Novel solTNF Inhibitor Improves Outcomes in a Mouse Model of TBI-Induced AD
Abstract
Fiscal Year 2022 (FY22) Peer Reviewed Alzheimer’s Research Program (PRMRP) Investigator-Initiated Research Award (IIRA) Focus Area: These studies will take advantage of a biologic known as XPro1595 that selectively neutralizes the soluble form of tumor necrosis factor (TNF), preventing it from activating its receptor TNFR1. XPro1595 has shown success in a phase 1b clinical trial of elderly Alzheimer’s patients, and a phase 2 clinical trial has just commenced. Given the selective nature of XPro1595, we will use this biologic to improve our understanding of the relationship (underlying mechanisms of action) between traumatic brain injury (TBI) and Alzheimer’s disease (AD), while simultaneously assessing its efficacy to minimize TBI as a risk factor for the development of AD. Therefore, these studies speak directly to the intent of the FY22 PRARP IIRA focusing on Foundational Research, which seeks to improve understanding of the mechanisms and develop therapeutics/treatments for AD/AD-related dementias after TBI. Rationale: TBI is a risk factor for the development of AD, and preclinical rodent studies suggest that TBI accelerates the development of AD brain pathology and cognitive impairment. Another risk factor for AD is the gene known as ApoE4 that also increases AD brain pathology. Both TBI and ApoE4 regulate an aspect of the brains inflammatory system: a specific cell signaling pathway, known as TNFR1 cell signaling (or Tumor Necrosis Factor Receptor 1), that may be responsible for causing underlying changes to the brains neural circuitry, which ultimately impacts cognitive abilities (learning and memory). Recently a biologic was developed that is a specific inhibitor of TNFR1 signaling, known as XPro1595, with no known side effects, and has been trialed in elderly Alzheimer patients. Interim data from the clinical trials reveals that XPro1595 can reverse (cf. slow progress of) brain and serum inflammatory levels. Given that both TBI and ApoE4 regulate TNFR1 signaling and XPro1595 is proving to improve outcomes in elderly Alzheimer patients, this prompted our interest to investigate the use of XPro1595 following TBI to prevent the development of AD pathology. Our preliminary data reveal that XPro1595 treatment following TBI in mice can almost completely prevent glial reactivity and AD pathology (amyloid beta and tau immunoreactivity), which is a precursor to cognitive impairment. These provocative new findings cannot be overstated. Who Will Be Helped by This Research: TBI affects 1.5 million people annually in the United States, including 20,000-30,000 new military personnel, costing $30,000 and $400,000 for each new mild and severe case, respectively. Although it is difficult to determine the exact percentage of individuals with a TBI who may develop AD, it is estimated that 5% to 15% of severe TBI patients may develop dementia, and the presence of the ApoE4 gene increases chances by 10-fold, compared to non-ApoE4 gene carriers. Therefore, we can postulate that at least 15% of the individuals who suffer a TBI may develop late-onset dementia and may be helped with this biologic. Potential Clinical Applications, Benefits and Risks: At present, XPro1595 has been used in trials for cancer patients, COVID patients, and Alzheimer’s patients, with no known side effects, and the biologic appears safe and well tolerated. Therefore, there are no known risks and only benefits. XPro1595 has also shown successful in numerous preclinical animal models of inflammatory-based injury and disease, including our own TBI, pancreatitis, and cardiac arrest studies (all peer-reviewed published), and in general the biologic appears to attenuate the inflammatory response to improve outcomes; therefore, these are all potential clinical applications of XPro1595. Projected Timeline to Achieve Patient Related Outcomes: As indicated, XPro1595 is already in clinical trials for various inflammatory indications, and we have published our p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310188
Entities
People
- Kirsty Dixon
Organizations
- United States Army
- Virginia Commonwealth University