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 The new technique produced results that lasted as long as three months from a single injection, and unpublished follow-up studies suggest that the effect could persist for a year or more.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.