Heart rhythm problems occur when heart muscle cells fail to properly transmit electrical signals that coordinate blood pumping. Now, scientists at Duke University have devised a promising method to restore normal electrical conduction in the heart through a gene therapy.
The novel approach used an adeno-associated virus (AAV) to deliver engineered bacterial genes that code for sodium ion channels, which are responsible for transmitting electrical charges in cells. Tests in cell cultures and computer models suggested the therapy could improve electrical conduction in human heart tissues to prevent abnormal heartbeats. The results were published in Nature Communications.
Microorganism-derived gene therapies thus represent a possible way to excite heart tissues and potentially treat cardiac arrhythmias, the Duke team said. The diversity of bacterial sodium channels also provides a toolbox for scientists to eventually design an appropriate treatment for humans, the team said.
“We were able to improve how well heart muscle cells can initiate and spread electrical activity, which is hard to accomplish with drugs or other tools,” Nenad Bursac, Ph.D., the study’s senior author, said in a statement. “The method we used to deliver genes in heart muscle cells of mice has been previously shown to persist for a long time, which means it could effectively help hearts that struggle to beat as regularly as they should.”
Voltage-gated sodium ion channels on the surface of heart cells are essential for the instruction of the heart’s beats. Certain heart diseases may alter the protein channels or disrupt sodium current signal that runs through them, leading to irregular heartbeats. Expression of functional channels through gene therapies holds potential to remedy the problem, but genes for mammalian channels are too large to fit in existing AAV delivery vehicles.
Bacterial genes for similar sodium channels are much smaller for packaging in viral vectors. Some members of the Duke team had previously shown that these bacterial genes could be modified to express channels that could become electrically active in human cells.
This time, the researchers further perfected the engineered channel genes to explore their therapeutic potential. They optimized the genetic codes and combined them with a “promoter” that restricts channel production to heart muscle cells.
In lab dishes, the genes, delivered through AAV, stably expressed in human heart muscle cells without affecting the expression of other channel genes. The therapy led to higher conduction velocity and reduced the incidence of electrical wave breaks.
The team also established computational models to better understand the effects of the gene therapy on human heart tissues. In a stimulated diseased condition, expression of the modified ion channel rescued heart electrical activity back to healthy levels, the researchers found. In another model of a rare genetic heart rhythm disorder called Brugada syndrome, the therapy also normalized the heart’s electrical activity as displayed on an electrocardiogram.
As a proof of concept, the researchers tested the therapy in living mice. The approach didn’t adversely affect the healthy heart, with small signs of improved cell excitability. Mice aren’t the best animal model to evaluate the therapeutic efficacy, given their hearts are very different from a human's, the researchers noted.
The essential role ion channels play in maintaining heart rhythm has made them potential targets for developing treatments. Canadian biotech LQT Therapeutics recently raised $19 million to work on inhibitors of SGK1, which regulates a variety of ion transport proteins, to tackle heart arrhythmias.
The current study showed that a bacterial gene therapy approach could also be used for a variety of heart diseases caused by electrical conduction problems, the Duke researchers said. The team has also identified different bacterial sodium channel genes that seemed to work better in early tests.