INmune Bio’s XPro1595 May Help Lower Neuroinflammation Triggered by High Fat and Sugar Diet, Mouse Study Suggests

Treatment with INmune Bio‘s lead candidate XPro1595 can help decrease neuroinflammation and amyloid beta accumulation triggered by a diet high in sugar and fats, according to results from a mouse model of Alzheimer’s disease (AD).

Malú Tansey, PhD, professor of neuroscience and director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida College of Medicine presented the results in a scientific poster titled  “Soluble TNF mediates obesogenic diet-induced alterations in peripheral and brain immunophenotype in a mouse model of Alzheimer’s disease,” at the Society for Neuroscience (SfN) 49^thAnnual Meeting in Chicago, Illinois, Oct. 19–23.

Our genetic makeup, along with our environmental exposures, are thought to be the main triggers for developing certain neurodegenerative conditions, including Alzheimer’s. One of the main contributors in mediating the gene-environment effect in AD is the immune system.

Neuroinflammation in the central nervous system (brain and spinal cord) is a key event underlying AD and it is mediated by an excessive activation of glial cells — nerve cells that surround and support neurons — and the overproduction of small pro-inflammatory molecules called cytokines.

The levels of tumor necrosis factor (TNF), a pro-inflammatory cytokine, are often increased in AD patients. Importantly, TNF mediates conditions involved in metabolic syndrome.

Environmental factors, such as a diet excessively high in fat and sugar, are known to trigger immune and metabolic responses that can result in metabolic syndrome and may increase the risk for AD.

XPro1595 is an investigational anti-inflammatory therapy that blocks inflammation by selectively neutralizing soluble tumor necrosis factor (sTNF).

Researchers studied the effects of a chronic high fat/sugar diet on neuro- and overall body inflammation in a mouse model of AD.

Female mice were fed either the high fat/sugar diet, or a control diet for eight weeks. After four weeks, XPro1595 was used to selectively inhibit sTNF signaling.

Alzheimer’s mice fed the high fat/sugar diet showed increased numbers of T-cells (a type of immune cell) in the brain. Furthermore, these mice showed higher levels of the protein amyloid-beta, a hallmark of AD, and ionized calcium binding adaptor molecule 1 (Iba1), a marker of microgial (a type of glial cell) activation.

Higher levels of TNF and ZO-1 mRNAs (the templates for protein production) in the hippocampus — a brain region involved in the formation, organization, and storage of new memories.

ZO-1 is a good indicator of structural changes in the blood-brain barrier, a highly selective membrane that shields the central nervous system from the general blood circulation and stops circulating immune cells from infiltrating the brain.

Treatment with XPro1595 lowered the increased levels of amyloid-beta, Iba1, TNF and ZO-1 in these animals.

“Together, these data suggest that diet-induced obesity alters immune cell populations in [Alzheimer’s] mice and promotes [blood-brain barrier] associated alterations that may enhance neuroinflammation, amyloid burden, and neurodegeneration,” the researchers wrote.

“The new data strengthen our findings that a potential connection between diets rich in fat and sugar and chronic inflammation can lead to an increased risk for Alzheimer’s disease,” Tansey said in a press release.

“With more than 93 million obese people in the U.S., according to the most recent data from the Centers for Disease Control and Prevention, understanding the link between obesity and Alzheimer’s disease is more relevant now than ever. By targeting inflammation with XPro1595 we may be able to effectively treat neurodegenerative diseases,” she said.

The safety and effectiveness of XPro1595 is being assessed in a multi-center, open-label Phase 1 clinical trial (NCT03943264).

The study is currently recruiting up to 18 patients with mild-to-moderate Alzheimer’s disease who have biomarkers for inflammation; it will take place at multiple sites across Australia. (More information is available here.)

“Finding new ways to stop, treat and prevent Alzheimer’s has been the holy grail of researchers for decades,” said R.J. Tesi, MD, CEO of INmune Bio.

“With more than 200 failed trials, the company believes that its novel approach to target neuroinflammation has the potential to change the treatment of neurodegenerative diseases,” Tesi said.