Gene Therapy for Chronic Pain Management | InTechOpen

Posted: March 8, 2015 at 12:51 pm

1. Introduction

This chapter provides an overview of the main current applications of gene therapy for chronic pain in what concerns animal studies and putative clinical applications. The value of gene therapy in unravelling neuronal brain circuits involved in pain modulation is also analysed. After alerting to the huge socioeconomic impact of chronic pain in modern societies and justifying the need to develop new avenues in pain management, we review the most common animal studies using gene therapy, which consisted on deliveries of replication-defective viral vectors at the periphery with the aim to block nociceptive transmission at the spinal cord. Departing from the data of these animal studies, we present the latest results of clinical trials using gene therapy for pain management in cancer patients. The animal studies dealing with gene delivery in pain control centres of the brain are analysed in what concerns their complexity and interest in unravelling the neurobiological mechanisms of descending pain modulation. The chapter will finish by analysing possible futures of gene therapy for chronic pain management based on the development of vectors which are safer and more specific for the different types of chronic pain.

Pain is not easy to define since it is a highly subjective experience. The more consensual definition of pain was provided by the International Association for the Study of Pain (IASP) and states that Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [1]. Acute pain is important as an alert signal to potentially threaten situations (internal or external to the organism) and it is important for survival. Acute pain may progress to chronic pain which, according to IASP, is the pain that lasts more than 3 months and persists beyond the normal tissue healing time [2].

Chronic pain may be divided into "nociceptive" and "neuropathic" [3]. Nociceptive pain is caused by activation of nociceptors, the thin nerve fibers which convey nociceptive input from the periphery to the spinal cord. Neuropathic pain is caused by malfunction or damage of the nervous system. Neuropathic pain is frequently difficult to treat being associated to spontaneous pain, exaggerated responses to nociceptive stimuli (hyperalgesia) and nociceptive responses to stimuli which are usually non-nociceptive (allodynia).

The number of people affected by chronic pain is increasing due to multifactorial causes such as increasing aging of the population. In Europe, about 20% of people suffer from moderate to severe chronic pain [4]. In the United States the prevalence of chronic pain ranges from 2% to 40%, with a median of 15% [5], which cost the country 560 to 635 million dollars [6]. People suffering from chronic pain are less able to walk, sleep normally, perform social activities, exercise or have sexual relations. Chronic pain strongly affects the productivity. About 60% of chronic pain patients are unable or less able to work, 19% lost their jobs and 13% change jobs due to their pain [6]. Chronic pain is associated to several co-morbidities, namely depression and anxiety [6]. Besides all of these indirect costs, chronic pain is a burden due to direct costs of pain management. Despite major investments in basic and clinical pain research, the available analgesics remain considerably unchanged during the last decades. Opioids are useful to manage several pain types but they have a modest efficacy in several pain conditions (e.g. neuropathic pain). Furthermore, long term treatments with opioids frequently induce severe off-target effects, like nausea, constipation and addiction [7]. Intractable pain remains a clinical problem and a drama for the patients and their families [8]. During the last decade, pain clinicians and pain researchers were challenged to search for alternatives to conventional pain treatment, which should be more specific and sustained than conventional analgesics. Gene therapy outstands as a powerful technique to overcome some current problems of chronic pain treatments.

Neurobiological research in the pain field provided solid information regarding the transmission and modulation of nociceptive information from the periphery to the brain, where a pain sensation is produced (Fig. 1). Nociceptive signals are conveyed by primary afferent fibers from peripheral organs, like the bladder or muscles, to the spinal cord. This is the first relay station involved in the modulation of nociceptive information namely by local inhibitory interneurons that use opioid peptides or aminoacids (-amminobutiric acid-GABA- and glycine). Nociceptive information is then transmitted supraspinally, namely to the thalamus, and to several brainstem areas, where additional modulation of the nociceptive signal occurs. The thalamo-cortical pathway ensures that the nociceptive information reaches the somatosensory and prefrontal cortices, where the nociceptive signal is finally perceived as a pain sensation [9, 10]. Some brain areas which directly or indirectly receive nociceptive information from the spinal cord are also involved in descending pain modulation. Both inhibition and facilitation may occur and chronic pain may derive from a reduction of the former and enhancement of the latter [9, 11]. This neurobiological knowledge has been used to design gene therapy studies for chronic pain, namely to choose the somatosensory system areas and neurotransmitters/receptors to be targeted in order to block nociceptive transmission.

