Viral Vector-Mediated Gene Transfer of Glutamic Acid Decarboxylase for Chronic Pain Treatment: A Literature Review

Abstract

Chronic pain is long-lasting nociceptive state, impairing the patient's quality of life. Existing analgesics are generally not effective in the treatment of chronic pain, some of which such as opioids have the risk of tolerance/dependence and overdose death with higher daily opioid doses for increasing analgesic effect. Opioid use disorders have already reached an epidemic level in the United States; therefore, nonopioid analgesic approach and/or use of nonpharmacologic interventions will be employed with increasing frequency. Viral vector-mediated gene therapy is promising in clinical trials in the nervous system diseases. Glutamic acid decarboxylase (GAD) enzyme, a key enzyme in biosynthesis of γ-aminobutyric acid (GABA), plays an important role in analgesic mechanism. In the literature review, we used PubMed and bioRxiv to search the studies, and the eligible criteria include (1) article written in English, (2) use of viral vectors expressing GAD67 or GAD65, and (3) preclinical pain models. We identified 13 eligible original research articles, in which the pain models include nerve injury, HIV-related pain, painful diabetic neuropathy, and formalin test. GAD expressed by the viral vectors from all the reports produced antinociceptive effects. Restoring GABA systems is a promising therapeutic strategy for chronic pain, which provides evidence for the clinical trial of gene therapy for pain in the near future.

Keywords: chronic pain; gene therapy; glutamic acid decarboxylase; viral vectors.

Figure 1.

The role of GABAergic system in the modulation of nociception in the spinal cord dorsal horn. (A) Two glutamic acid decarboxylases GAD67 and GAD65 induce cytoplasmic GABA synthesis from glutamate in the spinal cord dorsal horn. Within the dorsal horn, GABAergic neurons regulate nociceptive signals by GABA-A/B receptors. GABA-A receptor results in Cl⁻ influx and neuronal hyperpolarization, which are mainly located postsynaptically. Metabotropic GABA-B receptors is linked by a Gi protein to both K⁺ channels and calcium channels, leading to a hyperpolarization of the cell body by increasing K⁺ conductance and reducing Ca⁺⁺ currents, finally inducing analgesia. (B) Spinal cord or peripheral nerve injury, HIV infection with ART, and PDN lower the GAD67/GAD65 expression, finally decreasing the synthesis of GABA and inducing functional disinhibition.^,,,, (C) Viral vectors encoding gad1 and/or gad2 gene can increase GAD67/GAD65 synthesis for chronic pain treatment. ART, antiretroviral therapy; GABA, γ-aminobutyric acid; PDN, painful diabetic neuropathy.

Figure 2.

Gene therapy for pain using HSV vectors expressing GAD. After injection of nonreplicating HSV vectors into the skin, the vectors are picked up by the peripheral terminals of the DRG neurons and travel to the cell bodies of primary afferents by retrograde axonal transport. The vectors can establish life-long quiescent state (latency) in the DRG neurons as an intranuclear episomal element. The transgene product GAD from the HSV vectors can be released from nerve terminals in the spinal cord dorsal horn. DRG, dorsal root ganglion; HSV, herpes simplex virus.