Blocking Pain by Gene Transfer

From Bioscience Technology: Researchers say they have developed a way to block the signals responsible for neuropathic pain. The group used a disabled form of the herpes simplex virus (HSV) as a vector to deliver genes to the nucleus of neural cells in rats.
“We use the vector to provide targeted gene delivery to the nervous system,” says David Fink, MD, professor of neurology, University of Michigan Medical School, Ann Arbor, and a 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.”

Neuropathic pain is a common complication of many diseases and medical conditions, especially diabetes. Drugs have little effect on this type of constant pain in the hands and feet, which is caused by damage to sensory neurons that transmit pain, temperature, and touch signals to and from the brain.
In a recent study in the Annals of Neurology the researchers describe how laboratory rats with nerve damage receiving injections of the HSV-based vector, which contained a gene called GAD, or glutamic acid decarboxylase, showed reduced pain-related behavior. The treatment’s pain-killing effect lasted up to six weeks, they said, and even longer in rats that received additional injections.
The vector delivered GAD to the nucleus of nerve cells in the dorsal root ganglion near the spine. In previous studies, the researchers 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, says 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.
They believe 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.
“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. 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.”
The study, they say, is the first to demonstrate the successful use of gene transfer technology using a herpes viral vector to treat peripheral neuropathic pain in animals. The group hopes to conduct the first clinical study in human patients soon. They also plan to conduct the first phase I safety trial of a related HSV vector in patients with pain caused by terminal cancer that has spread to bone.

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