Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies
Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies
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药物和 siRNA 筛选将 ROCK2 确定为纤毛病的治疗靶点
DOI：
10.1101/2020.11.26.393801
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Lake A
中科院分区：
文献类型：
--
作者：
Lake A
初级纤毛是基于微管的细胞器，其充当细胞触角以介导脊椎动物发育和生长因子信号传导。初级纤毛缺陷导致一组遗传性发育条件，称为纤毛病。睫状体病通常表现为囊性肾病，这是需要肾脏替代治疗的早期肾衰竭的主要原因。目前，只有一种药物，托伐普坦，被许可减缓纤毛病变多囊肾病的肾功能下降。针对这些疾病的新型治疗干预措施仍然是紧迫的临床需求。我们筛选了临床开发化合物对纤毛形成和功能的积极影响，并确定盐酸法舒地尔为最受欢迎的药物。法舒地尔是一种非专利药，是一种有效但具有广泛选择性的Rho相关卷曲螺旋蛋白激酶（ROCK）抑制剂。在纤毛形成的正调节剂的平行的基于全基因组siRNA的反向遗传学表型筛选中，我们确定ROCK 2为靶分子。我们证明ROCK 2是纤毛形成和功能的关键介质，通过影响肌动蛋白细胞骨架重塑。我们的研究结果表明，特异性ROCK 2抑制剂，如belumosudil（KD-025），可用于囊性肾病的药物干预。我们认为ROCK 2抑制代表了一种新的、改善疾病的异质性纤毛病变治疗方法。
Primary cilia are microtubule-based organelles that act as cellular antennae to mediate vertebrate development and growth factor signalling. Defects in primary cilia result in a group of inherited developmental conditions known as ciliopathies. Ciliopathies often present with cystic kidney disease, a major cause of early renal failure that requires renal replacement therapies. Currently, only one drug, Tolvaptan, is licensed to slow the decline of renal function for the ciliopathy polycystic kidney disease. Novel therapeutic interventions for these conditions remain a pressing clinical need.We screened clinical development compounds for positive effects on cilia formation and function and identified fasudil hydrochloride as the top hit. Fasudil is a generic, off-patent drug that is a potent but broadly selective Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor. In a parallel whole genome siRNA-based reverse genetics phenotypic screen of positive modulators of cilia formation, we identified ROCK2 as the target molecule. We demonstrate that ROCK2 is a key mediator of cilium formation and function through effects on actin cytoskeleton remodelling. Our results indicate that specific ROCK2 inhibitors such as belumosudil (KD-025) could be repurposed for pharmacological intervention in cystic kidney disease. We propose that ROCK2 inhibition represents a novel, disease-modifying therapeutic approach for heterogeneous ciliopathies.
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