YSM Issue 86.3

GENE THERAPY
FEATURE
For the three million Americans who experience heartbeat irregularities,
expensive and bulky pacemakers may soon become a thing of
the past. In a December 2012 study led by Dr. Nidhi Kapoor at the
Cedars-Sinai Heart Institute, researchers found a way to use geneticallymodified
viruses to turn normal heart cells into specialized pacemaker
cells. With further development, this breakthrough could one day serve
as a simple, effective alternative to the implanted electronic devices that
patients rely on today.
This newly-developed technology is based on the heart’s natural
pacemaker, a specialized region called the sinoatrial node (SAN). The
SAN sends an electrical signal throughout the cardiac muscle to
stimulate contractions — or, heartbeats. While an
adult heart contains over ten billion cells, only
ten thousand of them are in the SAN.
If this small but critical population
of cells stops functioning properly,
the entire heart can fail
to beat.
Currently, patients with
irregular heartbeats are
treated using electronic
pacemakers, which
are implanted in the
upper chest and are
connected to the
heart using electrode
sensors. By detecting
the electrical
activity in the heart
and sending out electric
signals when necessary,
these devices mimic
the activity of natural
pacemaker cells. However,
the risks of infection and
tissue damage from the surgical
implantation, as well as the high cost
of the device, make a biological alternative
to the pacemaker very attractive.
Using a Virus to Jumpstart the Heart
Thanks to viral gene therapy, such an alternative
may now be feasible. Viral gene therapy involves
harnessing a virus’s natural ability to infect cells with
its own DNA; with some modification, the virus can
be used to “infect” cells with therapeutic genes instead. In Kapoor’s
study on pacemaker cells, scientists took advantage of this technology
to create new pacemaker cells by using a virus to deliver a critical gene,
Tbx18. According to Dr. Omar Samad, a Yale neuroscientist who studies
applications of viral gene therapy for neuropathic pain, the method was
particularly effective because “viral gene therapy works for well-defined
conditions that could be corrected by a specific gene, in this case Tbx18.”
In addition, the approach “would have fewer side effects because it
is specific to a particular gene, can be delivered to specific areas, and
perhaps most importantly, is long-lasting,” Samad said.
The protein that Tbx18 encodes is known to play a role in the differentiation
of SAN pacemaker cells by binding to DNA at certain sites
and promoting the production of other critical proteins that regulate
SAN development. Thus, it is essential for the proper growth and differentiation
of SAN cells. By using a virus to express Tbx18 in normal
heart cells, called myocytes, the researchers hoped to trigger the production
of proteins which would turn the myocytes into pacemaker cells.
The results of initial experiments testing this hypothesis were highly
promising. When the genetically-modified virus was added to a culture
of myocytes, the team found that about ten percent of the cells started
sending electrical signals just like those of actual SAN cells. Additionally,
the cells began to closely resemble pacemaker cells, taking on
their long, spindle-shaped form. The transformed
myocytes even developed new modifications
in their DNA that affected the expression
of SAN cell-related genes.
After successfully transforming
normal myocytes into
pacemaker cells, researchers
began tackling a larger
question: would the same
technique be effective
in living organisms?
To this end, the
researchers injected
the virus directly into
the hearts of live
guinea pigs. Then,
after two to four
days, they suppressed
the natural heartbeat
and found that the new,
transformed pacemaker
cells were able to compensate
and keep the heart
beating. This discovery shows
that the viral gene therapy method
was able to induce SAN cells in vivo,
representing a major step towards a new
treatment for use in humans.
For Kapoor and his colleagues, the prospect
of using the technology in human
patients is a hopeful one. In addition to
testing the long-term viability of the induced
pacemaker cells, the group plans to experiment with large-animal models
before eventually moving to human clinical trials. During this process the
safety of the virus vector will remain a central issue. “Any therapy that
interferes with the genome could have permanent effects,” says Samad.
“We need more studies to know that in the long run gene therapy does
not cause unwanted genetic alterations leading to cancer.”
Nonetheless, Samad considers the development very promising,
noting that clinical trials involving other viral gene therapies have already
been conducted. If further concerns about safety and long-term viability
are addressed, the viral therapy could become a highly effective treatment
for patients who need pacemakers.
IMAGE COURTESY OF THE UNIVERISTY OF COLORADO DENVER
Electronic pacemakers are currently the
main treatment for irregular heartbeats.
BY GRACE CAO
www.yalescientific.org
April 2013 | Yale Scientific Magazine 35