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MGH Research Shows Gene Therapy May Be Able To Reverse Heart Failure

Date:
December 7, 1999
Source:
Massachusetts General Hospital
Summary:
Researchers from the Massachusetts General Hospital (MGH) have for the first time shown that gene therapy may be able to reverse heart failure, one of the major causes of death and disability in North America and Europe.

Researchers from the Massachusetts General Hospital (MGH) have for the first time shown that gene therapy may be able to reverse heart failure, one of the major causes of death and disability in North America and Europe. In their study appearing in the December 7 issue of Circulation, the team from the MGH Cardiovascular Research Center (CVRC), along with collaborators from Boston University Medical Center and Imperial College in London, report delivering additional copies of a gene called SERCA2a to muscle cells from failing human hearts. Cells that incorporated the gene and produced elevated levels of its protein began to function in a normal fashion, contracting more quickly and more powerfully.

"This ability to modify the contraction of failing human cardiac cells represents an important step toward gene therapy for heart failure," says Roger Hajjar, MD, of the MGH CVRC, who led the study. "And by confirming the role the SERCA2a protein plays in heart failure, we now have a molecular target for other therapeutic approaches."

In heart failure the heart muscle is weakened and cannot pump effectively, allowing fluids to back up in the circulatory system and sometime into the lungs. Heart failure is a growing health problem in the developed world, with more than 400,000 people being diagnosed in the U.S. each year. While deaths from coronary heart disease have decreased in recent years, heart failure deaths are on the rise - more than doubling from 1979 to 1995.

Current treatments - primarily medications such as ACE inhibitors and beta blockers - can slow the progression of heart failure but not stop the condition. The only current cure, for which most patients are ineligible, is a heart transplant. Almost half of those diagnosed with heart failure will not survive five years after their diagnosis. It has been known for 15 years that failing hearts do not handle calcium properly. The contraction of heart muscle cells - like all muscle cells - is controlled by cycling levels of calcium, which is stored in a cellular structure called the sarcoplasmic reticulum (SR). In response to the electrical impulses that control heartbeat, calcium is released from the SR into the main body of the cell (the cytosol), stimulating the cell to contract.

After contraction, calcium moves back from the cytosol into the SR via a molecular calcium pump, the SERCA2a protein. In heart failure, the return of calcium into the SR is diminished. With this disruption to the normal cycling of calcium, the muscle cells cannot respond appropriately to the heartbeat impulses. They contract weakly and the heart's pumping activity decreases. Previous research linked these abnormalities to decreased function of the SERCA2a calcium pump, but it was unclear whether protein levels actually were reduced in failing hearts. Animal studies also had shown that increasing production of SERCA2a improved heart function, both in individual cells and in living animals. But it was not yet clear that gene transfer techniques also would work in human heart cells.

In the current study, the researchers isolated muscle cells from 10 failed hearts that had been removed for transplantation. Using a standard virus vector employed in gene therapy studies, they delivered additional copies of the SERCA2a gene to these heart muscle cells. Within 24 hours of receiving the gene, which induced overproduction of the SERCA2a protein, the cells from failed heart began beating and contracting at levels very similar to those seen in cells from normal hearts. The cycling of calcium also appeared normal in cells incorporating the additional gene copies.

"These results in isolated cardiac cells need to be validated in the whole human heart, but we're optimistic that this goal will be accomplished," Hajjar says. He adds that, while current gene therapy trials for a variety of conditions have had disappointing results, new vector systems currently under development may be more successful in producing long-lasting results.

The study's co-authors are Federica Del Monte, MD, PhD, first author; Ulrich Schmidt, MD, PhD; Takashi Matsui, MD, PhD; Zhao Bin Kang, MD; William Dec, MD; and Anthony Rosenzweig, MD, of the MGH; Sian Harding, PhD, of Imperial College; and Judith Gwathmey, VMD, PhD, of Boston University Medical Center. The study was supported by grants from the National Institutes of Health, the Doris Duke Charitable Foundation and the British Heart Foundation.


Story Source:

The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.


Cite This Page:

Massachusetts General Hospital. "MGH Research Shows Gene Therapy May Be Able To Reverse Heart Failure." ScienceDaily. ScienceDaily, 7 December 1999. <www.sciencedaily.com/releases/1999/12/991207075101.htm>.
Massachusetts General Hospital. (1999, December 7). MGH Research Shows Gene Therapy May Be Able To Reverse Heart Failure. ScienceDaily. Retrieved September 30, 2014 from www.sciencedaily.com/releases/1999/12/991207075101.htm
Massachusetts General Hospital. "MGH Research Shows Gene Therapy May Be Able To Reverse Heart Failure." ScienceDaily. www.sciencedaily.com/releases/1999/12/991207075101.htm (accessed September 30, 2014).

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