The present proposal is an extension of an ongoing 2-yr R21 (Watkins, P.I.) under the NIDA CEBRA program.
Its aims are focused on developing a new therapy for pain. Controlling chronic pain in humans is a major unresolved problem. Recent data strongly suggest that spinal cord gila (astrocytes & microglia) are critically involved in the creation & maintenance of diverse enhanced pain states. Spinal cord gila create enhanced pain via the release of proinflammatory cytokines (PlCs): tumor necrosis factor (TNF), interleukin-1 (IL1) & interleukin-6 (IL6). Recognition of the key importance of spinal cord gila & glial PICs in pathological pain opens new avenues for pain control. There are various pharmacological means available to control glial dysregulation of pain. Interleukin-10 (IL10) is very promising from a clinical point of view.' IL10 is an anti-inflammatory cytokine, which acts as an endogenous suppressor of proinflammatory cytokine production & activity. IL10 is an excellent candidate for preventing & reversing PIC-driven pathological pain states. However, two practical problems need to be overcome. First, control of chronic pain requires chronic delivery of IL10. Second, IL10 cannot cross the blood-brain barrier, thus negating systemic administration. To resolve these issues, we are exploring the feasibility of prolonged spinal release of Ll10 induced by gene therapy. Here, vectors encoding IL10 are injected into the cerebrospinal fluid surrounding the spinal cord (intrathecal; IT), so as to mimic a clinically relevant route of delivery. Our preliminary data provide strong support that spinal gene therapy with IL10 will prevent & reverse enhanced pain states.
The aims of the present proposal are straightforward: (1) To identify the optimal vectors from a limited number of candidates, in terms of their effectiveness in transcribing the gene of interest & reversing clinically relevant pain models; (2) To examine the mechanisms by which these optimal IL10-inducing vectors exert their effects in spinal cord; and (3) to examine potential short-comings of this approach. Together, these studies will test the premise that gene therapy with IL10 is worthy of clinical development for controlling diverse pathological pain states. This approach to pain control represents a dramatic departure from all other available therapies.
|Vanderwall, Arden G; Noor, Shahani; Sun, Melody S et al. (2018) Effects of spinal non-viral interleukin-10 gene therapy formulated with d-mannose in neuropathic interleukin-10 deficient mice: Behavioral characterization, mRNA and protein analysis in pain relevant tissues. Brain Behav Immun 69:91-112|
|Sanchez, Joshua J; Noor, Shahani; Davies, Suzy et al. (2017) Prenatal alcohol exposure is a risk factor for adult neuropathic pain via aberrant neuroimmune function. J Neuroinflammation 14:254|
|Whitehead, Ryan A; Lam, Nicholas L; Sun, Melody S et al. (2017) Chronic Sciatic Neuropathy in Rat Reduces Voluntary Wheel-Running Activity With Concurrent Chronic Mechanical Allodynia. Anesth Analg 124:346-355|
|Noor, Shahani; Sanchez, Joshua J; Vanderwall, Arden G et al. (2017) Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels. Brain Behav Immun 61:80-95|
|Dengler, Ellen C; Alberti, Lauren A; Bowman, Brandi N et al. (2014) Improvement of spinal non-viral IL-10 gene delivery by D-mannose as a transgene adjuvant to control chronic neuropathic pain. J Neuroinflammation 11:92|
|Dengler, Ellen C; Liu, Juewen; Kerwin, Audra et al. (2013) Mesoporous silica-supported lipid bilayers (protocells) for DNA cargo delivery to the spinal cord. J Control Release 168:209-24|
|Wilkerson, Jenny L; Gentry, Katherine R; Dengler, Ellen C et al. (2012) Immunofluorescent spectral analysis reveals the intrathecal cannabinoid agonist, AM1241, produces spinal anti-inflammatory cytokine responses in neuropathic rats exhibiting relief from allodynia. Brain Behav 2:155-77|
|Milligan, Erin D; Penzkover, Kathryn R; Soderquist, Ryan G et al. (2012) Spinal interleukin-10 therapy to treat peripheral neuropathic pain. Neuromodulation 15:520-6; discussion 526|
|Wilkerson, Jenny L; Gentry, Katherine R; Dengler, Ellen C et al. (2012) Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels. Pain 153:1091-106|
|Wilkerson, Jenny L; Milligan, Erin D (2011) The Central Role of Glia in Pathological Pain and the Potential of Targeting the Cannabinoid 2 Receptor for Pain Relief. ISRN Anesthesiol 2011:|
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