Targeting TYK2 in brain seen as potential strategy for MS treatment
Blocking protein's activity appears to reduce disease activity in mice
A small molecule that blocks the activity of a protein called TYK2 in the brain showed promise at reducing disease activity in mouse models of multiple sclerosis (MS), according to a study.
The study was conducted by Neuron23, which is advancing a small molecule TYK2 inhibitor called NEU-627 to treat MS. That molecule is expected to enter early safety testing in healthy volunteers in the first half of this year.
Neuron23 didn’t specify whether NEU-627 is the compound used in the study, but the study broadly supports the idea that targeting TYK2 in the brain could be a viable strategy for MS treatment.
“This body of work highlights the ability of TYK2 inhibition to regulate immune cells and mechanisms associated with harmful neuroinflammatory processes,” Arash Rassoulpour, PhD, corresponding author of the study and senior vice president of research operations at Neuron23, said in a company press release. “These novel findings reinforce our confidence in the potential of brain-penetrant therapies that selectively inhibit TYK2 for the treatment of neuroinflammatory diseases such as multiple sclerosis.”
The study, “Central TYK2 inhibition identifies TYK2 as a key neuroimmune modulator,” was published in PNAS.
Regulating inflammation
MS is caused by inflammation that damages cells in the brain and spinal cord. The molecular mechanisms that drive inflammation in MS are complex and incompletely understood.
TYK2 is known to help coordinate how cells respond to inflammatory signaling molecules, and there’s abundant evidence that this protein helps to regulate inflammation outside of the brain. But inflammation in the brain is controlled very differently from inflammation in the rest of the body, which usually helps to prevent too much damage to delicate brain tissue.
There’s not much data on if or how TYK2 regulates inflammation inside the brain. Genetic studies have indicated that people with less TYK2 activity are less likely to develop MS, which lends credence to the idea that this protein also plays important roles in brain inflammation that drives the disease. This notion has not been proven, however.
To investigate the protein’s role in brain inflammation, a team led by scientists at Neuron23 conducted a series of tests in mice with experimental autoimmune encephalomyelitis (EAE), a lab-induced disease commonly used as a model for MS. The researchers treated the mice with two TYK2 inhibitors, one that is able to get into the brain and one that isn’t.
Results showed that the TYK2 inhibitor that was able to enter the brain led to significantly lower clinical scores for mice with EAE. In contrast, the inhibitor that couldn’t get into the brain had little impact on disease severity, which implies that it’s specifically the inhibition of TYK2 in the brain, not elsewhere, that drives this effect.
Further analyses showed that inhibiting TYK2 in the brain led to reduced levels of pro-inflammatory signaling molecules, as well as reduced inflammatory activity of microglia, a type of immune cell in the brain known to play a role in MS. These data “establish TYK2 as a key neuroimmune modulator capable of regulating inflammatory insults within the [brain] in autoimmune disease,” the researchers wrote.
EAE is generally considered a model of relapsing types of MS, which are marked by relapses or flares, periods in which disease symptoms worsen, and periods of remission in which symptoms ease. A minority of MS patients develop primary progressive MS (PPMS), which is marked by continual disability progression independent of relapse activity from the onset. PPMS has historically proven much harder to treat than relapsing MS. Ocrelizumab (sold as Ocrevus and Ocrevus Zunovo) is approved for this disease type.
In addition to the tests in EAE, the researchers tested the effects of TYK2 inhibition in mice that were injected with antibodies derived from people with PPMS, which mimics some of the aspects of PPMS. Results showed that the brain-penetrant TYK2 inhibitor also reduced markers of inflammation in the PPMS model, implying that TYK2 in the brain plays a role in all types of MS.
“For the first time, we have demonstrated the comprehensive role of TYK2 in neuroinflammation, as well as the role of TYK2 inhibition in multiple sclerosis, including potentially progressive forms of the disease, which currently represent the greatest unmet medical need of people with multiple sclerosis,” Rassoulpour said.
Steve Wood, co-author of the study and executive vice president of drug discovery at Neuron23, said the study “represents a significant advancement in understanding the impact of TYK2 in the central nervous system, which to date has been less thoroughly studied compared to its role in driving [inflammation outside the brain] in immunological diseases.”
“Given the strong genetic link between TYK2 and diseases such as multiple sclerosis, and the potential for broader implications in other neuroinflammatory disorders, these findings help advance the potential therapeutic application of TYK2 inhibitors that” are able to enter the brain, Wood said.
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