Optogenetics-enabled assessment of viral gene and cell therapy for restoration of cardiac excitability

Abstract

Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias). In addition to electronic device therapy (i.e. implantable pacemakers and cardioverter/defibrillators), biological approaches have recently been explored to restore pacemaking ability and to correct conduction slowing in the heart by delivering excitatory ion channels or ion channel agonists. Using optogenetics as a tool to selectively interrogate only cells transduced to produce an exogenous excitatory ion current, we experimentally and computationally quantify the efficiency of such biological approaches in rescuing cardiac excitability as a function of the mode of application (viral gene delivery or cell delivery) and the geometry of the transduced region (focal or spatially-distributed). We demonstrate that for each configuration (delivery mode and spatial pattern), the optical energy needed to excite can be used to predict therapeutic efficiency of excitability restoration. Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation. More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations

“…As described previously (52), a leapfrogging approach was used to couple the monodomain partial differential equation with the system of ordinary differential equations that modeled cell-level phenomena. Our previous studies have described rigorous validation of this computational framework against experimental measurements (14,34,(54)(55)(56). All simulations were executed on 24 Intel Haswell CPUs (2.5 GHz) on the parallel computing resource at the Maryland Advanced Research Computing Center.…”

“…To simulate optogenetic transduction of the human ventricles via viral gene delivery, we used our previously validated computational modeling framework (13,14,57). Channelrhodopsin expression was modeled by incorporation of a photocycle model (15) in 58.2% of myocardial nodes (normal + PIZ) with a diffuse spatial pattern (Supplemental Figure 4).…”

“…Consistent with clinical observations, rapid electrical pacing from the ventricular apex in this model induced infarct-related, sustained VT (cycle length: ~350 ms; Supplemental Figure 3 and Supplemental Video 1), which was evident in the pseudo-ECG ( Figure 4A). Based on expression levels in our previous reports on AAV gene transfer (6), we simulated expression of ChR2 in 58.2% of the cardiomyocytes (Supplemental Figure 4) using an optogenetic modeling framework (13) validated by comparison with in vitro recordings from ChR2-expressing cardiomyocyte syncytia (14). The ChR2 tion rate in the absence of illumination in transgenic ChR2 hearts ( Figure 1C, black).…”

Optogenetics Design of Mechanistically-Based Stimulation Patterns for Cardiac Defibrillation

“…Additionally, the two orthogonal AODs give us the freedom to rapidly move the laser to design any desired ChR2 stimulation pattern. Our optical toolkit establishes an innovative approach that overcomes limitations present in previous studies 23,24 . Nussinovitch and Gepstein 8 employed optogenetics for cardiac pacing and resynchronization, simultaneously monitoring action potential propagation in whole mouse hearts.…”

Transfer of optogenetic vectors into the brain of neonatal animals to study neuron functions during subsequent periods of development

“…Это свойство фотоканалов привлекает к ним внимание даже в качестве потенциальных регуляторов сердечной деятельности при экспрессии в кардиомиоцитах (Ambrosi et al, 2015).…”