更新于：2024-11-01

Long QT Syndrome Type 3

3型QT间期延长综合征

更新于：2024-11-01

基本信息

别名

Long QT syndrome type 3、Long QT syndrome type 3 (disorder)、长QT症3型

简介-

关联

项与 3型QT间期延长综合征相关的药物

LQT-1213

靶点

SGK1

作用机制

SGK1 inhibitors

在研机构

Thryv Therapeutics, Inc.初创企业

原研机构

Thryv Therapeutics, Inc.初创企业

在研适应症

QT间期延长综合征2 [+2]

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

Eleclazine

靶点

Nav1.5

作用机制

Nav1.5阻滞剂

在研机构-

原研机构

Gilead Sciences, Inc.

在研适应症-

非在研适应症

稳定型心绞痛 [+8]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 3型QT间期延长综合征相关的临床试验

NCT05906732 / Recruiting临床1/2期

A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed With Type 1, 2 or 3 Long QT Syndrome

Part 1: This is a Phase 1b, randomized, double-blind, crossover, dose escalation, placebo-controlled study to evaluate the effect of oral LQT-1213 on dofetilide-induced QTc prolongation in healthy adult subjects. This is a 2-treatment, 2-period crossover study with approximately up to 28 healthy subjects, with screening procedures within 28 days of enrolment.
Part 2: This is a Phase 2a, single-blind, placebo run-in, multiple-dose safety study to evaluate the safety, tolerability, and PK of LQT-1213 in patients diagnosed with LQT1, LQT2 or LQT3. Up to 12 participants with LQT1, up to 20 participants with LQT2 and up to 12 participants with LQT3 will be recruited.

开始日期2023-03-12

申办/合作机构

Thryv Therapeutics, Inc.初创企业

NCT02300558 / Terminated临床3期

A Phase 3, Single-Blind Study to Evaluate the Effect of Eleclazine (GS-6615) on Shortening of the QT Interval, Safety, and Tolerability in Subjects With Long QT Syndrome Type 3

The primary objective of this study is to evaluate the effect of oral eleclazine on mean daytime QTcF interval after 24 weeks of treatment with elecalzine in participants with long QT syndrome Type 3. During the single-blind treatment period (24 weeks), participants will receive eleclazine and/or eleclazine placebo. Following the single-blind treatment period, participants who have not permanently discontinued study drug will be eligible, at the discretion of the investigator, to continue receiving eleclazine during an open-label extension (OLE) phase.

开始日期2014-12-17

申办/合作机构

Gilead Sciences, Inc.

NCT01728025 / Unknown status临床2期IIT

Long Term Prophylactic Therapy of Congenital Long QT Syndrome Type III (LQT3) With Ranolazine

The purpose of this study is to determine whether ranolazine will reduce the risk of arrhythmic events in patients with long QT syndrome type 3.

开始日期2012-10-01

申办/合作机构

Tel Aviv Sourasky Medical Center

100 项与 3型QT间期延长综合征相关的临床结果

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100 项与 3型QT间期延长综合征相关的转化医学

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0 项与 3型QT间期延长综合征相关的专利（医药）

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216

项与 3型QT间期延长综合征相关的文献（医药）

2024-10-15·Journal of the American Heart Association

Defining Cardiomyocyte Repolarization Response to Pharmacotherapy in Long‐QT Syndrome Type 3

Article

作者: O'Brien, Timothy ; Galvin, Joseph ; McInerney, Veronica ; Ge, Ning ; Prendiville, Terence W. ; McGorrian, Catherine ; Li, Rui ; Xia, Wenxin ; O'Brien, Stephen T. ; Liu, Min ; Shen, Sanbing ; Ward, Deirdre

BackgroundLong‐QT syndrome is a primary cardiac ion channelopathy predisposing a patient to ventricular arrhythmia through delayed repolarization on the resting ECG. We aimed to establish a patient‐specific, human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes model of long‐QT syndrome type 3 (LQT3) using clustered regularly interspaced palindromic repeats (CRISPR/Cas9), for disease modeling and drug challenge.Methods and Results HiPSCs were generated from a patient with LQT3 harboring an SCN5A pathogenic variant (c.1231G>A; p.Val411Met), and an unrelated healthy control. The same SCN5A pathogenic variant was engineered into the background healthy control hiPSCs via CRISPR/Cas9 gene editing to generate a second disease model of LQT3 for comparison with an isogenic control. All 3 hiPSC lines were differentiated into cardiomyocytes. Both the patient‐derived LQT3 ( SCN5A+/− ) and genetically engineered LQT3 ( SCN5A+/− ) hiPSC‐derived cardiomyocytes showed significantly prolonged cardiomyocyte repolarization compared with the healthy control. Mexiletine, a cardiac voltage‐gated sodium channel (Na V 1.5) blocker, shortened repolarization in both patient‐derived LQT3 and genetically engineered LQT3 hiPSC‐derived cardiomyocytes, but had no effect in the control. Notably, calcium channel blockers nifedipine and verapamil showed a dose‐dependent shortening of repolarization, rescuing the phenotype. Additionally, therapeutic drugs known to prolong the corrected QT in humans (ondansetron, clarithromycin, and sotalol) demonstrated this effect in vitro, but the LQT3 clones were not more disproportionately affected compared with the control. ConclusionsWe demonstrated that patient‐derived and genetically engineered LQT3 hiPSC‐derived cardiomyocytes faithfully recapitulate pathologic characteristics of LQT3. The clinical significance of such an in vitro model is in the exploration of novel therapeutic strategies, stratifying drug adverse reaction risk and potentially facilitating a more targeted, patient‐specific approach in high‐risk patients with LQT3.

2024-08-13·Circulation

Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes, Transgenic Rabbits, and Patients

Article

作者: Giovenzana, Fulvio L F ; Bos, J Martijn ; Odening, Katja E ; Giannetti, Federica ; Schwartz, Peter J. ; Conte, Giulio ; Sala, Luca ; Bos, J. Martijn ; Gnecchi, Massimiliano ; Cerea, Paolo ; Schwartz, Peter J ; Musu, Giulia ; Ackerman, Michael J. ; Dagradi, Federica ; Barbieri, Miriam ; Ackerman, Michael J ; Auricchio, Angelo ; Crotti, Lia ; Odening, Katja E. ; Torchio, Margherita ; Neves, Raquel ; Mura, Manuela

BACKGROUND:Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel–mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2.METHODS: Heart rate–corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD 90 ) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model. RESULTS: After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate–corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD 90 by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test ( r = −0.8; P <0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07–0.14) to 0.04 (95% CI, 0.02–0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16–0.84), reflecting a 60% reduction in the event rate ( P =0.01). CONCLUSIONS:Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.

2024-08-01·HeartRhythm Case Reports

Inappropriate ventricular pacing–induced ventricular fibrillation in a long QT type 3 syndrome patient with implantable cardioverter-defibrillator

Article

作者: Ohara, Minako ; Ishihara, Yu ; Tani, Ryosuke ; Minamino, Tetsuo ; Noma, Takahisa ; Takeuchi, Masaki