Could gene therapy prevent heart attacks?
Researchers from the University of Utah Health (UT, USA) have utilized gene therapy to correct arrhythmias in mice. This has significant implications for treating arrhythmogenic cardiomyopathy – a heart condition that is one of the principal causes of sudden cardiac arrest in athletes under 35.
Patients with arrhythmogenic cardiomyopathy begin to experience symptoms in their 20s or 30s. Until this age, they have normal heart function, which later develops into an irregular heart rhythm (arrhythmia). These arrhythmias can be dangerous as they can cause the heart rate to skyrocket during exercise, potentially leading to heart attacks.
The current advice for those with arrhythmogenic cardiomyopathy is to restrict exercise. Patients may also be fitted with a defibrillator, which is intended to correct their heart rhythm. However, over time the condition typically causes the heart muscle to become fatty and fibrotic (the tissue becomes thicker and scarred). Eventually, patients will require a heart transplant as the heart cannot pump blood around the body efficiently.
Previous studies from the team at the University of Utah Health have suggested that the protein Connexin 43 may be responsible for arrhythmogenic cardiomyopathy. It is involved in cell-cell communication in heart tissue by forming channels between cells.
However, the team subsequently showed that it wasn’t a lack of Connexin 43 causing issues in the diseased cardiac tissue. In fact, there was enough of the communicating protein, it was just located in the wrong areas of the tissue. Connexin 43 needs to be located at the edges of cells in order to be effective and form the channels necessary to facilitate communication.
From these observations, the researchers proposed that reduced levels of a trafficking protein, GJA1-20ka, were responsible for this issue. Without this protein, Connexin 43 cannot be transported to the correct location.
In a recent issue of the journal Circulation Research, the team published their findings investigating GJA1-20ka levels in mice and the implications on heart function. The researchers used mice with low levels of GJA1-20ka, which reflected patients with arrhythmogenic cardiomyopathy.
The researchers administered low doses of gene therapy to the mice with low levels of GJA1-20ka to increase levels of the trafficking protein to normal. The team observed that this led to the relocation of Connexin 43 to the edges of the heart cells and the return of normal heart rhythm in the mouse models.
Robin Shaw, head researcher of this project, had this to say about the impact of these findings: “The ease and low dose needed to fix the arrhythmias of even an inherited heart disease suggests that we have identified a critical pathway to stabilize cardiac electrical activity”.
It was, however, observed that the gene therapy did nothing to amend the scarring to the heart muscle. The team believes this indicates that these two phenomena have different underlying causes and, therefore, must be treated differently.
Despite this, the results from this paper are still a major leap forward in the treatment of heart conditions. Joseph Palatinus, first author of the paper, believes this gene therapy could significantly impact future treatments, suggesting GJA1-20ka could potentially be delivered directly to the heart in the future.
It is also thought that this gene therapy could be applied to other cardiac conditions that manifest as arrhythmias, in the future. This would provide an alternative to current treatment programs, such as ion-channel blockers, which can cause new and different rhythm issues for patients.