Gene Therapy for Heart Arrhythmias
February 8, 2022
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One possible treatment option for cardiac arrhythmias are approaches that enhance electrical excitability and action potential conduction in the heart. One way this could be done is by stably overexpressing mammalian voltage-gated sodium channels. However, the channels’ large size precludes delivery via viral vectors. Now, researchers have demonstrated a gene therapy that helps heart muscle cells electrically activate in live mice. The first demonstration of its kind, the approach features engineered bacterial genes that code for sodium ion channels and could lead to therapies to treat a wide variety of electrical heart diseases and disorders.
This detailed image of a single mouse heart muscle cell shows its cell membrane expressing the new sodium ion channel genes (magenta) after researchers delivered the therapy through an injection into the mouse veins
“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,” said Nenad Bursac, PhD, professor of biomedical engineering at Duke University. “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.”
The platform“utilizes small-size, codon-optimized engineered prokaryotic sodium channels (BacNav) driven by muscle-specific promoters that significantly enhance excitability and conduction in rat and human cardiomyocytes in vitro and adult cardiac tissues from multiple species in silico.”
Several years ago, members of the lab mutated bacterial genes so that the channels they encode could become active in human cells. In this new work, Tianyu Wu, doctoral student, further optimized the content of the genes and combined them with a promoter that exclusively restricts channel production to heart muscle cells.
“We worked to find where the sodium ion channels were actually formed, and, as we hoped, we found that they only went into 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.”
As a proof of concept, tests on cells suggested that the treatment improves electrical excitability enough to prevent human abnormalities like arrhythmias. More specifically, the work showed that “the expression of BacNav significantly reduces occurrence of conduction block and reentrant arrhythmias in fibrotic cardiac cultures.”
The work is published in Nature Communications, in the paper, “Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy.”
Source: https://pratt.duke.edu/
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Categories: Uncategorized
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Tags: arrhythmias, BacNav, cardiac arrhythmias, conduction, Duke University, electrical excitability, engineered bacterial genes, gene therapy, heart, sodium, sodium ion channels
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