INmune Bio's experimental drug XPro™ demonstrated significant neuroprotective effects in a preclinical study examining the link between traumatic brain injury (TBI) and Alzheimer's disease pathology. The research, conducted in collaboration with Virginia Commonwealth University, showed that XPro™ treatment reduced amyloid formation and improved neurological outcomes in transgenic mice following brain injury.
The study findings were presented at the Keystone Symposia's Neurodegeneration section in Whistler, British Columbia, Canada, by Dr. Kirsty Dixon and her research team from Virginia Commonwealth University. The poster demonstrated that traumatic brain injury increases amyloid deposition in high-risk animals and that XPro™ administration significantly reduces amyloid formation while improving clinical measures of brain function.
Targeting the TBI-Alzheimer's Connection
Traumatic brain injury represents a well-established risk factor for Alzheimer's disease development. The research revealed that TBI promotes neuroinflammation by increasing the inflammatory cytokine tumor necrosis factor (solTNF), which has been implicated in Alzheimer's disease progression. A key protein in Alzheimer's pathogenesis is the enzyme β-secretase (BACE1), which cleaves amyloid precursor protein (APP) to generate neurotoxic amyloid beta (Aβ42), potentially leading to neuronal loss.
Under pathological conditions, TNF receptor 1 (TNFR1) upregulates BACE1 and cell death pathways. The research team hypothesized that targeting TBI-induced solTNF/TNFR1 signaling could mitigate Aβ42 production and neuronal loss, providing a critical translational link between TBI and Alzheimer's disease.
Study Results Show Rapid Intervention Benefits
The study revealed that TBI triggered a transient increase in TNFR1, BACE1, and Aβ42 expression in the hippocampus, peaking three days post-injury and returning to baseline by day seven. When XPro™ was administered thirty minutes post-injury, it inhibited solTNF/TNFR1 activity and prevented elevations in TNFR1, BACE1, Aβ42, and caspase-3 levels.
Immunofluorescence analysis revealed that XPro™ treatment reduced intracellular neuronal amyloid accumulation in the hippocampus and improved neurological outcomes in treated animals. These findings suggest that early intervention with XPro™ following brain injury could prevent the cascade of molecular events that link TBI to Alzheimer's disease development.
Expert Commentary on Clinical Implications
"Our findings demonstrate that TBI exacerbates amyloidogenesis and behavioral deficits in the hippocampus through solTNF/TNFR1 signaling," said Dr. Dixon. "These results support XPro as a promising treatment to reduce AD pathology risk post-TBI and elucidate a key cellular mechanism linking inflammation to neurodegeneration."
Dr. Elliott Mufson, professor of neurobiology and director of the Alzheimer's disease research laboratory at Barrow Neurological Institute, emphasized the broader therapeutic potential. "An important feature of these findings is that XPro targets neurobehavioral dysfunction resulting from brain trauma and age-related neurodegenerative disease, which holds great promise for people suffering from these disorders."
Clinical Development and Mechanism of Action
XPro™ represents a next-generation inhibitor of tumor necrosis factor that is currently in clinical trials. The drug acts differently from currently available TNF inhibitors by neutralizing soluble TNF (sTNF) without affecting transmembrane TNF (tmTNF) or TNF receptors. This selective mechanism could provide substantial beneficial effects in patients with neurologic disease by decreasing neuroinflammation.
INmune Bio CEO Dr. RJ Tesi highlighted the clinical relevance of the findings. "Traumatic brain injury from falls is a significant concern for the elderly population at risk for Alzheimer's disease, as it accelerates dementia onset," he said. "Effectively treating the resulting CNS pathology is critical to preserving cognitive function in this vulnerable group."
Broader Development Pipeline
INmune Bio's DN-TNF product candidates, including XPro™, are currently in clinical trials to determine their efficacy in treating mild Alzheimer's disease, mild cognitive impairment, and treatment-resistant depression. The company's approach utilizes dominant-negative technology to selectively neutralize soluble TNF, identified as a key driver of innate immune dysfunction and a mechanistic driver of many diseases.
The preclinical findings provide important mechanistic insights into how traumatic brain injury may accelerate Alzheimer's disease pathology and suggest that targeting neuroinflammation immediately following brain injury could represent a novel therapeutic strategy for preventing long-term cognitive decline.
