ANN ARBOR, Mich. -- Remember how it felt the last time you burned your finger on a hot stove? Imagine what it's like to have that burning pain in your hands or feet all the time and know there's virtually nothing you can do about it.
It's called neuropathic pain, and it's a common complication of many diseases and medical conditions, especially diabetes. Drugs have little effect on this type of pain, which is caused by damage to sensory neurons that transmit pain, temperature and touch signals to and from the brain.
Now, scientists at the VA Ann Arbor Healthcare System and the University of Michigan Medical School have developed a way to block the signals responsible for neuropathic pain. The secret to their success is based on a virus called herpes simplex or HSV -- the same virus that causes cold sores and genital herpes. The scientists use a disabled form of the virus, called a vector, to deliver genes to the nucleus of neural cells.
A study published today in the June, 2005 of the Annals of Neurology describes how laboratory rats with nerve damage showed much less pain-related behavior after receiving injections of the HSV-based vector, which contained a gene called GAD, or glutamic acid decarboxylase. The treatment's pain-killing effect lasted up to six weeks, and even longer in rats that received additional injections.
The study is the first to demonstrate the successful use of gene transfer technology, using a herpes viral vector, to treat peripheral neuropathic pain in animals. Based on their success in related studies with research animals, the scientists hope to conduct the first clinical study in human patients soon.
"We use the vector to provide targeted gene delivery to the nervous system," says David J. Fink, M.D., the Robert W. Brear Professor of Neurology in the U-M Medical School and staff neurologist at the VA Ann Arbor Healthcare System, who co-directed the research study. "In this case, we're not trying to correct a genetic defect. Our goal is simply to deliver a gene to sensory nerve cells, so its product can be used to block transmission of pain signals from damaged nerves to the brain."
After removing genes that make it possible for the herpes simplex virus to infect a human host, VA/U-M scientists use it as a carrier to deliver GAD to the nucleus of nerve cells in the dorsal root ganglion near the spine. In previous studies, the researchers have confirmed that the vector remains in the dorsal root ganglion, but an enzyme expressed by the GAD gene moves to nerve terminals in the spinal cord where it triggers production of a powerful neurotransmitter called GABA.
"GABA is the main inhibitory neurotransmitter in the nervous system," Fink says. "It's like a hall monitor for the nervous system; it damps down neurotransmission between cells to keep things quiet. You can't have every neuron talking to every other neuron all the time or you'd have chaos."
Other scientists have shown that decreased GABA activity in the spinal cord contributes to the development of neuropathic pain, according to Fink.
Physicians have drugs that block neural transmission by mimicking the actions of inhibitory agents like GABA, but it's difficult to give these drugs in adequate doses, because the same drug that blocks pain also interferes with brain activity, leaving people drowsy and unable to think clearly.
"What we need is a way to release GABA in the spinal cord where it can selectively block incoming pain signals from peripheral nerves," says Fink. "If we can block transmission of the signal at the first neural synapse, it will never reach the brain and you won't feel pain."
That's where the herpes-based vector comes in. Although scientists can use many kinds of vectors to transfer genes into living cells, HSV has a natural ability to travel long distances along nerve fibers to reach the neural cell's nucleus, which makes it the perfect gene delivery vehicle for use in the nervous system.
"When we inject our HSV gene carrier under the skin of a laboratory rat, the vector is taken up by sensory nerve terminals in the animal's skin and carried through the axon back to the sensory ganglia cell bodies next to the spinal cord," says Shuanglin Hao, M.D., Ph.D., a U-M research investigator and first author of the study.
"Since the vector lacks essential viral genes for replication, it remains in the nucleus expressing the GAD enzyme, which triggers nerve terminals in the spinal cord to release GABA," Fink adds. "As long as the GAD gene remains active, GABA will continue to flood the spinal cord and block the transmission of pain signals to the brain."
In experiments reported in the Annals of Neurology paper, VA/U-M scientists tied off a nerve root in the sciatic nerve leading to the left hind paw of eight rats in the study. Tying off the nerve root makes the nerve degenerate and release substances that cause pain, according to Fink. A second group of eight rats received sham surgery, with no damage to their sciatic nerve. A third group served as normal controls.
"When we study pain in people, we can ask them if it hurts," says Fink. "But you can't ask questions of a rat. So we study the animals' behavior to discern whether they are experiencing pain using standard models used to assess pain in rodents."
One of the effects of neuropathic pain is called allodynia, which means that even ordinary touch feels painful. In both rats and people, scientists measure allodynia by touching the skin with a series of filaments or exposing the skin to small amounts of moderate heat. People with neuropathy perceive the filament's touch or heat as a painful sensation. Rats with neuropathy will lift their paw if the filament or heat produces pain. Rats without neuropathic pain don't even notice. By monitoring whether rats lift their paw, and how long it takes for them to do so, scientists can measure the degree of pain the animal is feeling.
One week after surgery, some of the rats received injections of the HSV vector with GAD, while control rats did not receive the vector. Rats given the transgene vector had significantly lower pain threshold responses to filament touch and heat exposure tests than rats that did not receive the vector.
"We saw a sustained, continuous pain-suppressing effect that began one week after inoculation with the vector and lasted for six weeks," says Marina Mata, M.D., staff neurologist at the VA Ann Arbor Healthcare System, professor of neurology in the U-M Medical School and co-director of the research team. "By seven weeks after inoculation, the pain-blocking effect disappeared, but a second inoculation into the same paw re-established the effect."
In previous research, Mata and Fink have used their HSV vector to deliver other neurotrophic factors and pain-suppressing drugs to spinal ganglion cells. But Fink says the effect of the GAD-expressing vector is substantially greater for neuropathic pain, because it helps correct the reduction of GABA in the spinal cord. He also emphasizes the excellent safety record of the HSV vector, which has produced no side effects or complications in many animal studies.
"I am a clinical neurologist and I see patients with neuropathic pain," Fink says. "These patients suffer tremendously and the treatments available to us now have limited effectiveness. Using our herpes vector to provide targeted gene delivery to the nervous system is a novel approach that shows tremendous promise for the treatment of neuropathic pain."
In future research, the scientists plan to conduct the first phase I safety trial of a related HSV vector in patients with pain caused by terminal cancer, which has spread to bone.
The research was supported by grants from the National Institute of Neurological Disorders and Stroke and the Department of Veterans Affairs. Additional collaborators in the study included Darren Wolfe, Ph.D. and Joseph Glorioso, Ph.D., from the University of Pittsburgh. The University of Michigan and the University of Pittsburgh hold patents related to the herpes simplex virus-based vector.
Citation: Annals of Neurology: 57(6), pp. 914-918.
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