Applications of Gene Therapy to the Treatment of Chronic Pain

Abstract

Chronic pain is a highly prevalent condition that impacts adversely on individual quality of life, imposes substantial costs on the healthcare system and a considerable burden on society. Advances in the understanding of pain mechanisms have opened the way for the development of new treatment strategies. The continuous delivery of short-lived potent bioactive molecules to sensory nerves, spinal cord or meninges -achieved by directed gene transfer -offers the possibility to selectively interrupt nociceptive neurotransmission or to interfere with the plastic changes in the nervous system underlying the development or persistence of chronic pain. In this review we describe advances in the use of non-viral and viral vector-based gene transfer for the treatment of pain, with a special focus on the use of recombinant non-replicating herpes simplex virus-based vectors and the prospects for clinical trials.

Pharmacogenetics and Obstetric Anesthesia and Analgesia

“…The design and execution of large clinical studies analyzing multiple haplotypes simultaneously remains to be the true challenge to date. Meanwhile, a genome-wide study in the context of acute post-operative pain was published 21 , the possible impact of epigenetics-based strategies for pain therapy is proposed 72 and researchers are actively working on gene therapies for chronic pain [73][74][75] . It will also be of interest to see the new insights and developments brought by more research on the SCN9A gene, a gene involved in channelopathies that result in the inability to experience pain, and potential targeted therapies 76 .…”

Development of Viral Vectors for Gene Therapy for Chronic Pain

“…Anti-inflammatory cytokines expressed by viral vector-mediated therapeutic gene can reduce central neuroimmune activation. Antisense or RNA sequences enact their analgesic effect by reducing the expression of gene products essential to the development of chronic pain [2]. …”

“…This leads to great suffering for patients and results in a heavy burden for society. Chronic pain is not simply related to anatomical reorganization; other changes in neurotransmission and electrophysiological activity are also involved in the pain pathway [2]. Conventional drug treatment has many limitations, such as drug dependence, tolerance, respiratory depression, and other systemic side effects.…”

HSV Recombinant Vectors for Gene Therapy

“…Gene transfer is a promising strategy that might circumvent these limitations [55]. Replication-defective HSV vectors have been tested in several different models of neuropathy leading up to studies in diabetes [56-61].…”

“…Defective HSV-1-derived vectors expressing anti-inflammatory cytokines, such as IL-4 or IL-10 [39, 73], have been deeply studied to examine the involvement of cytokines in the development of inflammatory pain. Mata and colleagues have demonstrated, in a rat model of inflammatory pain, that expression of IL-10 by a HSV-1 vector in DRG prevents activation of p38 mitogen-activated protein kynase (p38 MAPK) and expression of full-length membrane-spanning tumour necrosis factor-α (mTNFα) in dorsal horn and spinal cord, suggesting the involvement of TNFα in the development of inflammatory and neuropathic pain [55, 74]. Plans for an efficacy trial with an opioid producing vector in inflammatory pain and with a GAD producing vector in diabetic neurophatic pain are outlined.…”