Using a weakened herpes virus to deliver a neurotransmitter-related gene to sensory neurons alleviates pain for up to 6 weeks in rats with chronic pain caused by nerve damage, a new study shows.  The findings may lead to the first effective treatment for people affected by this type of "neuropathic" pain.

"Neuropathic pain is very difficult to control," says David J. Fink, M.D., of the University of Michigan and Ann Arbor VA Healthcare System in Ann Arbor, who led the study.  "By transferring the gene for GAD, we can substantially reduce this pain in rodents."  GAD, or glutamic acid decarboxylase, is the enzyme responsible for synthesizing the neurotransmitter GABA (gamma-aminobutyric acid), which dampens activity in nerve cells.  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the June 2005 issue of Annals of Neurology.*

Pain from damage to sensory nerves in the peripheral nervous system ¡V the vast network that transmits information from other parts of the body to the brain and spinal cord ¡V often occurs as a complication of peripheral neuropathy.  This type of pain is common and it is notoriously difficult to treat.  Available medications, including opioid drugs, antidepressants, and anticonvulsants, provide only partial relief.  As a result, many people with neuropathic pain live with spontaneous burning sensations and pain from stimuli that are normally painless, such as cloth rubbing against the skin.

In the new study, Dr. Fink and his colleagues injected a herpes virus vector either with or without the GAD gene into the hind paws of rats with damaged spinal nerves.  Because of pain resulting from the nerve damage, the rats quickly pulled their hind paws away when the paws were touched with a thin hair.  They also quickly pulled their paws away from a heat stimulus.  These responses are similar to those of people with the enhanced pain and heat sensitivity caused by peripheral neuropathy. 

Rats that received the vector containing the GAD gene showed less reaction to the touch and heat stimuli than those that received a viral vector without the gene, the researchers found.  The pain reduction began about 1 week after the injection and lasted for 6 weeks before the effect wore off.  A second injection of the GAD-containing vector reduced the pain again, however.

In addition to changing the rats' behavioral reactions to the stimuli, the gene therapy reduced the production of three proteins that serve as markers of pain in neurons, the study showed.

The herpes virus has a natural ability to travel from the peripheral nervous system to the sensory nerve centers (called the dorsal root ganglion) in the spinal cord, so vectors created from the herpes virus are particularly well-suited for treatment of nervous system diseases such as peripheral neuropathy.  Unlike normal herpes viruses, however, the vectors used in this experiment were unable to replicate, and they stayed in the dorsal root ganglion neurons, where they produced GAD.  The presence of GAD increased the levels of GABA in the neurons, modifying sensory transmission from the spinal cord in a way that dulled the pain signals.

Previous studies by Dr. Fink's team and others using herpes vector-mediated gene therapy with different pain-reducing genes, including proenkephalin and glial cell-derived neurotrophic factor, have shown positive effects for treating neuropathic pain, inflammatory pain (including arthritis), and bone pain from cancer.  However, the GAD gene therapy used in this study was much more effective for neuropathic pain than the other treatments, Dr. Fink says. 

The study supports previous research which showed that neuropathic pain is associated with lower-than-normal amounts of GABA in the spinal cord.  While several drugs are available to mimic the effects of GABA, they have significant side effects that limit their use, Dr. Fink says.  Gene therapy avoids these problems by increasing GABA levels only in the neurons that control pain sensitivity.

The study did not find any adverse effects of the gene therapy.  However, "we can't ask rats how they are feeling," Dr. Fink says.   Therefore human studies are needed to ensure that the treatment is safe and that it does not cause subtle side effects.

Dr. Fink and his colleagues are planning a clinical trial of the herpes vector to deliver the proenkephalin gene in patients with pain from metastatic cancer.  This study will examine whether the vector is safe to use in humans.  If that study goes well, the researchers might then be able to test GAD gene therapy in people with peripheral neuropathy or other types of pain.   

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation¡¦s primary supporter of biomedical research on the brain and nervous system.

*Hao S, Mata M, Wolfe D, Glorioso JC, Fink DJ.  "Gene transfer of glutamic acid decarboxylase reduces neuropathic pain."  Annals of Neurology, June 2005, Vol. 57, No. 6, pp.  914-918.

-By Natalie Frazin, NINDS Office of Communications and Public Liaison