Novel solTNF Inhibitor Improves Outcomes in Rat Model of GWI
Abstract
Gulf War Illness (GWI) affects approximately 30% of all military personnel deployed to the Persian Gulf War, who experience a cluster of unexplained diverse chronic symptoms including widespread pain, muscle aches, cognitive impairment, fatigue, and gastrointestinal symptoms. There are no cures for GWI, and existing treatments to abrogate symptoms come with side effects. For example, there are little to no therapies for improving cognition, and associated anti-depressive therapies have a myriad of side effects. Therefore, there is a critical need to develop effective therapeutic interventions for the individuals who are inflicted with GWI with the goal of preventing the chronic impairments, without inducing side effects. To achieve this, it is crucial to understand the pathophysiology of the GWI brain. GWI is known to cause a chronic inflammatory response within the brain. In other conditions of chronic inflammation, inflammatory cells within the brain secrete pro-inflammatory proteins that cause an array of structural and functional changes in the brain. A major pro-inflammatory protein known as Tumor Necrosis Factor (TNF) exacerbates hippocampal nerve cell death, as well as promoting changes to nerve cell generation (neurogenesis), structure, and circuitry. TNF is produced in two forms within the brain (transmembrane [tmTNF] and soluble [solTNF] forms), with only solTNF producing detrimental brain pathology, while tmTNF promotes beneficial brain health. Unfortunately, all traditional TNF inhibitors have been unable to distinguish between the TNF ligand or receptor subtypes and as a result come with U.S. Food and Drug Administration blackbox warnings, likely due to TNFR2 inhibition causing both immune and cardiac dysfunction. Recently however, a novel second-generation TNF inhibitor (XPro1595: INmuneBio, Inc.) has become available that selectively inhibits only solTNF, while sparing the activity of tmTNF. This novel TNF inhibitor can cross the blood-brain barrier, has a half-life of 17 hours, and has been used successfully in numerous neurological disease models (including Alzheimer’s, stroke, and multiple sclerosis), without any known side effects. Further, XPro1595 is currently in Phase I (safety study) metastatic cancer clinical trials with no observable side effects, and Alzheimer clinical trials are due to begin in the third quarter of 2019. For these reasons, we previously assessed the ability of XPro1595 to improve outcomes in a mouse model of traumatic brain injury (TBI) and observed improved brain pathology (reduced hippocampal inflammation, and nerve cell degeneration and plasticity) as well as improved neurological outcomes (cognition, depressive-like behaviors, and neuropathic pain), all of which are hippocampal-dependent functions. TBI and GWI share striking similarities in pathological and neurological outcomes, although the full range of hippocampal pathophysiology has not been assessed in all rodent GWI models, and the solTNF inhibitor XPro1595 has also not been assessed. There are numerous rodent models of GWI, although the organophosphate diisopropyl fluorophosphates (DFP) GWI model may most closely mimic the exposure of sarin to military personnel during the Persian Gulf War. However, questions remain over the long-term and latent effects of DFP organophosphate-induced hippocampal inflammation, synaptic plasticity, and synaptic degeneration and their effects on neurological outcomes. Therefore, using our rat DFP GWI model, we will address the overarching challenge of developing a novel non-opioid treatment strategy for individuals with GWI to improve hippocampal pathophysiology, resulting in a reversal of detrimental neurological outcomes, including cognitive impairment, anxiety and depression, and neuropathic pain. Our specific aims are to assess whether (1) DFP-induced GWI enhances hippocampal inflammation and neurological deficits, which can be reversed by inhibiting solTNF/TNFR1 activi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010420
Entities
People
- Kirsty Dixon
Organizations
- United States Army
- Virginia Commonwealth University