A new kind of gene therapy could bring relief to patients suffering from chronic pain while bypassing many of the debilitating side effects associated with traditional painkillers.
Researchers at Mount Sinai School of Medicine injected a virus carrying the gene for an endogenous opioid–a chemical naturally produced by the body that has the same effect as opiate painkillers such as morphine–directly into the spinal fluid of rats. The injections were targeted to regions of the spinal cord called the dorsal root ganglia, which act as a “pain gate” by intercepting pain signals from the body on their way to the brain. “You can stop pain transmission at the spinal level so that pain impulses never reach the brain,” says project leader Andreas Beutler, an assistant professor of hematology and medical oncology at Mount Sinai.
The injection technique is equivalent to a spinal tap, a routine procedure that can be performed quickly at a patient’s bedside without general anesthesia.
Because it targets the spinal cord directly, this technique limits the opiate-like substance, and hence any side effects, to a contained area. Normally, when opiate drugs are administered orally or by injection, their effects are spread throughout the body and brain, where they cause unwanted side effects such as constipation, nausea, sedation, and decreased mental acuity.
Side effects are a major hurdle in treating chronic pain, which costs the United States around $100 billion annually in treatment and lost wages. While opiate drugs can be very effective, the doses required to successfully control pain are often too high for the patient to tolerate.
“The side effects can be as bad as the pain,” says Doris Cope, director of the University of Pittsburgh Medical Center’s Pain Medicine Program. Achieving the benefits of opiate treatment without their accompanying side effects, Cope says, would be a “huge step forward.”
Beutler hopes to do just that. “Our strategy was to harness the strength of opioids but target it to the pain gate, and thereby create pain relief without the side effects that you always get when you have systemic distribution of opioids,” he says.
Several groups have previously attempted to administer gene therapy for pain through spinal injections, but they failed to achieve powerful, long-lasting pain relief. The new technique produced results that lasted as long as three months from a single injection, and unpublished follow-up studies suggest that the effect could persist for a year or more.
Beutler credits his team’s success to the development of an improved virus for delivering the gene. The team uses a specially adapted version of adeno-associated virus, or AAV–a tiny virus whose genome is an unpaired strand of DNA. All the virus’s own genes are removed, and the human endogenous opioid gene is inserted in their place. Beutler’s team also mixed and matched components from various naturally occurring AAV strains and modified the genome into a double-stranded form. These tweaks likely allow the virus to infect nerve cells more easily and stick around longer.
Once the virus is injected into the spinal fluid and makes its way into the nerve cells of the pain gate, it uses the host cells’ machinery to churn out the opioid protein–which then goes to work blocking pain signals on their way to the brain. Normally, the gene is rarely activated. But the version used for therapy has no such limitations because the gene carried by the AAV has been modified to continuously produce the opioid chemical.
Cope says that using endogenous opioids is inherently superior to injecting synthetic opiate drugs directly into the spinal fluid, an approach that requires the installation of a pump in order to deliver the drugs over a long time period. “It’s kind of a holy grail,” she says. “If the body’s own system for pain control were activated by genetic expression, that would be superior to an artificial medication.”
In Beutler’s study, which was published this week in PNAS, rats were surgically modified to have a stronger than usual response to pressure on their paws, mimicking the effects of so-called neuropathic pain. The gene-therapy treatment effectively restored the rats to a normal level of pain sensitivity. The team also tested a nonopioid gene, which produced comparable pain relief through an entirely different mechanism. But while the opioid gene’s effects will likely extend to humans, who respond to opiates the same way rats do, the nonopioid’s effects may be rat specific.
The Stockholm-based company Diamyd Medical has been developing a different approach to gene therapy for chronic pain that also bypasses the side effects of standard pain treatment. The approach uses a deactivated version of herpes simplex virus (HSV). HSV can be administered straight through the skin as it naturally finds and infects peripheral nerves and travels to the spinal cord on its own. Darren Wolfe of Diamyd says that this method is superior to spinal injection because it’s safer and easier, and it can be administered repeatedly.
Because of these considerations, the HSV method may be preferable for treating localized pain. However, when chronic pain involves multiple areas of the body–as it often does with, for example, metastasized cancers–going straight to the pain gate could work more efficiently.
While both of these methods have proved effective in animal models of pain, their efficacy in human patients remains to be shown. Diamyd recently applied to the FDA to begin phase I clinical trials, and Beutler estimates that his approach could be tested on humans in as few as three years.
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