June 1, 2007 Researchers from the University of Pittsburgh School of Medicine report that they have successfully used gene therapy to block the pain response in an animal model of neuropathic pain, a type of chronic pain in people for which there are few effective treatments.
Neuropathic pain is the result of damage to nerve fibers caused by injuries or diseases, such as diabetes and cancer. These damaged nerve fibers continue to send signals to pain centers in the brain even after the surrounding tissue has healed. Unfortunately, neuropathic pain often responds poorly to standard pain treatments and occasionally may get worse instead of better over time. For some people, it leads to serious, long-term disability and dependence on pain medications that have a variety of unwanted side effects, including addiction.
The Pitt research team, led by Joseph Glorioso, III, Ph.D., chair of the department of biochemistry and molecular genetics, University of Pittsburgh School of Medicine, used a genetically engineered herpes simplex virus (HSV) to deliver the gene for part of the human glycine receptor (GlyR), a receptor found primarily on the surface of nerve cells in the spinal cord and the lower brain but not in the nerves in the limbs, to the paws of rats. A group of control rats received only the HSV vector without the inserted gene.
After the delivery of the therapeutic gene or empty vector (for the control group), the researchers injected the same paws of each rat with formalin, an irritant known to simulate the symptoms of a peripheral neuropathic pain at the site of injection. Following formalin injection, the rats were then given an injection of glycine to activate the GlyR receptor.
Both control and GlyR-HSV-infected rats showed a typical pain response to formalin. However, the application of glycine eliminated the pain response in GlyR-HSV infected animals, while it had no effect on animals infected with vector only. This alleviation of the pain response in GlyR-HSV-treated mice was reversed by the subsequent addition of low concentrations of strychnine, a strong GlyR-specific inhibitor, or antagonist.
According to Dr. Glorioso, these findings suggest that HSV-directed expression of GlyR in peripheral neurons and subsequent selective activation by glycine has the potential to be used therapeutically not only for neuropathic pain management but a variety of pain syndromes.
"The inability to effectively manage neuropathic pain associated with injuries and illnesses is a growing national and international problem. Gene therapy offers a more targeted, less toxic approach for effectively managing this condition. It also is our hope that targeted transgene delivery of GlyR may have even broader implications for managing a number of chronic pain syndromes, including pain resulting from shingles, arthritis and cancer," explained Dr. Glorioso.
These findings are being presented at the 10th annual meeting of the American Society of Gene Therapy, being held May 30 to June 3 at the Washington State Convention & Trade Center, Seattle.
In addition to Dr. Glorioso, others involved in the study included Michael Cascio, Ph.D., James Goss, Ph.D., David Krisky, M.D., Ph.D., and Rahul Scrinivasin, M.D., Ph.D., all with the department of molecular genetics and biochemistry, University of Pittsburgh School of Medicine.
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