BETHESDA, MD. – Gene therapy is showing promise in early trials as a novel targeted approach to alleviating chronic pain while avoiding the off-target side effects common to most oral analgesics.
The genetic therapy approach is potentially appropriate for patients with focal musculoskeletal pain. "We are only just now starting the phase II trial, but in principle the approach could be applied to intractable joint pain in a patient in whom joint replacement is not an option," Dr. David J. Fink said in an interview.
However, gene therapy would not be applicable to a problem of diffuse multifocal pain such as that seen in fibromyalgia, he added.
Clinical research, funded by Diamyd Inc., is now entering phase II human trials, said Dr. Fink, the Robert Brear Professor and chair of the department of neurology at the University of Michigan, Ann Arbor.
The use of most standard oral analgesics to treat long-term chronic pain is severely limited because of their effects on neural pathways unrelated to the pain or on organs outside the nervous system, leading to side effects such as lethargy, confusion, and respiratory suppression. And, in the case of opiates, there is the added potential for addiction and abuse.
To overcome this problem, Dr. Fink and his associates have constructed a series of nonreplicating herpes simplex virus (HSV)–based vectors that target gene delivery to the dorsal root ganglion via skin inoculation. HSV was chosen as a vector because it is a naturally neurotropic virus, he said.
In preclinical research supported by the National Institutes of Health and the Department of Veterans Affairs, Dr. Fink and his colleagues demonstrated that an HSV vector that produces the opioid peptide enkephalin reduces pain-related behavior in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer (Pain Medicine 2009;10:1325-30).
A phase I human trial of a human-grade nonreplicating HSV vector expressing preproenkephalin has now been completed. Safety was the primary outcome, with secondary outcomes including evaluation of pain and performance status using the numeric rating scale (NRS) for evaluation of pain, along with other measures of pain and general health and function and concurrent analgesic drug utilization.
No serious vector-related adverse events were observed in the study, which enrolled 10 patients who had intractable localized cancer pain rated greater than 4 of 10 on a visual analog scale, despite taking at least 200 mg/day of oral morphine or the equivalent. Three patients received a dose of 107 plaque-forming units (pfu) of vector, another three received 108 pfu, and four were given 109.
No effect was seen with the lowest dose, but patients in the two higher-dose groups reported subjective improvements in pain, averaging an 80% reduction in the NRS score at 7 and 14 days after the injection. The average NRS score fell from 7.5 at baseline to below 2, Dr. Fink reported at the meeting sponsored by the University of Michigan.
While this study did not have placebo controls, the dose-response result prompted Diamyd to move to a phase I/II clinical trial that will include a placebo group. For this, they are currently constructing a human-grade glutamic acid decarboxylase–expressing vector that will release gamma-aminobutyric acid into the dorsal horn.
This trial will enroll 60 patients with painful diabetic neuropathy of at least 6 months’ duration, rated consistently at 4 or above on the 10-point pain scale. They will randomly be assigned to receive vector or placebo in a 2:1 ratio, injected into the distal lower extremity. Safety will be the primary outcome of the phase I trial, while the phase II primary outcome will be efficacy, as determined by electronic pain diary recording of 24-hour average pain intensity at 2, 4, and 6 weeks after vector inoculation.
Dr. Fink cautioned that the data are preliminary. "I’m very excited to see the preclinical data appear to be holding up in phase I, but we’ll see."
Dr. Fink disclosed that he is the inventor on patents that have been licensed by Diamyd, but said he has no direct financial relationship with the company.