Gene Therapy For Pain Research Articles

Gene Therapy for Pain: A Perspective

Gene Therapy for Pain: A Perspective

Gene therapy for pain: Results of a phase I clinical trial

Preclinical evidence indicates that gene transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)-based vectors can reduce pain-related behavior in animal models of pain. This clinical trial was carried out to assess the safety and explore the potential efficacy of this approach in humans. We conducted a multicenter, dose-escalation, phase I clinical trial of NP2, a replication-defective HSV-based vector expressing human preproenkephalin (PENK) in subjects with intractable focal pain caused by cancer. NP2 was injected intradermally into the dermatome(s) corresponding to the radicular distribution of pain. The primary outcome was safety. As secondary measures, efficacy of pain relief was assessed using a numeric rating scale (NRS), the Short Form McGill Pain Questionnaire (SF-MPQ), and concurrent opiate usage. Ten subjects with moderate to severe intractable pain despite treatment with >200mg/day of morphine (or equivalent) were enrolled into the study. Treatment was well tolerated with no study agent-related serious adverse events observed at any point in the study. Subjects receiving the low dose of NP2 reported no substantive change in pain. Subjects in the middle- and high-dose cohorts reported pain relief as assessed by NRS and SF-MPQ. Treatment of intractable pain with NP2 was well tolerated. There were no placebo controls in this relatively small study, but the dose-responsive analgesic effects suggest that NP2 may be effective in reducing pain and warrants further clinical investigation.

Gene therapy for pain: Introduction to the special issue

Gene therapy was first proposed as an approach to the treatment of recessive inherited disease, in which addition of a correct copy of the mutant gene would restore normal function. Although heuristically attractive, such applications of gene therapy have proven to be a high bar and with few exceptions the focus of gene therapy has moved to approaches designed to ameliorate acquired diseases processes. Chronic pain is an example of a disease process affecting a large proportion of the population for which effective long-term treatments have remained elusive. Recent studies of the mechanisms that underlie the development of chronic pain have created a base of physiological and genetic information that identify multiple points of intervention to treat chronic pain. On the basis of these insights, gene therapy may be used to produce products that block pain transmission or reverse the chronic pain state. In the review chapters provided in this special issue, the most current methods and strategies for treatment of chronic pain are described, which support the development of gene therapy as a potentially practical approach suitable for intervening in the treatment of intractable pain.

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

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.

Gene therapy for pain

Background: Management of chronic pain remains a challenge in spite of the numerous drugs either approved or still in development. Apart from inadequacy of relief, there are concerns about adverse effects and addiction in the case of drugs such as opioids. Gene therapy is being investigated for improving management of pain. Objective: To addresses the rationale of gene therapy for treatment of pain and its advantages over drugs. The prospects of translation of these techniques from experimental animals to clinical use are discussed. Methods: The review is based on the available literature and is confined to experimental work, as there are no approved therapies in this category. Results/conclusion: A number of promising gene therapies as well as antisense- and RNA interference-based approaches have been identified. These provide targeted approaches to delivery of antinociceptive molecules or interruption of pain pathways without subjecting the patient to systemic toxicity of drugs. Some of these approaches are aimed at correcting the underlying pathology of the diseases (e.g., treating degenerative joint diseases causing pain). Management of neuropathic pain is a challenge and a number of studies are addressing it. Overall the future of gene therapy for pain is promising.

A new player in gene therapy for pain?

In a recent report that has garnered notice by the popular press, Beutler and co-workers1 present evidence that intrathecal inoculation of an adeno-associated virus (AAV)-based vector of serotype 8 carrying a sequence coding for prepro-beta-en-dorphin reduces mechanical allodynia in the spinal nerve ligation model of neuropathic pain.

Gene Therapy for Pain

Gene Therapy for Pain

Gene Therapy for Pain

Gene Therapy for Pain

Gene Therapy for Pain

Gene Therapy for Pain

Gene Therapy for Pain

Gene Therapy for Pain