Aramchol shows promise as PSC treatment, mouse study finds
Oral therapy prevents, reverses inflammation and scarring
Aramchol, a small molecule in the Galmed Pharmaceuticals pipeline, prevented and reversed inflammation and scarring (fibrosis) of the bile ducts in mouse models of cholestasis-related injury and fibrosis, a study showed.
The bile ducts are the tubes that transport the digestive fluid bile from the liver to the intestines. Cholestasis refers to a slowed or stalled bile flow.
The investigational oral therapy also activated natural protective pathways signaled by PPAR, a protein that reduces the inflammatory response, in cholangiocytes, the cells that line the bile ducts.
The findings suggest Aramchol, which has shown promise in people with a severe form of fatty liver disease, may be a potential treatment for primary sclerosing cholangitis (PSC) and other diseases where the bile ducts become inflamed and scarred.
The study, “Aramchol attenuates fibrosis in mouse models of biliary fibrosis and blocks the [TGF-beta-induced] fibroinflammatory mediators in cholangiocytes,” was published in Hepatology Communications. It was funded by Galmed.
Suppressing a signaling protein
PSC is an autoimmune disease characterized by ongoing cholangitis, or bile duct inflammation, that ultimately results in cholestasis and bile duct fibrosis (biliary fibrosis).
As with other diseases that affect the bile ducts, like primary biliary cholangitis, this can lead to serious complications such as irreversible liver fibrosis (cirrhosis).
A signaling protein called TGF-beta becomes highly active in this type of diseases. When cholangiocytes are exposed to TGF-beta, they send signals that attract immune cells and activate myofibroblasts, the cells that produce the proteins that form scar tissue. This worsens both inflammation and fibrosis.
TGF-beta also controls the enzyme stearoyl-CoA desaturase (SCD), which helps process fats inside cells and fine-tune lipid signaling, a way cells communicate using fatty molecules.
Aramchol meglumine, or simply Aramchol, is an experimental oral therapy that works by suppressing SCD. It was previously associated with a favorable safety profile and some efficacy signs in clinical trials of people with metabolic dysfunction-associated steatohepatitis, a severe form of fatty liver disease.
However, its effects on bile duct inflammation and scarring have not been evaluated.
“There are currently no treatments for biliary fibrosis, which severely limits therapeutic options for these diseases,” wrote a team led by researchers at Virginia Commonwealth University.
The researchers evaluated the effects of Aramchol (12.5 mg/kg of body weight per day) against a placebo in two mouse models of cholestasis-induced biliary fibrosis.
One of the models concerned mice given a special diet that blocks the bile ducts, and was used to test whether Aramchol could prevent disease features. In the other model, mice were genetically engineered to lack the Mdr2 gene, which provides instructions for a protein that shuttles bile out of the liver into the bile ducts. These mice were used to test whether the experimental therapy could reverse established disease.
Results showed that compared with the placebo, three weeks of Aramchol treatment prevented liver fibrosis and inflammation in the diet-based mouse model, without affecting the animals’ body weight. It also significantly reduced TGF-beta signaling and cholangiocyte growth.
In mice lacking the Mdr2 gene, which had established liver inflammation and fibrosis, four weeks of treatment with Aramchol significantly reduced not only these disease features, but also myofibroblasts activation, and cholangiocyte growth.
Similar results were obtained when SCD production was suppressed in lab-grown human cholangiocytes, suggesting that Aramchol may act by blocking SCD.
In these cells, TGF-beta was also found to reduce the levels of the fatty molecule linoleic acid, thereby promoting inflammation. Aramchol partially restored linoleic acid levels and reduced these inflammatory signals.
In lab-grown cholangiocytes collected from people with PSC, Aramchol again reduced the levels of fibrotic markers, myofibroblast-activating mediators like VEGF-and inflammatory molecules like IL-6. At the same time, it increased the activity of PPAR and the levels of linoleic acid, which activates PPAR.
The results suggest that Aramchol can prevent and reduce liver scarring in diseases where the bile ducts become inflamed and scarred.
“These findings, combined with its favorable clinical safety profile, support the potential of Aramchol as a therapeutic candidate for PSC,” the researchers concluded, noting the need for “further clinical studies of Aramchol in patients with biliary fibrosis, in particular PSC, where treatments are desperately needed.”
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