Inhibiting cardiac protein through
gene therapy improves human heart cell function
BOSTON February 25, 2002 Blocking a key protein
involved in calcium regulation can improve the function of failing
heart cells, according to a study in the February 26 issue of Circulation.
The work holds promise for treating congestive heart failure. "We
set out to inhibit a protein that blocks normal calcium flow in
the heart," says principal investigator Roger Hajjar, MD, of
the Cardiovascular Research Center (CVRC) and Heart Failure Center
at Massachusetts General Hospital (MGH). "Usually with gene
therapy, you add things, but here the strategy was to take something
Hajjar says heart failure in the aging is due to abnormal calcium
levels in heart muscle cells. The current study focuses on phospholamban,
a protein that regulates the activity of a molecular pump that controls
calcium flow within cells and may be reduced in failing hearts.
By blocking normal calcium regulation in heart cells, the natural
inhibitory actions of phospholamban in a failing heart may prevent
the cardiac muscle from relaxing and the heart from filling with
blood appropriately. "When we targeted phospholamban, we were
able to diminish it, and then calcium movement in the cells became
normal," says Hajjar.
For the study, first author Frederica del Monte, MD, PhD, took
cells from the hearts of nine end-stage patients who were about
to undergo heart transplantations, with a goal of seeing if they
could improve contraction and relaxation in these diseased cells
using a gene therapy approach called antisense strategy. By injecting
into cultured cells single-strand DNA that binds to the RNA message
encoded by the phospholamban gene, the researchers were able to
prevent the formation of the phospholamban protein. "When we
knocked down the amount of protein that was formed, the heart cell
contractions became normal," says Hajjar.
Ultimately, del Monte and Hajjar hope the treatment strategy can
be used to correct heart failure and cut down on the need for heart
transplants. "Over the past year, five patients at MGH alone
have died while waiting for cardiac transplants," says Hajjar.
"And for every cardiac transplant that is performed, there
are so many patients on the waiting lists that die." He notes
that many patients cannot even get on the waiting lists. Currently,
preclinical trials are underway to test Hajjar's antisense strategy
in live animals.
Other co-authors of the report are G. William Dec, MD, of the MGH;
Sian E. Harding, PhD, of the National (British) Heart and Lung Institute
and Imperial College, London; and Judith K. Gwathmey, VMD, PhD of
Harvard Medical School. The study was supported by grants from the
National Institutes of Health, the British Heart Foundation, and
the Doris Duke Charitable Foundation.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $300 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, transplantation biology and photomedicine.
In 1994, the MGH joined with Brigham and Women's Hospital to form
Partners HealthCare System, an integrated health care delivery system
comprising the two academic medical centers, specialty and community
hospitals, a network of physician groups and nonacute and home health
Media Contact: Sue
McGreevey , MGH Public Affairs
Physician Referral Service: 1-800-388-4644
about Clinical Trials