PITTSBURGH, March 15, 1999 — Using a patented gene vector developed by the University of Pittsburgh, a University of South Carolina-led research team is the first to show that gene therapy blocks certain pain responses in animals. This landmark study, which paves the road for future clinical research, is published in the March 16 issue of the Proceedings of the National Academy of Sciences.
"Our research results clearly show that pain-associated behaviors diminished in mice treated with a herpes virus containing a gene that triggers production of a pain-blocking protein," said Joseph Glorioso, Ph.D., developer of the gene vector and professor and chairman of the department of molecular genetics and biochemistry at the University of Pittsburgh. "Our vector continued to produce this protein up to seven weeks after it was introduced into these animals, suggesting that this therapy may provide long-term pain relief if used clinically," added Dr. Glorioso, who also directs the Pittsburgh Human Gene Therapy Center.
Steven Wilson, Ph.D., professor of pharmacology and physiology at the University of South Carolina, who initiated this project while on sabbatical at the University of Pittsburgh, led the research team. David C. Yeomans, Ph.D., of the University of Illinois at Chicago, designed and performed the experiments demonstrating production of the pain-blocking protein and its pain-preventing effects.
The research team expects that within several years this approach could be used broadly to treat debilitating pain associated with cancer, arthritis, angina and peripheral neuropathies. Currently, these problems are often treated with narcotic-based medications given systemically, which can cause generalized side effects such as mental confusion and lethargy. Moreover, they are potentially addictive and in some cases ineffective for complete relief of pain.
Specifically, Dr. Wilson’s team found that the gene acted on C-type neurons, which transmit information felt as slow, burning pain by humans. This observation is particularly encouraging for future clinical applications, according to the investigators, because C-type neurons are thought to be the primary transmitters of chronic pain.
"The gene-vector-based therapy, in contrast to current pain control methods, is highly localized, and the release of the potentially pain-relieving substance is self-limiting because it is triggered only when the nerves encounter hyper-stimulation," added Dr. Wilson.
"Our engineered herpes virus used for this research is exceptionally well-suited to deliver genes for pain relief," according to Dr. Glorioso.
The herpes virus resides exclusively in neurons and does not integrate with the host cell’s DNA, where it could potentially alter the function of other genes. Further, the herpes virus is capable of transporting large genes or multiple genes required to carry out biological processes, such as regulating insulin production for the treatment of diabetes or producing multiple hormones that protect neurons against the destructive effects of neuropathologic conditions, including chemotherapy-induced damage.
In their experiments, the investigators used a gene for preproenkephalin. Once produced inside the body, this substance is enzymatically processed into opiate-like peptides known as enkephalins. The researchers placed the gene inside a herpes virus capable of establishing latency in the nervous system, a state where the viral genes are inactive while the enkephalin gene remains active. The researchers transferred the gene-containing virus to the paws of mice, where it naturally infected sensory neurons, including those that respond to noxious stimuli such as heat.
"These results are quite exciting, because we don’t interfere with an animal’s ability to detect a noxious stimulant and react to danger," said Dr. Wilson. "Only when sensitivities to noxious stimuli are enhanced, a phenomenon that may be important in chronic pain states, does the gene therapy act, with the result that gene-treated animals respond more slowly to this hyper-stimulation than do untreated ones," he added.