A human trial of HSV-mediated gene transfer for the treatment of chronic pain

Abstract

Gene transfer to the dorsal root ganglion using replication defective herpes simplex virus (HSV)-based vectors reduces pain-related behaviors in rodent models having inflammatory pain, neuropathic pain and pain caused by cancer in bone. HSV vectors engineered to produce inhibitory neurotransmitters, including the delta opioid agonist peptide enkephalin, the mu opioid agonist peptide endomorphin-2 and glutamic acid decarboxylase (GAD), to effect the release of gamma amino butyric acid (GABA) act to inhibit nociceptive neurotransmission at the first synapse between primary nociceptive and second-order neuron in the dorsal horn of the spinal cord. HSV vectors engineered to release anti-inflammatory peptides, including interleukin (IL)-4, IL-10 and the p55 soluble tumor necrosis factor alpha (TNFalpha) receptor reduce neuroimmune activation in the spinal dorsal horn. The path leading from preclinical animal studies to the ongoing phase 1 human trial of the enkephalin-producing vector in patients with pain from cancer, and plans for an efficacy trial with an opioid-producing vector in inflammatory pain and an efficacy trial with a GAD-producing vector in diabetic neuropathic pain are outlined.

Figure 1

Subcutaneous inoculation of an HSV vector expressing endomorphin-2 reduces mechanical allodynia in the CFA model of chronic inflammatory pain. Arrow indicates time of vector inoculation. Reprinted from with permission.

Figure 2

Subcutaneous inoculation of an HSV vector expressing GAD attenuates mechanical allodynia in the selective L5 spinal nerve ligation model of chronic neuropathic pain. Arrow indicates time of vector inoculation. Reprinted from with permission.

Figure 3

Schematic of the nonreplicating HSV vector backbone approved by the FDA for human use.