Key result
Cav1.3-C-terminus gene therapy normalized Cav1.3 expression, restored calcium currents and conduction velocity, and prevented arrhythmia susceptibility in patient-derived hiPSC-CMs.
Why the study?
To investigate whether Cav1.3-C-terminus could reverse arrhythmic events associated with a de novo CACNA1D variant identified in a pediatric patient with ventricular tachycardia and conduction abnormalities.
Does Cav1.3-C-terminus gene therapy restore normal electrophysiological properties in hiPSC-CMs harboring a loss-of-function CACNA1D variant?
Does Cav1.3-C-terminus gene therapy restore normal electrophysiological properties in hiPSC-CMs harboring a loss-of-function CACNA1D variant?
Cav1.3-C-terminus gene therapy can rescue electrophysiological defects and prevent arrhythmias in patient-derived cardiomyocytes with a loss-of-function CACNA1D variant.
Hypothesis-generating for CACNA1D arrhythmia therapy in patient-derived cells; leaves open clinical translation pending in vivo validation.
Inherited arrhythmia syndromes are caused by genetic variants that alter cardiac ion channel function. We investigated a complex presentation in a pediatric patient with ventricular tachycardia and conduction abnormalities, harboring a de novo CACNA1D (c.3786G>T) variant, and two inherited variants, the SCN5A (c.2618C>G), and a DSP desmosome (c.1582C>G). The CACNA1D variant, which encodes Cav1.3 L-type calcium channel is the focus of this study, because the C-terminus fragment of Cav1.3 has recently been identified as a transcription auto-enhancer of its own gene and able to prevent arrhythmic events in a mouse model of ischemic heart failure. Leveraging this intrinsic property, we hypothesized that the Cav1.3-C-terminus could reverse the arrhythmic events associated with the CACNA1D variant. Patch-clamp and optical mapping experiments demonstrated a loss of Cav1.3 function, characterized by reduced L-type calcium current densities, and decrease of conduction velocity, leading to inducible re-entrant arrhythmias in human induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs). RNA sequencing confirmed this loss-of-function via the downregulation CACNA1D gene expression. Interestingly, Cav1.3-C-terminus treatment of hiPSC-CMs successfully normalized Cav1.3 gene expression, restored calcium currents, and conduction velocity, and prevented the susceptibility to arrhythmias. These findings highlight the electrophysiological consequences resulting from a de novo Cav1.3 variant and demonstrate an important transcriptional role of Cav1.3-C-terminus as a transcriptional regulator and as a promising therapeutic tool to restore normal electrical properties in patients with calcium channels loss of function.
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Reisqs et al. (2025) studied Inherited arrhythmia syndrome (ventricular tachycardia and conduction abnormalities) (n=1). AAV6-Cav1.3-C-terminus gene therapy vs. Untreated hiPSC-CMs was evaluated on Cav1.3 gene expression, calcium currents, conduction velocity, and susceptibility to arrhythmias. Cav1.3-C-terminus gene therapy normalized Cav1.3 expression, restored calcium currents and conduction velocity, and prevented arrhythmia susceptibility in patient-derived hiPSC-CMs.
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