Herpes virus-based recombinant herpes vectors: gene therapy for pain and molecular tool for pain science

Abstract

This paper reviews work by Yeomans and Wilson in the area of herpes vector-mediated gene transfer to sensory neurons. Beginning in 1997, these researchers have published a number of papers describing and exploiting this technology in altering the phenotype of pain-sensing neurons (nociceptors). Their initial work, continuing to the present, inserted a transgene cassette encoding the human preproenkephalin gene into the thymidine kinase locus under control of a cytomegalovirus promoter. This vector induced enkephalin expression selectively in the nociceptors innervating the tissue onto which it was applied, producing a profound analgesic and antihyperalgesic in acute and chronic pain models in both rodents and non-human primates. An improved version of this vector is now in clinical trials. In addition to inducing the de novo expression of foreign transgenes, this group also investigated the utility of herpes vectors in altering the endogenous genome of nociceptors. Thus, they inserted antisense sequences for genes of interest in the physiology of these neurons and successfully and selectively knocked down expression of several proteins known or thought to be involved in various pain states, including calcitonin gene-related peptide and mu-opioid receptors. They also used similar techniques to investigate the involvement of acid-sensing ion channels and Nav1.7 sodium channel in different pain states. These experiments uniquely allowed for spatially and temporally selective investigations into the function of these proteins in pain, highly valuable information in target validation for therapy development.