OBJECTIVE Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells-derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except one Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy. CONCLUSIONS Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy.

中文翻译：

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依维莫司拯救了患者诱导的多能干细胞衍生的血管平滑肌细胞中弹性蛋白不足的表型。

目的弹性蛋白基因的缺失或突变由于血管平滑肌细胞（SMC）增殖而导致动脉狭窄。人类诱导的多能干细胞来源的SMC可以在体外模拟弹性蛋白不足的表型，但仅显示雷帕霉素的部分拯救。我们的目标是确定弹性蛋白不足患者在挽救SMC表型方面具有优异疗效的候选药物。方法和结果：5名具有严重复发性血管狭窄（3 Williams综合征和2个弹性蛋白突变）的弹性蛋白不足患者的诱导多能干细胞产生的SMC在表型上不成熟，过度增殖，对内皮素的反应较差，并在3维平滑肌中降低了张力肌肉生物丝。与健康对照SMC相比，患者SMC中的弹性蛋白mRNA和蛋白质减少。在患者的SMC上测试了14种候选药物。在研究的雷帕霉素抑制剂的哺乳动物靶标中，除一种威廉姆斯综合征外，依维莫司可恢复所有患者SMC中的分化，挽救增殖并改善内皮素诱导的钙通量。在钙通道阻滞剂中，维拉帕米在Williams综合征患者的细胞中增加SMC分化并减少增殖，但在弹性蛋白突变患者中却没有，并且对内皮素反应没有影响。依维莫司和维拉帕米联合治疗并不优于依维莫司单独治疗。其他候选药物疗效有限。结论依维莫司对有症状和无症状弹性蛋白不足的患者的SMC分化，增殖和SMC功能的改善最为稳定，