LONDON - A naturally occurring growth factor is being investigated as a therapy for neuropathic pain, which affects many people with diabetes, AIDS and injuries caused by trauma. Studies in rats suggest that the growth factor, glial cell-line derived neurotrophic factor (GDNF), could be evaluated in human clinical trials within a few years.

Stephen McMahon, Sherrington professor of physiology at Kings College London, told BioWorld International: "We have shown that GDNF has very strong efficacy in an animal model of neuropathic pain. That is very encouraging but we don't know how translatable that would be to humans. We are keen for Amgen, which has exclusive rights to develop GDNF as a drug candidate, to consider clinical trials." First, however, he and his colleagues are planning to continue their basic scientific studies, to define more closely the conditions under which GDNF is effective.

James Treanor, research scientist in the Department of Neurobiology at Amgen Inc. in Thousand Oaks, Calif., told BioWorld International: "This is very interesting work directed at the mechanism involved in the generation and, more importantly, the maintenance of neuropathic pain. But we need to remember that these are very early results and we are still a long way from the drug development stage." Amgen would continue to support the work of McMahon and others conducting research on GDNF by sharing its research materials, he added.

The results of the experiments carried out by McMahon and his colleagues are reported in the Oct. 6, 2000, Science in a paper titled, "Potent Analgesic Effects of GDNF in Neuropathic Pain States." The first author is Timothy Boucher, also of King's College London.

Neuropathic pain is caused by damage to peripheral nerves. It is persistent and intense in nature and, unlike inflammatory pain, for example, it frequently does not respond well to existing types of analgesia. Many people with diabetes suffer from diabetic neuropathy, which starts as a burning sensation on the soles of the feet and works up the legs on both sides.

Patients with AIDS whose lives have been prolonged by treatment with antiretroviral drugs also are prone to develop neuropathy, which is estimated to affect about half of all people terminally ill with AIDS.

A third group of sufferers includes those recovering from shingles, in which post-herpetic pain can persist for months or even years. Traumatic nerve injuries, which are rare except during times of war, are yet another cause of neuropathic pain.

McMahon and his colleagues set out to investigate the mechanisms underlying neuropathic pain. They also wanted to evaluate possible treatments, including GDNF, a naturally occurring protein. This growth factor is normally produced by the body during development of the nervous system, where its role is to promote the survival and growth of neurons.

For the experiments, the group used an established animal model of neuropathic pain, which involves causing partial damage to a nerve - for example, the sciatic nerve - and then quantifying the animal's response to pain. McMahon said, "One of the hallmarks of neuropathic pain is that the lightest touches are excruciatingly painful for people with this condition. In the animal model, a very light touch produces limb-withdrawal behavior, and this can be quantified."

The researchers knew from previous work carried out by themselves and others that GDNF is able to nurture the nerve fibers that contribute to the neuropathic pain state. What they show in Science, McMahon said, is that GDNF treatment of the rodent model can completely prevent the emergence of neuropathic pain. "Perhaps more important clinically," he added, "it can also reverse an established neuropathic pain state."

The group went on to investigate the mechanism by which GDNF had this effect. Research already had demonstrated that one factor contributing to neuropathic pain is abnormal spontaneous nerve activity. "Whereas these nerves are normally quiescent, in neuropathic pain they become spontaneously active and bombard the central nervous system with signals which are misinterpreted as pain," McMahon said. "So one strategy for treating neuropathic pain is to try to dampen down this abnormal activity."

Nerve impulses arise when pores in the membrane of the nerve cell open to allow sodium ions in. In neuropathic pain, McMahon explained, "abnormal nerve activity is caused partly by abnormal expression of ion channels in the damaged nerve. We found, using the polymerase chain reaction, that GDNF protects the cell by normalizing the expression of these ion channels."

"We are very encouraged," he concluded, "to see such dramatic effects, but we remain cautious. Several other strategies for tackling this problem have shown promise in animal models but have not translated well to humans. In addition, this treatment could have any number of side effects. Nevertheless, GDNF is clearly worth considering as a potential therapeutic agent."

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