Comparative effectiveness of antinociceptive gene therapies in animal models of diabetic neuropathic pain

Abstract

Peripheral neuropathic pain is one of the most common and debilitating complications of diabetes. Several genes have been shown to be effective in reducing neuropathic pain in animal models of diabetes after transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)1-based vectors, yet there has never been a comparative analysis of their efficacy. We compared four different HSV1-based vectors engineered to produce one of two opioid receptor agonists (enkephalin or endomorphin), or one of two isoforms of glutamic acid decarboxylase (GAD65 or GAD67), alone and in combination, in the streptozotocin-induced diabetic rat and mouse models. Our results indicate that a single subcutaneous hindpaw inoculation of vectors expressing GAD65 or GAD67 reduced diabetes-induced mechanical allodynia to a degree that was greater than daily injections of gabapentin in rats. Diabetic mice that developed thermal hyperalgesia also responded to GAD65 or endomorphin gene delivery. The results suggest that either GAD65 or GAD67 vectors are the most effective in the treatment of diabetic pain. The vector combinations, GAD67 + endomorphin, GAD67 + enkephalin or endomorphin + enkephalin also produced a significant antinociceptive effect but the combination did not appear to be superior to single gene treatment. These findings provide further justification for the clinical development of antinociceptive gene therapies for the treatment of diabetic peripheral neuropathies.

HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a

“…GAD65 knockout mice show significant reduction in response latency measured by the hot plate test but there is no genotype-specific difference when measured by the von Frey test, and GAD65-mediated GABA synthesis plays relatively small roles in nociceptive processing via supraspinal mechanisms 59 . In mouse diabetic model of neuropathic pain, GAD65 vector inoculation most significantly relieves thermal pain compared to mechanical allodynia by Von Frey filaments 25 . Introduction of either GAD65 or GAD67 by HSV or AAV vectors to the DRG/spinal cord has been shown to effectively relieve different neuropathic pain states 25 , 32 , 33 , 41 , 60 , 61 .…”

“…In mouse diabetic model of neuropathic pain, GAD65 vector inoculation most significantly relieves thermal pain compared to mechanical allodynia by Von Frey filaments 25 . Introduction of either GAD65 or GAD67 by HSV or AAV vectors to the DRG/spinal cord has been shown to effectively relieve different neuropathic pain states 25 , 32 , 33 , 41 , 60 , 61 . Clinical data show that patients with HIV-related painful neuropathy do not usually present with thermal hypersensitivity 62 .…”

“…Previous studies have shown that HSV-mediated human proenkephalin expression in primary afferent axons at the dorsal root entry zone of the dorsal horn was reported 23 . We and others have demonstrated that replication-defective HSV-based vectors delivered by subcutaneous inoculation express enkaphalin or GAD67 in the DRG neurons and spinal dorsal horn, and produce a pain-relieving effect in rodent models of different pain models 25 , 26 , 33 , 41 . The present studies demonstrate, 1) that subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, 2) that the anti-allodynic effect of HSV vectors expressing GAD67 was mediated through GABA-A and-B receptors, 3) that HSV vectors expressing GAD67 reversed the lowered GABA-IR expression, and 4) that the HSV vectors expressing GAD67 suppressed the upregulated spinal mitochondrial superoxide and Wnt5a.…”

“…GABA agonist drugs are approved for treatment of selected neuropathic pain syndromes, but the ubiquitous distribution of GABA receptors in the central nervous system results in side effects that impose severe restrictions on the dose of baclofen, even when administered intrathecally in attempting to control pain 33 . Previous reports that the GAD-expressing HSV vector reduces pain-related behaviors over the course of several weeks in different models of neuropathic pain 25 , 33 , 41 , 53 . In our first report using the vectors expressing GAD67, we used spinal cord injury (SCI) model induced by T13 spinal cord hemisection 33 , which is a direct spinal cord mechanic injury-related motor and sensory dysfunction, including neuropathic pain.…”

The Dorsal Root Ganglion as a Therapeutic Target for Chronic Pain

“…The GAD therapies were more effective at reducing mechanical allodynia, proving more effective better as analgesia than gabapentin injections. 107 Early-phase human clinical trials of intradermal injection of the gene for preproenkephalin with a replication-defective HSV1based vector had a dose-dependent analgesic effect. Such intradermal inoculation has been termed the nerve-targeting drug delivery system and may also have utility for delivering neuroprotective proteins or other antinociceptive proteins to DRG neurons that lack native supplies.…”