Israeli researchers have modulated cardiac pacing in vivo using optogenetics using an AAV vector loaded with a light-sensitive protein transgene injected directly into myocardium.
The light-sensitive nonselective cation channel, ChR2, was used to modulate cell excitability. The team used intramyocardial delivery of the ChR2 transgene and monochromatic blue-light illumination to pace the rat heart (a biological pacemaker approach) and to synchronize ventricular contraction (a biological CRT approach). The AAV9 vector was used owing to its efficiency in transducing myocytes. The works builds on prior application of the technique using cultured cardiomyocytes in animal models and computer simulations.
Blue light illumination, both in vivo and in isolated perfused hearts, allowed optogenetic pacing of the heart at different beating frequencies. The authors determined that the source of the new pacemaker activity was indeed the site of ChR2 transgene delivery through optical mapping. Interestingly, diffuse illumination of the hearts through delivery of the transgene to many ventricular sites resulted in electrical synchronization.
“Our work is the first to suggest a non-electrical approach to cardiac resynchronization therapy,” said author Lior Gepstein, Professor of Physiology and Medicine (Cardiology) at the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology (Haifa, Israel) and head of the Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine.
“Before this, there have been a number of elegant gene therapy and cell therapy approaches for generating biological pacemakers that can pace the heart from a single spot. However, it was impossible to use such approaches to activate the heart simultaneously from a number of sites for resynchronization therapy.”
The authors admit that there are many hurdles to overcome on the road to clinical translation. These include ensuring long-term expression of the transgene, determining the optimal size of the transduced area and creating a device capable of transmitting focussed illumination to initiate pacemaker cells. The technique could be further optimised by substituting the constitutive promoter (CAG) with a cardiac-specific one to restrict transgene expression to cardiomyocytes. In addition optogenetic suppression of heart excitability, rather than excitation, may also be clinically promising.
Source: Nussinovitch U, Gepstein L. Optogenetics for in vivo cardiac pacing and resynchronization therapies. Nature Biotechnology, doi:10.1038/nbt.3268