Current state of the art for cardiac arrhythmia gene therapy

Abstract

Cardiac arrhythmias are a leading cause of morbidity and mortality. Currently available therapeutic options lack sufficient efficacy and safety. Gene therapy has been proposed for treatment of cardiac arrhythmias. This review will discuss the current state of development for arrhythmia gene therapy. So far, all published studies are short-term, proof-of-concept animal studies. Potential replacement of cardiac pacemakers has been shown for combination gene therapy using the HCN2 gene and either the gene for adenylate cyclase, the skeletal muscle isoform of the sodium channel, or a dominant negative mutant of the potassium channel responsible for resting membrane potential. Atrial fibrillation has been prevented by gene transfer of either a dominant negative mutant of a repolarizing potassium channel, a gap junction, or an siRNA directed against caspase 3. Inherited arrhythmia syndromes have been corrected by replacement of the causative genes. Post-infarct ventricular tachycardia has been reduced by gene therapy with the skeletal muscle sodium channel and connexins and eliminated with the dominant negative mutant of the potassium channel responsible for resting membrane potential. These ideas show considerable promise. Long-term efficacy and safety studies are required to see if they can become viable therapies.

Translational Models of Arrhythmia Mechanisms and Susceptibility: Success and Challenges of Modeling Human Disease

“…As with current clinical therapies for arrhythmias (ablation, antiarrhythmic drugs), translating interventions developed in large animals to long-term efficacy is highly challenging and must be considered. If an intervention is expected to induce reverse remodeling (as in biventricular pacing in HF), it can be expected to potentially mitigate long term arrhythmia substrates and triggers, but a one-time intervention (as with gene transfer interventions for specific reentrant arrhythmias) may only provide more short term improvements, particularly if underlying arrhythmia substrates continue to progress (133). Specific themes and examples of difficulties with translating findings in large animal models of arrhythmia and SCD are reviewed below:…”

“…The investigators demonstrated improved heart rate response to exercise, and although the duration of effect was only on the order of 2 weeks, they proposed this could represent a temporizing therapy for patient with lead infections requiring explanation, antibiotics and time prior to reimplantation (155). Although targeted gene delivery has potentially significant therapeutic potential, this has yet to be realized, and has significant limitations which need to be overcome (133).…”

Regulatory mechanism of calcium/calmodulin‑dependent protein kinase II in the occurrence and development of ventricular arrhythmia (Review)

“…A total of 17 million deaths occur per year, worldwide, as a result of cardiovascular disease, 50% of which are attributable to sudden cardiac death (SCD) (2). The major cause of SCD is VA, particularly ventricular tachycardia (VT) and VF, which account for ~85% of all SCD events (3,4).…”

“…In the presence of ATP, continuously increasing Ca 2+ /CaM sustainably combines with the intermediate regulatory region of CaMKII, which results in the autophosphorylation of Thr287. Thr287 autophosphorylation significantly increases the affinity of Ca 2+ /CaM to the intermediate regulatory region, slowing the release of Ca 2+ /CaM and retaining residual activity even after the dissociation of Ca 2+ /CaM, further resulting in CaMKII activation(3,16,24). A previous study by Erickson et al(25) showed that the methionine 281/282 (Met281/282) site is oxidized in the presence of reactive oxygen species (ROS).…”

“…A previous study by Erickson et al(25) showed that the methionine 281/282 (Met281/282) site is oxidized in the presence of reactive oxygen species (ROS). Oxidation of Met281/282 can not only lead to the autonomous activation of CaMKII by preventing the recombination of the catalytic domain and the intermediate regulatory region, but also promote CaMKII activation at low intracellular Ca 2+ concentrations by increasing the capability of CaMKII to be activated by Ca 2+ /CaM(3,18). In addition, O-linked glycosylation at serine 280 (Ser280) and nitric oxide (NO)-dependent nitrosation at cysteine 290 (Cys290) can activate CaMKII.…”