Viral Vector-based Gene Transfer for Treatment of Chronic Pain

Abstract

Acute pain is a normal physiologic adaptive response to noxious stimuli that is essential for survival and maintenance of the integrity of the organism. Chronic pain, on the other hand, is a maladaptive, pathologic and persistent condition that results in a marked decrease in the quality of life and secondary symptoms such as anxiety and depression. Chronic pain is a common phenomenon. It is estimated that more than 50 million people in the United State alone are affected by chronic pain. Much of currently available clinic treatments for chronic pain are only partially effective and many are limited by off-target side effects, or have the potential of abuse.1 Furthermore, analgesics that are highly effective in the management of pain often provide only very short-term relief, and some forms of pain, for example, neuropathic pain are practically difficult to treat.2 In recent years, significant progress has been made in the fundamental understanding of the neurobiology of pain. In parallel, detailed molecular biologic characteristics of many of the receptors, neurotransmitters, neuropeptides, cytokines, chemokines, and ion channels that play significant roles in nociception have become available.3,4 Taking advantage of these advances, therapeutic gene transfer is emerging as an intriguing option for the development of novel treatment for chronic pain. Gene therapy was first proposed as a treatment for genetically determined inherited disorders5 and the first successful human gene therapy for X-linked severe combined immunodeficiency in children, was reported 6 years ago.6 Therapeutic gene transfer for treatment of chronic pain is not directed at correcting a genetic defect. Rather the regional specialization of spinal cord and/or brain function and the widespread and redundant use of a limited repertoire of neurotransmitters and receptors in diverse pathways in the nervous system means that the local production of neurotransmitters achieved by therapeutic gene transfer may be used to achieve desired outcomes while avoiding unwanted adverse side effects that would result from activation of the same receptors in other pathways by a systemically administered drug.7 In this review we summarize recent studies of recombinant virus vectors for in vivo pain treatment in animal. Viruses have the ability to infect and transduce their genome into host cells, and viral vector-based gene therapy takes advantage of the natural biology of virus to transduce exogenous genes into host cells. The general principle for creating a viral vector involves the deletion of nonessential genes from the virus, incapacitating its replication and, therefore, rendering it nonpathogenic, while retaining the structural motifs that allows the vector attach and transfer its genome into the host. Recently developed viral vectors provide a powerful vehicle for effective gene transfer to the nervous system.8 An ideal vector for gene therapy should achieve stable, tissue-specific regulated gene expression without eliciting the host immune response.9 The vector must possess sufficient capacity to carry the transgene, efficiently deliver that gene to the cell of interest, and express appropriate amounts of transgene product to provide a therapeutic effect, all without detectable toxicity resulting from the vector itself.10 It should be noted that rendering a virus replication deficient does not assure elimination of direct cytotoxicity or abolition of host immune response caused by expression of other viral proteins not critical for replication.11 The most commonly used viral vectors in studies of treatment of pain are based on recombinant adenovirus, adeno-associated virus (AAV), or herpes simplex virus. We will review the published data for each of these vectors below.