Intrathecal polymer-based interleukin-10 gene delivery for neuropathic pain

Abstract

Research on communication between glia and neurons has increased in the past decade. The onset of neuropathic pain, a major clinical problem that is not resolved by available therapeutics, involves activation of spinal cord glia through the release of proinflammatory cytokines in acute animal models of neuropathic pain. Here, we demonstrate for the first time that the spinal action of the proinflammatory cytokine, interleukin 1 (IL-1) is involved in maintaining persistent (2 months) allodynia induced by chronic-constriction injury (CCI). The anti-inflammatory cytokine IL-10 can suppress proinflammatory cytokines and spinal cord glial amplification of pain. Given that IL-1 is a key mediator of neuropathic pain, developing a clinically viable means of long-term delivery of IL-10 to the spinal cord is desirable. High doses of intrathecal IL-10-gene therapy using naked plasmid DNA (free pDNA-IL-10) is effective, but the dose required limits its potential clinical utility. Here we show that intrathecal gene therapy for neuropathic pain is improved sufficiently using two, distinct synthetic polymers, poly(lactic-co-glycolic) and polyethylenimine, that substantially lower doses of pDNA-IL-10 are effective. In conclusion, synthetic polymers used as i.t. gene-delivery systems are well-tolerated and improve the long-duration efficacy of pDNA-IL-10 gene therapy.

Intrathecal herpes simplex virus type 1 amplicon vector-mediated human proenkephalin reduces chronic constriction injury-induced neuropathic pain in rats

“…intrathecal delivery of recombinant adeno-associated virus expressing the anti-inflammatory gene product human IL-10 or brain-derived neurotrophic factor has been shown to attenuate chronic neuropathic pain after partial nerve injury (32)(33)(34). These studies indicate that the i.t.…”

Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion

“…The antiinflammatory cytokines TGF-β and IL-10 have been implicated in the beneficial effects of BMSCs in asthma and sepsis (28,29). TGF-β and IL-10 also inhibit neuropathic pain and spinal neuroinflammation after nerve injury (30,31). To assess their involvement in BMSC-elicited pain relief, we measured TGF-β1 and IL-10 release in BMSC culture medium.…”

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

“…IL-10 then activates STAT3 signaling by IL-10 receptors 1 and 2, resulting in decreased synthesis of multiple cytokines, including TNF␣, IL-1␤, and IL-6 (de Waal Malefyt et al, 1991;Murray, 2005;Sabat et al, 2010). Supporting the anti-nociceptive and anti-inflammatory properties of IL-10, the administration of exogenous IL-10: 1) decreases TNF␣ induced hyperalgesia and 2) produces prolonged reversal of neuropathic pain when administered in the intrathecal space (Milligan et al, 2006a;Milligan et al, 2006b;Wagner et al, 1998). Clinical research has documented further that there are significantly lower levels of IL-10 in the CSF of patients with chronic pain as compared to age-matched healthy controls (Backonja et al, 2008).…”