Enhanced functional recovery from spinal cord injury following intrathecal or intramuscular administration of poliovirus replicons encoding IL-10

Abstract

Poliovirus-based vectors (replicons) have been shown to maintain the in vitro tropism of poliovirus for motor neurons of the CNS. To determine if replicons could be effective for delivery of potentially beneficial proteins to the CNS, we have constructed and characterized a replicon encoding IL-10. IL-10 was rapidly produced in tissue culture cells following in vitro infection with replicons encoding IL-10. Intrathecal inoculation of replicons encoding IL-10 into the non-injured CNS of mice transgenic for the poliovirus receptor resulted in expression of IL-10 within motor neurons at 24-48 h post-inoculation, which subsided by 72-96 h post-inoculation. Single intrathecal or intramuscular injections of replicons were given following spinal cord trauma. Animals receiving replicons encoding IL-10 demonstrated a greater functional recovery in the first 24 h after injury that was maintained throughout the testing period. Compared to animals given replicons encoding gfp, CNS tissue from animals given replicons encoding IL-10 revealed extensive expression of IL-10 from astrocytes around the CNS lesion during the first week following injury. The expression of IL-10 from astrocytes also correlated with more resting microglia as opposed to the rounded activated microglia seen in animals given replicons encoding gfp. Results of these studies establish that replicons can be used to express biologically active molecules in motor neurons of the CNS and these biologically active molecules can have a direct effect on the CNS or induce a cascade of molecules that can influence the cellular composition and activation state of cells within the CNS.

Immunomodulatory and neuroprotective effect of cryopreserved allogeneic mesenchymal stem cells on spinal cord injury in rats

“…Some of the results include a reduction in the inflammatory infiltrate, activation of cells in the microglia with an anti-inflammatory phenotype (Wirjatijasa et al, 2002), increase in neuronal survival (Brewer et al, 1999, Jackson et al, 2005Zhou et al, 2009), reduction in the activation of astrocytes , and improvement of motor function Jackson et al, 2005;Zhou et al, 2009). In all of these studies, beneficial effects were observed when IL-10 was increased in the first 24 h after spinal cord injury Brewer et al, 1999;Jackson et al, 2005;Zhou et al, 2009), as observed in the present study. Therefore, IL-10 may be involved in reducing the inflammatory infiltrate by activating microglia/macrophage cells with an anti-inflammatory phenotype and reducing astrocyte activation.…”

“…This cytokine displayed anti-inflammatory action, either by direct administration or by the use of other treatments that lead to its increase Brewer et al, 1999;Jackson et al, 2005;Zhou et al, 2009). Some of the results include a reduction in the inflammatory infiltrate, activation of cells in the microglia with an anti-inflammatory phenotype (Wirjatijasa et al, 2002), increase in neuronal survival (Brewer et al, 1999, Jackson et al, 2005Zhou et al, 2009), reduction in the activation of astrocytes , and improvement of motor function Jackson et al, 2005;Zhou et al, 2009). In all of these studies, beneficial effects were observed when IL-10 was increased in the first 24 h after spinal cord injury Brewer et al, 1999;Jackson et al, 2005;Zhou et al, 2009), as observed in the present study.…”

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

“…IL‐10 has been demonstrated to promote functional recovery in SCI models in rats66, 67, 68, 69, 72, 73, 74 and mice 58, 64, 65, 70, 71. IL‐10 affects inflammation through regulation of activation of microglia/macrophages70, 71 and astrocytes,72 as well as reducing the production of TNF‐α,72, 73 IL‐1β, S100β, and inducible nitric oxide synthase (iNOS) 65.…”

“…Jackson et al intrathecally injected poliovirus vectors to express IL‐10 in SCI animals 70. This treatment inhibited microglia activation and improved functional recovery.…”

CD34+ hematopoietic stem cells support entry and replication of poliovirus: a potential new gene introduction route

“…First-generation transcapsidation systems have been developed: these may potentially permit delivery of up to 7 kb nucleic acids. 54 Examples of genes that have been delivered this way include biologically active murine tumor necrosis factor a, 55 green fluorescent protein, [56][57][58] murine interleukin-2, 59 HIV-1/SIV antigens, 60,61 interleukin-10, 62 Helicobacter pylori urease, 63 firefly luciferase 64 and tetanus toxin. 65 These systems present the advantage of a nonintegrating, nonreplicating vector with high, transient expression levels.…”