Treatment With XPro1595 Promotes Remyelination in Mouse Model
The experimental therapy XPro1595 was found to promote remyelination — the repair of the myelin sheath — in a mouse model of myelin loss, new data show.
Myelin, the fatty covering that helps nerve fibers send electrical signals, is damaged by the immune system in multiple sclerosis (MS). These findings support the development of XPro1595, which inhibits the soluble form of tumor necrosis factor (TNF), as a potential treatment for MS.
The research results were presented at the European Conference on Neuroinflammation, in London, by Athena Boutou, a PhD student at the Hellenic Pasteur Institute, in Greece. Her talk was titled “Beneficial microglia responses drive remyelination through inhibition of solTNF-TNFR1 in the cortical grey matter.”
TNF is a powerful pro-inflammatory signaling molecule that is often found at high levels in people with autoimmune conditions. Therapies that block TNF have shown promise in some autoimmune diseases that are driven by inflammation.
In MS, however, prior studies of TNF-blocking therapies showed that these medicines actually exacerbated the disease.
According to Boutou, the reason for this paradoxical effect is that there are two forms of TNF: soluble and transmembrane TNF. These separate forms activate two different protein receptors — TNF receptor 1 and 2, respectively.
When soluble TNF binds to TNF receptor 1, it tends to promote damage in the nervous system. By contrast, transmembrane TNF binding to TNF receptor 2 tends to be beneficial for nervous system function. Completely blocking all TNF signaling may worsen disease by inhibiting some of these beneficial effects.
XPro1595, or XPro for short, was designed to selectively block soluble TNF without affecting the transmembrane form of this signaling protein. The therapy is currently being developed by INmune Bio as a potential treatment for MS and Alzheimer’s disease.
Data from a Phase 1 study (NCT03943264) involving Alzheimer’s patients indicated that Xpro treatment promoted myelin repair, as measured via a new MRI analytic developed by INmune Bio’s imaging partner IMEKA.
“One reason few understand that demyelination is part of degenerative diseases such as [Alzheimer’s] is because it has been difficult to measure in patients,” CJ Barnum, PhD, vice president of central nervous system development at INmune, said in a press release.
“Using non-invasive MRI imaging metrics, we can see and quantify the amount of demyelination and remyelination in patients with neurodegenerative disease,” Barnum said.
Now, researchers evaluated the effects of XPro treatment in a mouse model in which myelin loss was induced by a chemical called cuprizone. The results showed that XPro treatment markedly increased myelin levels after about five weeks, indicating that the therapy promoted remyelination.
Additional analysis showed that XPro treatment led to the early activation of two types of glial cells: microglia — the resident immune cells of the nervous system — and astrocytes, which are star-shaped cells that support neuronal function.
More specifically, the treatment promoted these cells to more effectively clear damaged myelin through a process called phagocytosis or “cellular eating.” That paves the way for later repair by myelin-making cells called oligodendrocytes.
“Soluble TNF paralyzes the ability of microglial cells to remove myelin debris. By eliminating soluble TNF, glial phagocytosis returns, myelin debris is cleared, and oligodendrocytes can remyelinate damaged axons [nerve fibers],” said Lesley Probert, PhD, head of the department of immunology at the Hellenic Pasteur Institute, and a study co-author.
In separate experiments, the researchers genetically engineered mice so that they would lack TNF receptor 1 (the receptor for soluble TNF) in their microglia. This had a similar remyelination-promoting effect as inhibiting soluble TNF with XPro.
“Overall, our results suggest that therapeutic inhibition of soluble TNF allows beneficial glial responses that favor the CNS [central nervous system] repair, indicating soluble TNF as a potential target to promote remyelination,” Boutou concluded.
“Time and experience of more patients treated will tell if XPro’s ability to promote remyelination in diseases such as [Alzheimer’s] and MS translates into measurable clinical benefits,” Barnum said.