Controlling Neuropathic Pain by Adeno-Associated Virus Driven Production of the Anti-Inflammatory Cytokine, Interleukin-10

Milligan, Erin D.; Sloane, Evan M.; Langer, Shelby L.; Cruz, Pedro; Chacur, Marucia; Spataro, Leah E.; Wieseler-Frank, Julie; Hammack, Sayamwong E.; Maier, Steven F.; Flotte, Terence R.; Forsayeth, John; Leinwand, Leslie A.; Chavez, Raymond A.; Watkins, Linda R.

doi:10.1186/1744-8069-1-9

Cited by 166 publications

(145 citation statements)

References 66 publications

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“…Nitric oxide was found to be key in mediating elevations of IL1, TNF and IL6 mRNA and protein in lumbar spinal cord leading to allodynia in gp120-treated animals (Holguin et al, 2004). In addition, IL-1 was shown to be important for the maintenance of neuropathic pain states because established neuropathic pain can be reversed either by proinflammatory cytokine antagonists or by the anti-inflammatory cytokine interleukin-10 (IL10) (Abraham et al, 2004, Johnston et al, 2004, Ledeboer et al, 2007, Milligan et al, 2005a, Milligan et al, 2005b, Milligan et al, 2006a, Milligan et al, 2006b, Plunkett et al, 2001, Sloane et al, submitted, Yu et al, 2003 that inhibits the production and activity of proinflammatory cytokines ). Such results are important when one is considering the potential of targeting proinflammatory cytokines for clinical pain control.…”

Section: Pathological Pain Statesmentioning

confidence: 99%

“…Gene-encoding vectors, such as viral and non-viral vectors to deliver the IL-2, IL-4 or IL-10 gene to the spinal cord to control pain in neuropathic rodent models have been examined and show promise (Hao et al, 2006, Ledeboer et al, 2007, Milligan et al, 2005a, Milligan et al, 2005b, Yao et al, 2003, Yao et al, 2002a, Yao et al, 2002b. For example, spinal cord over-expression of IL-10 controls pain produced by sciatic inflammatory neuropathy and chronic constriction injury (Milligan et al, 2005a, Milligan et al, 2007, Milligan et al, 2005b. The duration of pain control by spinal IL-10 gene therapy was observed from 1-3 months (Milligan et al, 2006a, Sloane et al, submitted).…”

Section: Targeting Activated Glia With Anti-inflammatory Cytokines Tomentioning

confidence: 99%

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Glia in pathological pain: A role for fractalkine

Milligan

Sloane

Watkins

2008

Journal of Neuroimmunology

104

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Microglia and/or astrocytes play a significant role in the creation and maintenance of exaggerated pain states with inflammatory and/or neuropathic etiologies. The chemokine, fractalkine, has several functions, including the newly recognized role of mediating neuropathic pain conditions. Although constitutively expressed and released during inflammation, increased release of fractalkine binds to and activates microglia glia leading to pathological pain. We review the critical role of fractalkine in neuron-to-glial communication after peripheral nerve injury and inflammation and explore anti-inflammatory cytokines like interleukin-10 as a novel and effective approach for clinical pain control. KeywordsNeuropathic pain; spinal cord; microglia; astrocytes; interleukin-10; gene therapy Previously Understood Views of PainTraditionally, our understanding about neuronal signaling for pain transmission from the body to the central nervous system (CNS) occurs as a series of relay signals that are eventually processed in the brain. These relay signals are thought to serve protective and adaptive roles, with the first synaptic relay, between the first order (sensory) neuron and the second order neuron in the dorsal horn of the spinal cord. Neurons that receive and respond to pain information are primarily located in anatomically discrete regions of the spinal cord, that is, laminae I, II and V of the spinal cord dorsal horns. From the spinal cord dorsal horn, pain projection neurons relay their information to higher pain centers, such as to the brainstem and various relevant pain areas in the brain. Interestingly, the dorsal horn of the spinal cord can strongly modulate pain signaling (Millan, 1999). Although the neuronal functioning of these pain pathways has been examined for decades, the induction and maintenance of non-adaptive, pathological pain is poorly understood. However, since the early 1990's, there has been mounting evidence that glial cells (both astrocytes and microglia), in addition to neurons, also play a critical role in pain modulation (DeLeo et al., 2007).

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Section: Pathological Pain Statesmentioning

confidence: 99%

Section: Targeting Activated Glia With Anti-inflammatory Cytokines Tomentioning

confidence: 99%

Glia in pathological pain: A role for fractalkine

Milligan

Sloane

Watkins

2008

Journal of Neuroimmunology

104

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“…Preclinical studies of chronic pain have used several gene therapy vectors (Cope et al, 2006). Adenoviral, AAV, and HSV vectors have been used to deliver therapeutic genes including β-endorphin (Finegold et al, 1999), proopiomelanocortin (Lu et al, 2002), interleukin 2 (IL-2) (Yao et al, 2003), proenkephalin-A (Braz et al, 2001), IL-10 (Milligan et al, 2005a;Milligan et al, 2005b), glial-derived growth factor (Hao et al, 2003) and neurotrophin-3 (Pradat et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

et al. 2006

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First-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of antiadenovirus immune responses expression in the brain lasts 6-18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, ≥1 × 10 7 infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates >90% of transgene expression from 1 × 10 7 -1 × 10³ iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8 + T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1 × 10 7 iu) is crossed, the immune response eliminates transgene expression by >90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression.

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“…Long-term gene expression by rAAV is such a universal finding in laboratory animals regardless of the organ targeted or the transgene used, that a finding of early cessation of vector activity (for example, Milligan et al, 21 ) should raise concerns, whether the observed gene transfer was indeed due to rAAV or instead due to a contaminant (that should have been removed from the vector preparation) such as plasmid DNA.…”

Section: Favorable Characteristics: Targeting Of Non-dividing Cells Amentioning

confidence: 99%

AAV for pain: steps towards clinical translation

Beutler

Reinhardt

2009

Gene Ther

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Recombinant adeno-associated virus (rAAV) vectors consisting of self-complementary genomes and packaged in certain capsids can target primary sensory neurons efficiently and can control neuropathic pain long term by expressing opioid or non-opioid analgesic genes. This review examines the therapeutic potential of the approach in five sections: Pain control in oncology (including a discussion of cancer centers as translational pain research environment); vector biology; safety considerations and immunological lessons learned from rAAV clinical trials of other disorders; development of intrathecal rAAV therapy in rodent models of pain; and preclinical steps towards clinical translation of rAAV for pain. In the field of analgesic drug development, clinical validation of new approaches identified in rodents is currently a critical limiting step. Small-molecule therapeutics suitable as conventional drugs to probe novel targets in clinical trials are often unavailable. In this context, gene therapy could fill an important gap in the drug development process facilitating first-into-human trials of untested targeted treatments, each instantiated as a therapeutic gene.

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Controlling Neuropathic Pain by Adeno-Associated Virus Driven Production of the Anti-Inflammatory Cytokine, Interleukin-10

Cited by 166 publications

References 66 publications

Glia in pathological pain: A role for fractalkine

Glia in pathological pain: A role for fractalkine

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

AAV for pain: steps towards clinical translation

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