IRX4204 promotes myelin repair, improves gait in MS mouse model
Symptomatic animals given therapy show less nerve damage, better movement
IRX4204, a compound that Io Therapeutics is developing to treat neurological diseases, facilitated myelin repair and improved walking abilities in a mouse model of multiple sclerosis (MS) in a recent study, scientists report.
“Our findings support the therapeutic potential of IRX4204 to promote functional neurologic recovery in MS, a long-sought therapeutic objective in the MS research community,” George S. Robertson, PhD, a study co-author at Dalhousie University in Canada and lead scientist for this work, said in a company press release.
The study, “Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis,” was published in Acta Neuropathologica Communications.
Remyelination and nervous system protection are central MS therapy goals
MS is characterized by inflammation in the brain and spinal cord that causes damage to the myelin sheath, a fatty substance that wraps around nerve fibers and helps them send electrical signals.
While several MS therapies work to reduce the inflammatory response that drives myelin damage, existing approaches have a limited ability to promote myelin repair, which means they generally cannot restore lost functions. Finding ways to promote myelin repair is a major goal of modern MS research.
An emerging body of data has suggested that activating a protein called the retinoid X receptor, or RXR, may help to promote myelin repair. IRX4204 is an orally available molecule that selectively activates the RXR protein. It was developed to have fewer side effects than an approved compound (for a particular cancer) that targets RXR and multiple other receptors, which was not well tolerated when tested in people with MS.
Researchers at Io and Dalhousie conducted a series of tests examining the effects of IRX4204 in mice with experimental autoimmune encephalomyelitis (EAE), a lab-induced disease that’s commonly used as a model to study MS.
They were particularly interested in assessing how IRX4204 affected walking ability, as movement difficulties are one of the most impactful of the disease’s varied symptoms. Their results showed that, in untreated mice, knee and ankle movement diminished as the disease progressed, while in mice treated with IRX4204, movement of these joints improved.
Greater activity in genes tied to myelin repair seen with IRX4204
Gait studies “showed that IRX4204 restored leg joint movements in EAE mice. … Not only did IRX4204 largely restore normal average [knee and ankle movements], these improvements persisted until the end of the study. This indicates that IRX4204 produced an enduring improvement of motor function in EAE mice,” the researchers wrote.
Analyses of the mice’s nervous systems indicated that mice treated with IRX4204 experienced less myelin loss than their untreated counterparts. Consistently, IRX4204-treated mice showed less evidence of damage to nerve fibers.
Assessments of genetic activity suggested that IRX4204 treatment led to an increase in the activity of genes involved in myelin repair, whereas there was a decrease in the activity of genes involved in inflammation. Further experiments confirmed that IRX4204 was promoting myelin repair in the mice.
“These results inform the discovery of restorative neural therapeutics for MS by demonstrating that selective RXR agonism [activation] is sufficient for effective myelin repair,” Robertson said.
Early, but ‘compelling’ evidence for therapy’s potential in MS
In addition to the mice experiments, the researchers conducted several experiments using different types of brain cells in dishes. They found that IRX4204 treatment lowered the inflammatory activity of microglia, a type of immune cell that lives in the brain and has been implicated in MS-driving inflammation. IRX4204 also promoted the differentiation of progenitor cells into mature oligodendrocytes, which are the brain cells mainly responsible for making myelin.
“Myelin restoration has long been viewed as a primary strategy for neuroprotection in the context of MS. The current study shows that RXR activation by IRX4204 promotes remyelination … in vivo [in living animals] in the context of autoimmune-mediated demyelination. Furthermore, IRX4204 led to a recovery of motor function even after deficits were established,” the researchers wrote.
These and other studies “position IRX4204 as a promising drug to promote functional recovery in patients with progressive forms of MS and inform drug discovery efforts … for MS,” they added.
The scientists noted that this study was limited to mouse and cell experiments, and further work will be needed to determine whether IRX4204 can benefit people with MS. Still, they said findings provide “compelling evidence that support the therapeutic potential for IRX4204 as a remyelinating and neurorestorative treatment for MS.”
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