Cholankeril, George;Gadiparthi, Chiranjeevi;Ahmed, Aijaz
通讯作者：
Ahmed, Aijaz