Chronic pain and hypersensitivity associated with inflammation affects millions of Americans. Recently, it has become apparent that a critical mechanism in developing and maintaining inflammatory pain is the overexpression of certain sodium channels in the sensory neurons that innervate the inflamed tissue. Thus, pharmaceutical companies have for some years attempted to develop selective blockers of these sodium channels, but without success. A more promising avenue for the treatment of chronic inflammatory pain might be a gene therapy approach that selectively knocks down the expression of the overexpressed sodium channels. One of the most promising approaches to selectively knocking down or silencing gene expression has been the development of small inhibitory RNAs. RNAi's, and particularly small buttonhook RNAs (shRNA), have shown great promise in producing long duration silencing of aberei1t gene expression. The primary limitation of this technology has been the selective targeting of these molecules to the tissue and cells of interest, in this case, the sensory neurons that mediate pain in inflamed structures. For a number of years, recombinant herpes simplex viruses (those that cause cold sores) have been used as vectors for selective delivery of transgenes to the nuclei of pain sensing neurons. Thus herpes viruses are naturally neurotropic, and an estimated 85% of the US population have these viruses in our sensory neurons at anyone time. The toxicity of these viruses is remarkably low naturally, and the recombinant viruses in use for gene therapy purposes are non-replicating, thus, removing residual toxicity. Thus, recombinant herpes viruses, encoding a transgene of interest, applied to peripheral tissue, e.g., skin, are taken up by the terminals of sensory neurons, transported back to the cell bodies, and exist as endosomes in the nucleus of these cells, presenting the transgene to the transcription machinery of the cell. Work in rodents and primates has demonstrated prolonged (> 20 wks) transgene expression using these means, limited to the cells that innervate the treated tissue. In this Phase I project, it is our intention to use herpes vectors to deliver shRNAs directed toward silencing the expression of particular sodium channels to the sensory neurons innervating the inflamed tissue of mice. It is our long term goal to develop herpes based gene therapy vectors for the treatment of inflammatory and other chronic pain states in patient
