Researchers at Boston Children’s Hospital may have developed a gene therapy treatment for cardiac patients with irregular heartbeats.

Gene therapies are generally developed for the treatment of diseases caused by genetic defects. Researchers at Boston Children’s Hospital might be changing that narrative –– at least for the gene therapy they are developing to treat an inherited form of heart arrhythmia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal form of arrhythmia triggered by exercise or sudden emotional stress. Approximately 50% of patients with CPVT have mutations in the RYR2 gene, which is involved in releasing calcium, a chemical key to initiating contraction of the heart muscle. Current treatments for the inherited disease, which causes irregular heartbeats, include beta-blockers and surgery, but neither is sufficient.

To develop a more effective therapy, the scientists first constructed a human tissue model of CPVT using blood cells from two patients who had RYR2-associated CPVT. These were reprogrammed into pluripotent stem cells from which the diseases heart tissue models were grown. When contractions were induced in the diseased models, calcium waves were observed to move inconsistently, leading to arrhythmias. The enzyme CaM kinase (CaMKII) was found to modify the RYR2 gene and cause the release of calcium. Modification of the genes with mutations led to excessive calcium release.

In their model of the disease, arrhythmias were eliminated by blocking CaMKII modification on RYR2 or simply suppressing CaMKII with the peptide inhibitor AIP.

The next step was to tackle the disease in animal models. Blocking the CaMKII enzyme was not possible because it is involved in the activity of many other tissues. So the researchers looked to “fix” the effects of mutated RYR2 gene by delivering an AIP-expressing viral vector directly to the heart. In a mouse model of CPVT, the therapy affected half of the heart cells, which was sufficient to suppress arrhythmias, and importantly did not accumulate in non-heart tissues.

Now the researchers are attempting to refine the therapy and demonstrate its effectiveness in larger animal models before moving into clinical trials. They ultimately hope that it will not only be effective for the treatment of RYR2-mutated CPVT, but for other common heart diseases. The reason: in many mouse models of various forms of heart diseases, chronic CaMKII activation has been shown to be detrimental. Therefore, because the gene therapy approach being developed at Boston Children’s Hospital involves inhibiting CaMKII, it could also potentially be a useful treatment for other, nongenetic types of heart disease.