Schematic diagram of pain pathways involved in pain transmission and modulation. Nociceptive information is transmitted from the periphery to the spinal dorsal horn by primary sensory neurons. At the spinal level, these neurons transmit nociceptive information to second order neurons (Ascending pathways) through the release of neurotransmitters like the excitatory amino acids (EAA) glutamate and aspartate, calcitonin gene-related peptide (CGRP), substance P (SP) galanin (Gal) and neuropeptide Y (NPY). In the brain, the nociceptive information is then perceived as a pain sensation. The transmission of nociceptive information at the spinal level is modulated by interneurons (mainly inhibitory) through the release of opioid pepides and GABA and also by supraspinal descending neurons (Descending pathways) through the release of serotonin (5-HT) and noradrenaline (NA). Descending pathways may inhibit or enhance nociceptive transmission from the spinal cord.

Gene therapy is an especially versatile tool for chronic pain management since it is based in a triad of controllable parameters: the vector, the transgene and the promoter. By knowing the neurobiological features of each chronic pain type, namely the neurotransmitters and receptors affected, it is possible to design gene therapy strategies based on the best combination of vectors, transgenes and promoters. As to vectors, gene therapy for pain uses mainly vehicles which have a certified experience in infecting neurons, namely replication-defective forms of viruses. Non-viral vectors have seldom been used in gene therapy studies for pain but their transduction efficiency and specificity are much lower than those of viral vectors. Some of these vectors have the ability to migrate retrogradely (i.e., contrary to the direction of nerve impulse) which is very useful to target neurons that are located in structures of difficult surgical access. A good example is the application of replication-defective forms of Herpes Simplex Virus type 1 (HSV-1) at the periphery (e.g. the skin) to transduce neurons at the spinal ganglia (dorsal root ganglia-DRGs), which are difficult to access due to their bone protection. Regarding the transgenes to include in the vectors for gene therapy of pain, it is possible to increase the expression of neurotransmitters and receptors involved in nociceptive inhibition (e.g. opioids), neurotrophic factors or substances with anti-inflammatory properties. Finally, and in what concerns the promoters, it is possible to choose those that restrict transgene expression to a cell type, such as a neuron or a glial cell, or even target selective neurochemical neuronal populations. Examples of neuron-specific promoters are synapsin I, calcium/calmodulin-dependent protein kinase II, tubulin alpha I and neuron-specific enolase [12]. Some possibilities of controlling the vectors, transgenes and promoters will be discussed in the next two sections using gene therapy in animal models.

One of the main advantages of experimental gene therapy studies is that they can be performed using several pain models. This is important since each pain type may induce specific changes in neuronal circuits devoted to the transmission and modulation of nociceptive transmission [13]. Studies of gene therapy for pain have used clinically relevant models of inflammatory [14-22] and neuropathic pain [23-34]. In a much lower incidence, models of acute [35-38], post-operative pain [39] and cancer [40] pain have been used in experimental gene therapy studies. The large majority of studies were performed in pain models affecting the limbs or the trunk, in the latter case being of visceral origin [22, 37]. Two studies used gene therapy to block nociceptive transmission coming from the head/face in pain models that reproduces some types of craniofacial pain, like trigeminal neuralgia [41] or temporomandibular joint disorders [42].

Gene therapy studies for pain in animal models may be divided in studies targeting the spinal cord (Table 1) and studies directed to pain control centres located in the brain (Table 2). Studies directed to the spinal cord mainly aim to manipulate the expression of transgenes in order to block the transmission of nociceptive input at the spinal dorsal horn (Table 1). Most of the spinal cord studies using gene therapy for pain elected HSV-1 as the most suitable vector, due to its natural affinity to the neuron and its ability for retrograde transport [43]. HSV-1 has the additional advantage over other vectors of carrying multiple transgenes or large transgenes and not integrating in the host genome, which reduces the possibility of mutagenic events [44, 45]. After application of replication-defective forms of HSV-1 at the periphery in order to transduce DRG neurons (or trigeminal ganglion neurons), delivery of the transgene product by the spinal branch of transduced neurons at the spinal dorsal horn induced analgesia in several rodent models of pain (Table 1). Gene therapy in animal models of craniofacial pain [41, 42] aimed to release the transgene products at the level of the spinal trigeminal nucleus and this structure is homolog of the spinal cord, which prompted to include these studies in the section devoted to spinal cord studies.

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Gene Therapy for Chronic Pain Management | InTechOpen

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