Gene Therapy Painkillers

A treatment, now being tested in humans, may avoid the disabling side effects of opiate drugs.

A new gene-therapy technique, which entered early-stage clinical trials last week, may bring relief to cancer patients who suffer from chronic, untreatable pain. By delivering the gene for an opiate-like chemical directly to affected nerves, the treatment may circumvent the debilitating side effects normally associated with opiate drugs.

Credit: Technology Review

"This is a breakthrough study," says Talal Khan, director of the Chronic and Interventional Pain Clinic at the University of Kansas Medical Center. "It's the first gene-therapeutic trial for the management of pain." Khan is not involved in the trial.

The new technique, developed by clinical neurologist David Fink and his colleagues at the University of Michigan, uses a crippled version of herpes simplex virus (HSV)--the virus responsible for cold sores--to deliver a therapeutic gene to affected nerves. This is also the first clinical trial that uses HSV to shuttle a foreign gene into the body.

HSV's natural behavior makes it an ideal delivery vehicle, says Fink. It infects sensory neurons near the skin and travels to a group of cells near the spinal cord, but no farther, allowing the researchers to precisely target the therapy to those neurons involved in sensing pain. To administer the treatment, a doctor simply injects the virus into the skin wherever the pain occurs.

HSV also avoids what has been a troubling side effect of gene therapy: viral genes inserting themselves into the host's genome. In a French trial of gene therapy for severe combined immunodeficiency, for instance, several children died when the therapeutic gene inserted itself into a cancer-related gene and caused leukemia. HSV merely ferries its genes to the nucleus, where they remain indefinitely, separate from the host's genome. Unlike the naturally occurring virus, which can periodically reactivate itself and cause symptom flare-ups, the virus used for therapy is incapable of replicating.

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Along with its own genes, the HSV vector is engineered to carry the gene for an opiate-like peptide called enkephalin. Enkephalin is involved in the body's own pain-fighting response, binding to the same receptors as opiate drugs but far more effectively. Because it degrades quickly, enkephalin isn't normally a candidate for treating pain. But by administering the gene encoding the peptide rather than the peptide itself, gene therapy can provide a continuously replenished supply.

The clinical trial will target cancer patients with localized pain for whom conventional painkillers have failed, either because the maximum dose was ineffective or because the side effects were incapacitating. Opiate drugs, which act on opiate receptors all over the body, generate a slew of side effects, including drowsiness, confusion, constipation, and respiratory depression. Patients often find these side effects more troublesome than their initial pain, says Fink. "They say, 'I'd rather be awake with the pain than asleep with your medicine,'" he says.