The Technology:
Current treatments for cardiac arrhythmias suffer from a fundamental limitation, a lack of spatial and temporal precision. Systemic anti-arrhythmic drugs often have limited efficacy and carry significant pro-arrhythmic and off-target risks, while cell and gene therapies lack a reliable mechanism to externally control the electrical behavior of treated cells once delivered.
This technology introduces a chemogenetic gene therapy approach that enables precise, reversible, and dose-dependent control of cardiac electrical activity. It is based on engineered chemogenetically gated ion channels that are genetically introduced into cardiac cells and activated by clinically approved small-molecule ligands at sub-therapeutic doses.
By combining a modified ligand-binding domain with a high-conductance ion channel, the system allows external pharmacological control over cellular excitability. Importantly, different ligand doses produce distinct functional outcomes, from increasing automaticity at low doses to silencing electrical activity at higher doses, enabling bidirectional modulation of cardiac rhythm.
The approach has been validated in human iPSC-derived cardiomyocytes, cardiac tissue models, and ex vivo heart systems, demonstrating localized control of electrophysiological behavior without affecting surrounding non-engineered tissue. This provides an unprecedented level of control for both native myocardium and transplanted therapeutic cells.
Advantages:
• Targeted and reversible control of cardiac electrical activity.
• Spatial precision: affects only genetically modified cells.
• Dose-dependent, bidirectional modulation (activation or silencing).
• Uses clinically approved small-molecule ligands, enabling external control.
• Addresses key safety limitations of current anti-arrhythmic drugs and cell therapies.
Applications and Opportunities:
• Treatment of cardiac arrhythmias, including tachyarrhythmias and bradyarrhythmias
• Biological pacemakers with externally adjustable activity
• Safety switch for cardiac cell therapy, enabling silencing of arrhythmogenic transplanted cells
• Gene therapy products for precision electrophysiological modulation
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