Duke Team Overcomes Sodium Ion Channel Gene Therapy Challenge

Biomedical engineers at Duke University have successfully demonstrated a gene therapy that helps heart muscle cells electrically activate in live mice, and say the method could lead to therapies that treat a wide variety of electrical heart diseases and disorders.

The therapy works by delivering genes responsible for creating sodium channel proteins, which reside in the outer membranes of electrically excitable cells and transmit electrical charges into the cell.  In the heart, these channels tell muscle cells when to contract and pass the instruction along so that the organ pumps blood as a cohesive unit. Damaged heart cells, however, whether from disease or trauma, often lose all or part of their ability to transmit these signals.

By delivering the genes responsible for creating sodium channel proteins, gene therapy can produce more ion channels in the diseased cells to help boost their activity. However, sodium channel genes in mammals are too large to fit within the viruses currently used in human gene therapies.

To address this, Nenad Bursac, professor of biomedical engineering at Duke and his laboratory, turned to smaller genes that code for similar sodium ion channels in bacteria. While these bacterial genes are different than their human counterparts, evolution has conserved many similarities in the channel design since multi-cellular organisms diverged from bacteria hundreds of millions of years ago.

Several years ago, Hung Nguyen, a former doctoral student in Bursac’s laboratory who now works for Fujifilm Diosynth Biotechnologies, mutated these bacterial genes so that the channels they encode could become active in human cells. In the new work, current doctoral student Tianyu Wu further optimized the content of the genes and combined them with a “promoter” that exclusively restricts channel production to heart muscle cells.

The researchers then tested their approach by delivering a virus loaded with the bacterial gene into veins of a mouse to spread throughout the body.  Sodium ion channels were only formed in the working muscle cells of the heart within the atria and ventricles, Wu said. “We also found that they did not end up in the heart cells that originate the heartbeat, which we also wanted to avoid,” he added.

Previous research with this viral gene delivery approach suggests the transplanted genes should remain active for many years.

Tests on cells suggest that the treatment improves electrical excitability enough to prevent human abnormalities like arrhythmias. Within live mice, the results demonstrate that the sodium ion channels are active in the hearts, showing trends toward improved excitability. However, further tests are needed to measure how much of an improvement is made on the whole-heart level, and whether it is enough to rescue electrical function in damaged or diseased heart tissue to be used as a viable treatment.

The results appeared in a recent issue of Nature Communications.