Gene therapy advances as treatment for pain Tuesday, March 16, 1999
By Anita Srikameswaran, Post-Gazette Staff Writer

Ironic as it sounds, scientists are experimenting with a modifed form of the herpes virus, known for causing extremely tender sores and blisters, as an agent to provide relief from chronic pain.

A team of researchers, including some from the University of Pittsburgh, have shown for the first time that gene therapy can block the slow, burning pain sensation transmitted by certain nerve fibers. The results are being published today in the Proceedings of the National Academy of Sciences.

If successful, this approach might provide relief for people with chronically painful conditions such as arthritis, diabetes-induced nerve pain and phantom limb pain. It could provide relief only at the site of pain, making it unnecessary to use drugs that cause grogginess.

The experiments, conducted in mice, used a Type I herpes simplex virus engineered to carry a human gene that makes a protein called proenkephalin. The body processes this protein to make enkephalins, which kill pain in a morphine-like fashion.

The project began when Steven Wilson of the University of South Carolina spent six months working on the herpes virus in the lab of Joseph Glorioso, director of Pitt's Human Gene Therapy Center.

"Our lab has been working on basic biology of herpes simplex virus for many years," Glorioso said. "Back in the'80s when gene therapy ideas began to surface, we thought it might be useful for transferring genes into the brain and nerves because of the natural biology of this virus in the nervous system."

A person infected with the normal herpes virus can have recurrent cold sores or genital ulcers because the virus gets inside nerve cells and stays there for the individual's lifetime. That localization and longevity prompted the scientists to engineer the herpes virus into a "vector" to transport a gene for long-term pain treatment into body cells.

The viruses used as vectors are altered so they cannot replicate or cause disease.

David Yeomans of the University of Illinois tested the vector, carrying the proenkephalin gene, by injecting the hindpaws of mice. "You cannot ask a mouse whether they're feeling pain or not," he noted, and so pain was assessed by timing how long it took for the mouse's hindpaw to withdraw from a painful stimulus, namely a beam of light that heated up the skin. This reflex withdrawal, just like pulling back from touching a hot pan, does not require any interaction with the brain, allowing the mice to be anesthetized for the procedure.

Yeomans found that both treated and untreated mice took about 12 seconds to pull their paw away from the heat. He then lowered the threshold for feeling pain by applying capsaicin, the chemical that gives chili peppers their heat, onto the skin before turning on the heat source. Untreated mice flinched in less than five seconds, but the animals that received the enkephalin-producing gene still took around 12 seconds before they felt pain.

The treated mice pulled away quickly, just like the normal group, if they were given a substance, called naloxone, that blocks the effect of drugs like morphine. The findings suggest that if people were given the gene therapy, the effects would only occur if there was already pain present. Standard pain killers like morphine can create problems of addiction and drug tolerance, which is unlikely with the gene approach.

The effect is also localized because the virus and gene enter nerves only at the site of injection. If a treated mouse's other hindpaw was given a painful stimulus and capsaicin, it reacted similarly to those of untreated mice. So even if a person got pain relief from an injection into an arthritic knee, his shoulder arthritis would still hurt.

Yeomans has found human proenkephalin in the mice 14 weeks after the injection. Further study is needed to see if the pain relief remains and it may be years before the gene therapy can be tested in humans.