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Researchers Develop Gene Therapy
To Successfully Halt Heart Failure in Animals
at the University of California, San Diego (UCSD) School of Medicine have
developed a therapeutic gene and molecular delivery system that provides
successful long-term gene therapy that halts chronic heart failure in
A major disease that
affects more than 4.5 million Americans, heart failure occurs when the
heart loses its ability to pump enough blood through the body. Currently,
there is no cure for chronic heart failure other than transplantation
or mechanical pump devices including new types of artificial hearts.
In a study published
online July 22, 2002 by the journal Nature Medicine, the UCSD researchers
describe their modification of a gene called phospholamban (PLN), which
regulates the strength of each heartbeat and is known to malfunction in
heart failure. With this therapy and development of a long-lasting,
highly effective method to deliver the gene directly to heart muscle,
the researchers significantly improved heart contraction and relaxation
in the animals, ultimately halting deterioration of cardiac function and
preventing heart failure.
The therapeutic strategy
published in Nature Medicine was successful in hamsters with a
naturally occurring genetic mutation that causes them to develop progressive
heart failure similar to that in humans. Currently, the research
team is testing the therapy in pigs, a larger animal model with heart
physiology similar to humans, and they hope to expand the study to human
clinical trials in 12-18 months. The gene would be delivered by special
catheters and would be performed in a normal hospital setting.
to right, Drs. Kenneth Chien and Masahiko Hoshijima.
Chien, M.D., Ph.D., professor of medicine, director of the UCSD Institute
of Molecular Medicine and senior author of the Nature Medicine
article, noted that like cancer, heart failure has many causes.
Included are such conditions as underlying coronary disease, genetic abnormalities,
high blood pressure, irregular heartbeat, and complications of diabetes.
As a result, researchers have had difficulty zeroing in on one cause or
condition as a target for heart failure prevention.
In recent years,
the Chien team has linked heart failure and specifically, defects in the
heart's pumping action, to PLN, which is a calcium-cycling regulator gene
whose normal function is to regulate the movement of calcium within heart
muscle cells. It does so by acting as a brake on the calcium pump,
which is responsible for increasing calcium into storage sites so that
it can be released with each heartbeat. Hormones that increase heart
rate and function, such as adrenaline, release the brake.
This balance between accelerator and brake is disrupted in heart failure.
In that setting, because of injury such as a heart attack or genetic defect,
the PLN brake becomes defective. It is on too hard, restricting
calcium and weakening heart function.
M.D., Ph.D., first author of the Nature Medicine paper and a lead
project scientist in Chien's lab, explained that the research team attacked
the problem by replacing one amino acid within PLN for another to form
a mutant version of the gene that would inhibit its normal counterpart.
"In essence, we inhibited the inhibitor," he said. "The
PLN mutation was able to replace the defective PLN gene, generate normal
cardiac contraction and prevent heart failure."
In experiments with 30 hamsters that received the mutant PLN gene, compared
to 28 that did not, researchers noted a dramatic improvement in the heart's
ability to pump blood. The progressive impairment of cardiac contraction
was stopped as early as the 5-week point. The hamsters that did
not receive the gene therapy developed heart failure comparable to late
stage human heart failure.
In addition, the thickness of the heart wall increased in hamsters that
received the mutant PLN gene, which reflects a protection of myocardial
cells and reduction in the progressive thinning of the ventricular wall
that accompanies heart failure. Another indicator of increased heart
function was measurement of calcium uptake in the animals that received
the PLN mutation. Their calcium activity was enhanced more than
In addition to developing a gene that would prevent the progression of
heart failure, the team needed an effective molecular method, called a
vector, to deliver the gene through the coronary arteries, directly to
the heart. Vectors used to transfer genes within the body are inactivated
The UCSD team first
used an inactivated adenovirus to serve as the vector, but it was not
an ideal choice. More commonly known as the cold virus, adenovirus
has a relatively short life within the human body. Within 7 days,
the body's immune system killed the virus and eliminated its cargo, the
mutant PLN gene.
The UCSD authors noted in their paper that "clearly, for gene therapy
to become a feasible therapeutic strategy for chronic cardiac muscle diseases,
it will be necessary to express the target gene for many months..."
right, Drs. Yusuhiro Ikeda and John Ross, Jr.
achieve this goal, John Ross, Jr., M.D., UCSD professor of medicine and
Yasuhiro Ikeda, M.D., Ph.D., the co-first author of the paper, developed
a high efficiency gene delivery method, which was then successfully used
an adeno-associated viral vector (AAV), a different viral agent than its
"AAV has few immunostimulatory effects, it became stabilized within
the heart muscle cell nucleus and was effective for a much longer period
of time than adenovirus," Ross said.
With AAV, there was no cardiac inflammation, indicating that the immune
system did not eliminate the gene. For 7 months, the length of the
experiment, the progression of heart failure was halted in hamsters that
received the mutant PLN gene. The researchers also found that
AAV had a high affinity for heart muscle and was attracted to it, rather
than diffusing in other tissue within the body. Over 60 percent
of the ventricular muscle expressed the transferred gene.
Current experiments by the Chien team will determine how long the mutant
PLN gene will continue to be effective within the body. In addition,
the investigators are studying the safety of mutant PLN when it's used
with beta-blockers, medications frequently taken by heart patients.
important additional area of development for the new gene therapy is an
efficient, catheter-based system that can be used in humans to infuse
the AAV vector and its mutant-PLN cargo. Current tests in pigs are
investigating potential catheter-based systems.
In addition to Hoshijima, Ikeda, Ross and Chien, additional authors of
the Nature Medicine paper are Yoshitaka Iwanaga, M.D., Ph.D., Susumu
Minamisawa, M.D., Ph.D., Moto-o Date, M.D., Ph.D., Yusu Gu, M.D., and
Mitsuo Iwatate, M.D., Ph.D., UCSD Department of Medicine; Manxiang Li,
Ph.D., University of Maryland, Baltimore; and Yibin Wang, Ph.D., and James
M. Wilson, Institute for Human Gene Therapy, University of Pennsylvania.
The research was funded by the Jean Leducq Foundation.