Featured Research

from universities, journals, and other organizations

First Evidence That Localized Arthritis Gene Therapy Heals Distant Diseased Joints

Date:
April 16, 1998
Source:
University Of Pittsburgh Medical Center
Summary:
University of Pittsburgh researchers have made the unprecedented and totally unexpected finding that localized gene therapy for arthritis produces healing effects on distant joints affected with the disease.

PITTSBURGH, April 13 -- University of Pittsburgh researchers have made the unprecedented and totally unexpected finding that localized gene therapy for arthritis produces healing effects on distant joints affected with the disease. Results of this landmark study, conducted in a rabbit model of rheumatoid arthritis, appear in the April 15 issue of the Proceedings of the National Academy of Sciences. It is a major advance in the quest to bring arthritis gene therapy into widespread clinical use.

"This offers the first evidence that arthritis gene therapy can produce widespread, or systemic, effects. Our hope is that it would be possible to inject one arthritic joint in a patient with a therapeutic gene and find that arthritic joints elsewhere in the body respond to this therapy," said Steve Ghivizzani, Ph.D., a post-doctoral fellow in the department of molecular genetics and biochemistry at the University of Pittsburgh and lead author of the study.

Rheumatoid arthritis (RA), which affects about 2.1 million Americans, causes painful inflammation and erosion of joints. This disease process has been linked with two proteins, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF"), which are overproduced in arthritic joints. These substances bind to specific receptors located on cells lining joints (synoviocytes). In doing so, they trigger the progressive, irreversible destruction caused by RA. Researchers have long sought to block the action of these proteins to reduce or halt the disease process.

In their study, the Pitt investigators provoked rheumatoid-like arthritis in rabbit knee joints by injecting them with a protein that causes inflammation and joint erosion. The investigators used an adenovirus (a virus that causes the common cold) to carry therapeutic genes, in this case genes for an altered form of cell receptors for TNF" and IL-1. The adenovirus used was disabled to render it harmless. Local production of the modified TNF" and IL-1 receptors would be expected to "mop up" extra TNF" and IL-1 before they could bind to receptors on synoviocytes.

The researchers induced arthritis in both knees of 32 rabbits. One day later, some rabbits received the gene for the receptor to TNF" in one diseased knee. (The second knee served as a control). Other rabbits received the gene for the receptor to IL-1 in one diseased knee. A third group of rabbits received genes for both IL-1 receptor and TNF" receptor in one diseased knee. A fourth group of rabbits received a control injection of saline solution or an irrelevant gene in one diseased knee.

The IL-1 receptor gene or the IL-1 receptor gene given together with the TNF" receptor gene lessened inflammation and cartilage destruction in the rabbit joints. To detect these effects, the researchers collected joint fluid and found reductions in the number of white blood cells (indicative of inflammation) and the amount of proteins normally associated with cartilage destruction. Unexpectedly, the investigators found that the altered IL-1 receptor gene, alone or together with altered TNF" receptor gene diminished arthritic effects in untreated, distant knee joints.

"The best therapeutic effect appears when the IL-1 receptor gene and the TNF" receptor gene are combined," noted Dr. Ghivizzani. "Knees injected with both these genes showed an 85-90 percent reduction in white blood cell levels compared with untreated knees, and a similar protection of cartilage."

In a related experiment, the investigators injected an adenovirus containing a marker gene into one knee of several rabbits. Although not therapeutic, a marker gene allows scientists to easily track the distribution of introduced genes within the body. Seven days after injecting the marker gene, the researchers analyzed tissues and fluids from both rabbit knee joints. They found the marker gene had been taken up by white blood cells, which travel throughout the body to sites that include diseased joints.

"This suggests a way that the IL-1 receptor and TNF" receptor genes traffic through the body and cause anti-arthritic responses in joints that have not been directly injected with these genes," added Dr. Ghivizzani.

The research on arthritis gene therapy is part of a large research initiative to develop effective gene therapies for arthritis. In July 1996, a University of Pittsburgh team of scientists began a clinical protocol using gene therapy for RA. This study is led by Chris Evans, Ph.D., Sc.D., Henry J. Mankin professor of orthopaedic surgery at the University of Pittsburgh and director of the UPMC's Ferguson Laboratory for Orthopaedic Research, and Paul Robbins, Ph.D., associate professor of molecular genetics and biochemistry at the University of Pittsburgh and director of the UPMC's Viral Vector Laboratory.

The protocol -- the first gene therapy for a chronic disease -- involves nine post-menopausal women. It is designed to test the safety of this approach and yield preliminary data suggesting whether or not it works at the tissue level. This clinical trial differs from the rabbit study in several ways. The gene used is for interleukin-1 receptor antagonist (IL-1Ra), a protein that fastens to the IL-1 receptor on synoviocytes, thus blocking the receptor's ability to bind with IL-1. The IL-1Ra gene is combined with a replication-defective retrovirus, and this package is then given to fibroblasts that are extracted from patients' joints during a medically necessary surgical procedure for RA. After these gene-carrying fibroblasts are cultured and tested to ensure their safety, they are returned to a patient's arthritic knuckles. One week later, the treated knuckles are removed and replaced with artificial joints during a medically required joint replacement surgery. These knuckles are being examined for evidence of gene therapy activity. The Pitt researchers have found evidence of gene expression in all patients tested thus far, and no adverse effects have been seen.

For additional information about arthritis gene therapy research, please access UPMC Health System's web site at http://www.upmc.edu.


Story Source:

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


Cite This Page:

University Of Pittsburgh Medical Center. "First Evidence That Localized Arthritis Gene Therapy Heals Distant Diseased Joints." ScienceDaily. ScienceDaily, 16 April 1998. <www.sciencedaily.com/releases/1998/04/980416081239.htm>.
University Of Pittsburgh Medical Center. (1998, April 16). First Evidence That Localized Arthritis Gene Therapy Heals Distant Diseased Joints. ScienceDaily. Retrieved August 30, 2014 from www.sciencedaily.com/releases/1998/04/980416081239.htm
University Of Pittsburgh Medical Center. "First Evidence That Localized Arthritis Gene Therapy Heals Distant Diseased Joints." ScienceDaily. www.sciencedaily.com/releases/1998/04/980416081239.htm (accessed August 30, 2014).

Share This




More Health & Medicine News

Saturday, August 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

3 Things To Know About The Ebola Outbreak's Progression

3 Things To Know About The Ebola Outbreak's Progression

Newsy (Aug. 29, 2014) Here are three things you need to know about the deadly Ebola outbreak's progression this week. Video provided by Newsy
Powered by NewsLook.com
Killer Amoeba Found in Louisiana Water System

Killer Amoeba Found in Louisiana Water System

AP (Aug. 28, 2014) State health officials say testing has confirmed the presence of a killer amoeba in a water system serving three St. John the Baptist Parish towns. (Aug. 28) Video provided by AP
Powered by NewsLook.com
Who Could Be Burnt by WHO's E-Cigs Move?

Who Could Be Burnt by WHO's E-Cigs Move?

Reuters - Business Video Online (Aug. 28, 2014) The World Health Organisation has called for the regulation of electronic cigarettes as both tobacco and medical products. Ciara Lee looks at the impact of the move on the tobacco industry. Video provided by Reuters
Powered by NewsLook.com
CDC Director On Ebola Outbreak: 'It's Worse Than I Feared'

CDC Director On Ebola Outbreak: 'It's Worse Than I Feared'

Newsy (Aug. 28, 2014) CDC director Tom Frieden says the Ebola outbreak is even worse than he feared. But he also said there's still hope to contain it. 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