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首页> 外文期刊>Circulation. Genomic and precision medicine. >Suppression and Replacement Gene Therapy for KCNH2-Mediated Arrhythmias
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Suppression and Replacement Gene Therapy for KCNH2-Mediated Arrhythmias

机译：KCNH2介导的心律失常的抑制和替代基因治疗

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BACKGROUND: KCNH2-mediated arrhythmia syndromes are caused by loss-of-function (type 2 long QT syndrome [LQT2]) or gain-of-function (type 1 short QT syndrome [SQT1]) pathogenic variants in the KCNH2-encoded Kv1 1.1 potassium channel, which is essential for the cardiac action potential.METHODS: A dual-component "suppression-and-replacement" (SupRep) KCNH2 gene therapy was created by cloning into a single construct a custom-designed KCNH2 short hairpin RNA with ~80% knockdown (suppression) and a "short hairpin RNA-immune" KCNH2 cDNA (replacement). Induced pluripotent stem cell-derived cardiomyocytes and their CRISPR-Cas9 variant-corrected isogenic control (IC) induced pluripotent stem cell-derived cardiomyocytes were made for 2 LQT2- (G604S, N633S) and 1 SQT1- (N588K) causative variants. All variant lines were treated with KCNH2-SupRep or non-targeting control short hairpin RNA (shCT). The action potential duration (APD) at 90% repolarization (APD90) was measured using FluoVolt voltage dye.RESULTS: KCNH2-SupRep achieved variant-independent rescue of both pathologic phenotypes. For LQT2-causative variants, treatment with KCNH2-SupRep resulted in shortening of the pathologically prolonged APD90 to near curative (IC-like) APD90 levels (G604S IC, 471±25 ms; N633S IC, 405±55 ms) compared with treatment with shCT (G604S: SupRep-treated, 452±76 ms versus shCT-treated, 550±41 ms; P<0.0001; N633S: SupRep-treated, 399±105 ms versus shCT-treated, 577±39 ms, P<0.0001). Conversely, for the SQT1-causative variant, N588K, treatment with KCNH2-SupRep resulted in therapeutic prolongation of the pathologically shortened APD90 (IC: 429±16 ms; SupRep-treated: 396±61 ms; shCT-treated: 274±1 2 ms).CONCLUSIONS: We provide the first proof-of-principle gene therapy for correction of both LQT2 and SQT1. KCNH2-SupRep gene therapy successfully normalized the pathologic APD90, thereby eliminating the pathognomonic feature of both LQT2and SQT1.
机译：背景:KCNH2-mediated心律失常综合征是由功能丧失(2型长QT综合症[LQT2])或功能(1型短QT综合征[SQT1])致病变种1.1的KCNH2-encoded Kv1钾通道,这是必不可少的心脏行动的潜力。“suppression-and-replacement”(SupRep) KCNH2基因治疗是由克隆到一个构建一个专门设计的KCNH2短发夹RNA与~ 80%击倒(抑制)和一个“短发夹RNA-immune”KCNH2互补脱氧核糖核酸(替换)。细胞衍生心肌细胞及其CRISPR-Cas9variant-corrected同基因的控制(IC)诱导多能干细胞心肌细胞(N588K)诱发变异。服用KCNH2-SupRep或新吗控制短发卡RNA (shCT)。潜在的持续时间(adp) 90%的复极化(APD90)用FluoVolt电压测量variant-independent救援的病理表型。治疗KCNH2-SupRep导致缩短APD90病态的延长治疗附近(IC-like) (G604S APD90水平IC 471±25 ms;治疗shCT (G604S: SupRep-treated,452±76与shCT-treated女士,女士550±41;P < 0.0001;与shCT-treated, 577±39毫秒,P < 0.0001)。相反,SQT1-causative变体,与KCNH2-SupRep导致N588K、治疗治疗病态的延长缩短APD90 (IC: 429±16女士;396±61 ms;我们提供第一原理的基因治疗修正LQT2和SQT1。KCNH2-SupRep基因治疗成功规范化病理APD90,从而消除了特殊的功能的LQT2and SQT1。

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