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Updated: Aug 26, 2025
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
QTc interval and ventricular action potential prolongation in the Mecp2Null/+ murine model of Rett syndrome
Hongwei Cheng1, Ian Charles1, Andrew F James1
1School of Physiology, Pharmacology and Neuroscience, University Walk, Bristol, UK.
Insights
Rett Syndrome (RTT) in female mice shows prolonged QT intervals and delayed ventricular repolarization. The investigational drug GS-6615 reduced these effects, suggesting potential for treating RTT-related cardiac issues.
Area of Science:
- Cardiology
- Neuroscience
- Genetics
Background:
- Rett Syndrome (RTT) is a genetic disorder linked to MECP2 gene mutations, causing developmental issues and potential cardiac abnormalities like QT prolongation.
- While QT prolongation is noted in RTT patients and mouse models, ventricular action potential characteristics in female RTT mice remain understudied.
Purpose of the Study:
- To investigate the electrocardiogram (ECG) and ventricular action potential (AP) characteristics in female Mecp2Null/+ mice, a model for Rett Syndrome.
- To assess the impact of the investigational INa,Late inhibitor, GS-6615, on these cardiac parameters.
Main Methods:
- ECG recordings were performed on 12-13-month-old female Mecp2Null/+ mice and wild-type (WT) controls.
- Ventricular action potentials were analyzed from isolated myocytes.
- The effects of GS-6615 (eleclazine) on APD90 and AP triangulation were evaluated.
Main Results:
- Female Mecp2Null/+ mice exhibited significantly prolonged rate-corrected QT (QTc) intervals compared to WT controls.
- Mecp2Null/+ myocytes displayed longer APD90 and increased AP triangulation, indicating delayed ventricular repolarization.
- GS-6615 effectively reduced both APD90 and AP triangulation in both Mecp2Null/+ and WT myocytes.
Conclusions:
- This study provides the first direct evidence of delayed ventricular repolarization in female Mecp2Null/+ mice.
- The findings suggest that GS-6615 may hold therapeutic potential for managing QT prolongation and associated cardiac risks in Rett Syndrome.
Abstract:
Rett Syndrome (RTT) is a congenital, X-chromosome-linked developmental disorder characterized by developmental delay, dysautonomia, and breathing irregularities. RTT is also associated with sudden death and QT intervals are prolonged in some RTT patients. Most individuals with RTT have mutations in the MECP2 gene. Whilst there is some evidence for QT prolongation in mouse models of RTT, there is comparatively little information on how loss of Mecp2 function affects ventricular action potentials (APs) and, to-date, none on ventricular APs from female RTT mice. Accordingly, the present study was conducted to determine ECG and ventricular AP characteristics of Mecp2Null/+ female mice. ECG recordings from 12-13 month old female Mecp2Null/+ mice showed prolonged rate corrected QT (QTc) intervals compared to wild-type (WT) controls. Although Mecp2Null/+ animals exhibited longer periods of apnoea than did controls, no correlation between apnoea length and QTc interval was observed. Action potentials (APs) from Mecp2Null/+ myocytes had longer APD90 values than those from WT myocytes and showed augmented triangulation. Application of the investigational INa,Late inhibitor GS-6615 (eleclazine; 10 μM) reduced both APD90 and AP triangulation in Mecp2Null/+ and WT myocytes. These results constitute the first direct demonstration of delayed repolarization in Mecp2Null/+ myocytes and provide further evidence that GS-6615 may have potential as an intervention against QT prolongation in RTT.
