Featured Research

from universities, journals, and other organizations

Duke Scientist Reports Advances In Gene Therapy For Heart Failure

Date:
November 10, 1998
Source:
Duke University Medical Center
Summary:
Scientists are one step closer to making gene therapy for heart failure a reality, scientists from Duke University Medical Center report.

DALLAS -- Scientists are one step closer to making gene therapy for heart failure a reality, scientists from Duke University Medical Center reported Sunday.

Molecular biologist Walter J. Koch and his colleagues said in a report prepared for the 71st scientific sessions of the American Heart Association that they have for the first time delivered therapeutic genes throughout a rabbit's heart and have shown that the genes can increase heart function.

The animal experiments are a crucial step in developing a genetic treatment for congestive heart failure, a debilitating and deadly condition in which heart muscle loses its ability to stretch and contract, usually due to clogged arteries caused by coronary artery disease. People with congestive heart failure often experience fatigue, weakness, and an inability to carry out routine daily tasks. Right now, there is no effective means to reverse heart failure, only to treat symptoms.

According to the American Heart Association, about 400,000 new cases are recorded every year in the United States. Death rates from congestive heart failure tripled between 1974 and 1994, making it the leading cause of hospitalization among people 65 and older and costing more than $10 billion a year.

Koch, an associate professor of experimental surgery, and his colleagues have been working for several years to find ways to efficiently deliver genes to the heart to boost heart function.

Early experiments focused on identifying the molecular players that are responsible for efficient pumping action in the heart and showing which ones aren't doing their jobs in failing hearts. Using mouse models and sophisticated genetic techniques, the Duke scientists showed that two key proteins in heart cells work together to regulate heart function.

In diseased hearts, the body releases the hormone norepinephrine, the "fight-or-flight" hormone, directly into the heart, causing it to work up to five times harder than normal. Norepinephrine binds to molecules called beta adrenergic receptors (BARs) present on heart cells. This stimulation initially allows the heart to increase the power of its contractions, but in heart failure it quickly becomes self-defeating: the receptors become desensitized, meaning they no longer are able to respond to hormone stimulation. Desensitization is caused by a second molecule called B-adrenergic receptor kinase (BARK), which in healthy hearts helps restore heart contractions to normal after norepinephrine stimulation. Studies subsequently showed that BARK is elevated in failing human heart tissue.

In 1994, Duke researchers showed that mice genetically altered to produce excess beta adrenergic receptors (bARs) have supercharged hearts that beat faster and stronger than a normal mouse's heart. In 1997, the researchers inserted a gene that encodes the bAR into an adenovirus, the same virus that causes the common cold. When Koch and his colleagues allowed the virus to infect isolated failing rabbit heart cells, the bAR gene made up to 15 times the normal amount found in rabbit cells and restored normal heart signaling.

"Our studies have shown that a malfunctioning beta adrenergic receptor system leads directly to heart failure," Koch said. "By contrast, boosting levels of beta adrenergic receptors or inhibiting BARK can reverse heart failure in our mouse genetic models. Now, we are beginning to see the same result when we deliver these genes to rabbits."

The researchers used the results of the mouse studies to design their latest gene therapy experiments in rabbits. They increased the number of bARs by infusing a common cold virus genetically engineered to contain the bAR gene into a living rabbit's heart and allowing it to spread throughout the coronary arteries. Then they measured the ability of the heart to pump. Animals that received extra copies of bAR, which is equivalent to 10 times the normal number of bARs on heart cells, had significantly increased ability to pump, demonstrated by a 20 percent increase in the force of the heart's contraction.

The key to the researchers' success, Koch said, was using a new surgical method to ensure that the adenovirus spread throughout the heart. They injected the virus into the left ventricle of live rabbits while the aorta was clamped for a few seconds. This allowed the virus enough time to spread through all the coronary vessels. Clamping the aorta is sometimes used in human heart surgery, Koch said, making this gene delivery method feasible.

In previous experiments, the researchers used a catheter similar to the ones used in opening blocked arteries in people to inject the virus into the coronary arteries, the arteries that feed the heart, in live rabbits. Using this method, Koch and his colleagues demonstrated that they could get genes into heart muscle and that the heart cells made the appropriate protein product, but only in a limited area of heart muscle.

The researchers are continuing experiments with a new generation of gene transfer agents such as the cold virus. But, he said, better gene therapy vectors need to be developed before gene therapy for heart failure in people becomes a practical option.


Story Source:

The above story is based on materials provided by Duke University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Duke University Medical Center. "Duke Scientist Reports Advances In Gene Therapy For Heart Failure." ScienceDaily. ScienceDaily, 10 November 1998. <www.sciencedaily.com/releases/1998/11/981110075311.htm>.
Duke University Medical Center. (1998, November 10). Duke Scientist Reports Advances In Gene Therapy For Heart Failure. ScienceDaily. Retrieved September 22, 2014 from www.sciencedaily.com/releases/1998/11/981110075311.htm
Duke University Medical Center. "Duke Scientist Reports Advances In Gene Therapy For Heart Failure." ScienceDaily. www.sciencedaily.com/releases/1998/11/981110075311.htm (accessed September 22, 2014).

Share This



More Health & Medicine News

Monday, September 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Sierra Leone in Lockdown to Control Ebola

Sierra Leone in Lockdown to Control Ebola

AP (Sep. 21, 2014) Sierra Leone residents remained in lockdown on Saturday as part of a massive effort to confine millions of people to their homes in a bid to stem the biggest Ebola outbreak in history. (Sept. 20) Video provided by AP
Powered by NewsLook.com
Sierra Leone's Nationwide Ebola Curfew Underway

Sierra Leone's Nationwide Ebola Curfew Underway

Newsy (Sep. 20, 2014) Sierra Leone is locked down as aid workers and volunteers look for new cases of Ebola. Video provided by Newsy
Powered by NewsLook.com
Changes Found In Brain After One Dose Of Antidepressants

Changes Found In Brain After One Dose Of Antidepressants

Newsy (Sep. 19, 2014) A study suggest antidepressants can kick in much sooner than previously thought. Video provided by Newsy
Powered by NewsLook.com
Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins