Scientists ID, test 2 immune proteins as possible therapeutic targets in PBC
Results may provide 'roadmap' toward new treatments for chronic liver disease
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A team of scientists has identified two key immune proteins — CD58 and IL7R — as therapeutic targets in primary biliary cholangitis (PBC), with their work based on comprehensive genetic and protein analyses that also involved samples from PBC patients.
In addition, in a relevant mouse model, treatment with a compound targeting CD58 significantly lowered blood markers of liver damage, the data showed.
“These findings provide a roadmap for developing effective, targeted therapies, addressing an unmet need in PBC management,” the researchers wrote.
The team noted that available treatment “exhibits suboptimal efficacy in 30-40% of patients, underscoring the urgent need for novel therapeutic targets.”
The research findings were described in “Integrative Mendelian randomization and experimental validation unveil novel druggable targets in primary biliary cholangitis,” a study published in the European Journal of Pharmacology.
In PBC, the immune system mistakenly attacks the bile ducts, the tubes that transport the digestive fluid bile from the liver to the intestines. These autoimmune attacks result in inflammation that slows or blocks bile flow, known as cholestasis, which causes bile to build up to toxic levels. This can lead to scarring, called fibrosis, and, if left untreated, eventual liver failure.
The first-line treatment for PBC is ursodeoxycholic acid (UDCA), sold in the U.S. as Urso and Actigall, with generic versions available. While UDCA improves liver function for many patients, as many as 4 in 10 do not respond adequately, leaving them at continued risk of disease progression.
New therapeutic target needed for developing treatment options
To identify and validate therapeutic targets for new treatment options, researchers in China applied Mendelian randomization (MR). This statistical method uses genetic information to determine whether a cause and effect relationship exists between an exposure — in this case, genetic variants — and an outcome, here, PBC.
MR analysis drew on druggable gene data from liver and blood samples, combined with genome-wide association study (GWAS) data from European populations. GWAS are studies that collect genetic and clinical information from thousands of people to identify genetic variants associated with disease risk.
The analysis identified 14 genes significantly associated with PBC risk. After further refinement, two genes, CD58 and IL7R, emerged as the strongest potential drug targets. These genes provide instructions to produce CD58 and IL7R, two receptor proteins known to play key roles in immune function.
Moreover, higher levels of these two proteins were significantly associated with an elevated risk of PBC.
“The genes CD58, and IL7R, … showed strong evidence of causality and potential for therapeutic intervention,” the researchers wrote.
Further analyses showed no significant associations between genetically influenced CD58 and IL7R levels and other health conditions, “implying that the potential side effects of drugs targeting these sites … are likely minimal,” the researchers wrote.
Functional studies confirmed that both CD58 and IL7R regulate the balance of immune T-cells, which can destroy microbes but are also involved in autoimmunity, as well as processes needed for immune cell activation, communication, and target destruction.
The genes CD58, and IL7R, … showed strong evidence of causality and potential for therapeutic intervention.
Importantly, these two proteins were found to be elevated in liver biopsy samples from PBC patients compared with control samples, the researchers noted.
To identify potential drug candidates, the team used computational methods, including molecular docking, which simulates how well a drug molecule fits and binds to its target protein.
The compound PHA-00665752 showed the most favorable binding to the CD58 protein, while monorden, a natural antibiotic also known as radicicol, exhibited the strongest binding to the IL7R protein.
PHA-00665752 is under investigation by scientists as an anticancer therapy. While monorden has also been investigated as a potential treatment candidate, it rapidly breaks down into inactive byproducts in the body and is not considered a viable candidate for clinical evaluation, according to the researchers.
Mouse model of acute cholestasis used to test 1 compound
To test the therapeutic potential of PHA-00665752, the team used a mouse model of acute cholestasis in which mice are exposed to a chemical called ANIT.
“While this model primarily reflects chemical-induced bile duct injury rather than the autoimmune component of human PBC, it provides a robust platform for evaluating anti-cholestatic and [liver-protective] effects,” the researchers wrote.
In these experiments, the effects of PHA-00665752 were compared with those of UDCA and no treatment.
Liver tissue analysis showed that untreated mice developed bile duct blockages and significant inflammatory cell infiltration. Both PHA-00665752 and UDCA significantly reduced markers of liver damage compared with the untreated group.
The team noted that PHA-00665752 outperformed UDCA in reducing one of those markers, alanine aminotransferase or ALT, an enzyme that rises in the blood when the liver is under stress.
“This study identified several promising therapeutic targets for PBC through a systematic druggable genome-wide Mendelian randomization approach,” the researchers concluded, noting the identification of the genes CD58 and IL7R as “key discoveries.”
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