Gene Therapy for Chronic Neuropathic Pain: How Does It Work and Where Do We Stand Today?

Kumar, Sanjeev; Ruchi, Rupam; James, Stephen R.; Chidiac, Elie Joseph

doi:10.1111/j.1526-4637.2011.01120.x

Cited by 10 publications

(7 citation statements)

References 132 publications

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“…Neuropathic pain presents as nerve damage or functional defects [15]. The spinal dorsal horn is an important component that transmits and controls the nociception transmitted from the peripheral nociceptors [16,17].…”

Section: Discussionmentioning

confidence: 99%

Intrathecal Administration of Mesenchymal Stem Cells Reduces the Reactive Oxygen Species and Pain Behavior in Neuropathic Rats

Zhang

Song

et al. 2014

Korean J Pain

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BackgroundNeuropathic pain induced by spinal or peripheral nerve injury is very resistant to common pain killers, nerve block, and other pain management approaches. Recently, several studies using stem cells suggested a new way to control the neuropatic pain. In this study, we used the spinal nerve L5 ligation (SNL) model to investigate whether intrathecal rat mesenchymal stem cells (rMSCs) were able to decrease pain behavior, as well as the relationship between rMSCs and reactive oxygen species (ROS).MethodsNeuropathic pain of the left hind paw was induced by unilateral SNL in Sprague-Dawley rats (n = 10 in each group). Mechanical sensitivity was assessed using Von Frey filaments at 3, 7, 10, 12, 14, 17, and 24 days post-ligation. rMSCs (10 µl, 1 × 105) or phosphate buffer saline (PBS, 10 µl) was injected intrathecally at 7 days post-ligation. Dihydroethidium (DHE), an oxidative fluorescent dye, was used to detect ROS at 24 days post-ligation.ResultsTight ligation of the L5 spinal nerve induced allodynia in the left hind paw after 3 days post-ligation. ROS expression was increased significantly (P < 0.05) in spinal dorsal horn of L5. Intrathecal rMSCs significantly (P < 0.01) alleviated the allodynia at 10 days after intrathecal injection (17 days post-ligation). Intrathecal rMSCs administration significantly (P < 0.05) reduced ROS expression in the spinal dorsal horn.ConclusionsThese results suggest that rMSCs may modulate neuropathic pain generation through ROS expression after spinal nerve ligation.

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Section: Discussionmentioning

confidence: 99%

Intrathecal Administration of Mesenchymal Stem Cells Reduces the Reactive Oxygen Species and Pain Behavior in Neuropathic Rats

Zhang

Song

et al. 2014

Korean J Pain

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“…Viral transduction induces a strong immune response and the duration of gene transduction is limited [22]. Toxicity with viral vectors remains a concern; study subjects have died during clinical trials of adenovirus vectors [10] and adeno-associated virus vectors [7].…”

Section: Introductionmentioning

confidence: 99%

Ex vivo nonviral gene delivery of μ-opioid receptor to attenuate cancer-induced pain

Yamano¹,

Viet

Dang

et al. 2016

Pain

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Virus-mediated gene delivery shows promise for treatment of chronic pain. However, viral vectors have cytotoxicity. To avoid toxicities and limitations of virus-mediated gene delivery, we developed a novel non-viral hybrid vector: HIV-1 Tat peptide sequence modified with histidine and cysteine residues combined with a cationic lipid. The vector has high transfection efficiency with little cytotoxicity in cancer cell lines including HSC-3 (human tongue squamous cell carcinoma) and exhibits differential expression in HSC-3 (~45-fold) relative to HGF-1 (human gingival fibroblasts) cells. We used the non-viral vector to transfect cancer with OPRM1, the μ-opioid receptor gene, as a novel method for treating cancer-induced pain. After HSC-3 cells were transfected with OPRM1, a cancer mouse model was created by inoculating the transfected HSC-3 cells into the hind paw or tongue of athymic mice to determine the analgesic potential of OPRM1 transfection. Mice with HSC-3 tumors expressing OPRM1 demonstrated significant antinociception compared to control mice. The effect was reversible with local naloxone administration. We quantified β-endorphin secretion from HSC-3 cells, and showed that HSC-3 cells transfected with OPRM1 secreted significantly more β-endorphin than control HSC-3 cells. These findings indicate that non-viral delivery of the OPRM1 gene targeted to the cancer microenvironment has an analgesic effect in a preclinical cancer model, and non-viral gene delivery is a potential treatment for cancer pain.

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“…2 More recently, herpes simplex virus (HSV)-based gene transfer with specific targeting of primary sensory neurons in dorsal root ganglia (DRGs) has been used to treat neuropathic pain in animal models. 3 Based on the natural neurotropism of HSV1, peripheral intradermally injected HSV1 vectors expressing antinociceptive genes are taken up by sensory nerve endings and transported in a retrograde manner to DRGs where the antinociceptive gene products are produced. These products are released in the dorsal horn of the spinal cord (SC) where they modulate nociceptive neurotransmission between primary nociceptors and second-order neurons.…”

Section: Introductionmentioning

confidence: 99%

Comparative effectiveness of antinociceptive gene therapies in animal models of diabetic neuropathic pain

et al. 2012

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Peripheral neuropathic pain is one of the most common and debilitating complications of diabetes. Several genes have been shown to be effective in reducing neuropathic pain in animal models of diabetes after transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)1-based vectors, yet there has never been a comparative analysis of their efficacy. We compared four different HSV1-based vectors engineered to produce one of two opioid receptor agonists (enkephalin or endomorphin), or one of two isoforms of glutamic acid decarboxylase (GAD65 or GAD67), alone and in combination, in the streptozotocin-induced diabetic rat and mouse models. Our results indicate that a single subcutaneous hindpaw inoculation of vectors expressing GAD65 or GAD67 reduced diabetes-induced mechanical allodynia to a degree that was greater than daily injections of gabapentin in rats. Diabetic mice that developed thermal hyperalgesia also responded to GAD65 or endomorphin gene delivery. The results suggest that either GAD65 or GAD67 vectors are the most effective in the treatment of diabetic pain. The vector combinations, GAD67 + endomorphin, GAD67 + enkephalin or endomorphin + enkephalin also produced a significant antinociceptive effect but the combination did not appear to be superior to single gene treatment. These findings provide further justification for the clinical development of antinociceptive gene therapies for the treatment of diabetic peripheral neuropathies.

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Gene Therapy for Chronic Neuropathic Pain: How Does It Work and Where Do We Stand Today?

Cited by 10 publications

References 132 publications

Intrathecal Administration of Mesenchymal Stem Cells Reduces the Reactive Oxygen Species and Pain Behavior in Neuropathic Rats

Intrathecal Administration of Mesenchymal Stem Cells Reduces the Reactive Oxygen Species and Pain Behavior in Neuropathic Rats

Ex vivo nonviral gene delivery of μ-opioid receptor to attenuate cancer-induced pain

Comparative effectiveness of antinociceptive gene therapies in animal models of diabetic neuropathic pain

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