Spinal cord injury (SCI) is a complex and devastating clinical condition mediated by proinflammatory cytokines that produce neuronal loss, axonal destruction, and demyelination during the secondary injury cascade. There are currently no proven therapies targeting posttraumatic inflammation that have been shown to have clinical value. We have previously shown that central nervous system (CNS) neurons express the NLRP1 inflammasome, a multiprotein complex that regulates the activation of caspase-1 and the pro-inflammatory cytokines IL-1? and IL-18 production after spinal cord injury, traumatic brain injury and stroke. The adaptor protein apoptosis associated speck-like protein containing a caspase activating recruitment domain (ASC) is important for the recruitment of inflammasome proteins into the multiprotein complex that activates caspase-1. The long-term goal of this project is to develop an anti-inflammatory therapy that improves outcomes after SCI in humans. The objective of this application is to develop a humanized monoclonal antibody termed ICCN100 that will be safely delivered to humans and to test the efficacy and safety of this drug as an anti- inflammatory therapy in mini-pigs, prior to testing in humans. We hypothesize that ICCN100 delivered after SCI inhibits inflammasome activation thus lowering the expression of IL-1 proinflammatory cytokines, resulting in improved histopathological and functional outcomes in micro-pigs. Our laboratory has provided data summarized in peer-reviewed journal articles indicating that antibodies directed at the abnormal inflammasome activation reduces the detrimental effects of various types of CNS injury including SCI, traumatic brain injury and stroke. The following milestones (specific aims) will be pursued as we continue to move this therapy forward for clinical testing: Phase I: Milestone Aim 1. To determine the efficiency of ICCN100 in inhibiting inflammasome activation in human astrocytes, neurons and peripheral blood mononuclear cells (HPBMCs) exposed to inflammasome inducers. Phase II: Milestone Aim 2: To determine the optimum dose of ICCN100 needed to inhibit inflammasome activity following SCI in Yucatan mini-pigs and to establish whether the optimum dose leads to improvements in functional and histopathological outcomes following SCI. Milestone Aim 3: To determine the pharmacokinetics and toxicity of ICCN100 treatment strategy in mini-pigs. Once efficacy and toxicity studies are conducted, we will be able to begin to interact with biotech companies and other agencies that may be interested in helping us move this novel therapy to the clinic. Thus, translation to the clinic is a major component of this research program.
Spinal cord injury (SCI) occurs throughout the world with an annual incidence of 15 to 40 million people per year and results in life long disabilities. The proposed research seeks to reduce cell death by inflammation that occurs within days of SCI, and to devise therapies to treat SCI and help in long-term recovery of function. The development of new treatments that can be given in the first hours after SCI may prevent or reverse much of the spinal cord damage resulting from SCI with a goal of restoring normal functioning in behavior.
|de Rivero Vaccari, Juan Pablo; Dietrich, W Dalton; Keane, Robert W (2016) Therapeutics targeting the inflammasome after central nervous system injury. Transl Res 167:35-45|