First approach to promote electrical excitation of heart cells in live
mammals could lead to new gene therapy treatments for a wide range of heart diseases

Date:
February 4, 2022
Source:
Duke University
Summary:
Biomedical engineers have demonstrated a gene therapy that
helps heart muscle cells electrically activate in live mice. 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.



FULL STORY ========================================================================== Biomedical engineers at Duke University 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.


==========================================================================
The results appeared online February 2 in the journal Nature
Communications.

"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, professor of biomedical engineering
at Duke. "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." Sodium-ion channels are proteins in the outer membranes
of electrically excitable cells, such as heart or brain cells, that
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 and join the effort.

One approach researchers can take to restoring this functionality is
gene therapy. By delivering the genes responsible for creating sodium
channel proteins, the technique can produce more ion channels in the
diseased cells to help boost their activity.

In mammals, sodium channel genes are unfortunately too large to fit
within the viruses currently used in modern gene therapies in humans. To
skirt this issue, Bursac and his laboratory instead 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.

"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." This gene therapy approach
only delivers extra genes within a cell; it does not attempt to cut out, replace or rewrite the existing DNA in any way. Scientists believe these
types of delivered genes make proteins while floating freely within the
cell, making use of the existing biochemical machinery. Previous research
with this viral gene delivery approach suggests the transplanted genes
should remain active for many years.

As a proof of concept, tests on cells in a laboratory setting 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.

Moving forward, the researchers have already identified different
bacterial sodium channel genes that work better in preliminary benchtop studies. The team is also working with the laboratories of Craig
Henriquez, professor of biomedical engineering at Duke, and Andrew
Landstrom, director of the Duke Pediatric Research Scholars Program,
to test the ability of these genes to restore heart functionality in
mouse models that mimic human heart diseases.

"I think this work is really exciting," Bursac said. "We have been
harnessing what nature made billions of years ago to help humans with modern-day disease." This work was supported by the National Institutes
of Health (HL134764, HL132389, HL126524, 1U01HL143336-01), the Duke
Translating Duke Health Initiative, and the American Heart Association Predoctoral Fellowship (829638).

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by Duke_University. Original written
by Ken Kingery. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hung X. Nguyen, Tianyu Wu, Daniel Needs, Hengtao Zhang, Robin
M. Perelli,
Sophia DeLuca, Rachel Yang, Michael Tian, Andrew P. Landstrom, Craig
Henriquez & Nenad Bursac. Engineered Bacterial Voltage-Gated Sodium
Channel Platform for Cardiac Gene Therapy,. Nature Communications,
2022 DOI: 10.1038/s41467-022-28251 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220204093113.htm

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