Targeting Hepatic Stellate Cells to Reverse Liver Fibrosis

Researchers are working on a method of targeting stellate cells in the liver to prevent them from causing fibrosis when overactivated in response to infections, autoimmunity, and other causes of liver disease:

Liver fibrosis and its more severe form, cirrhosis, are caused by scar tissue that forms in the liver. The progressive stiffening of the liver, a hallmark of the disorders, occurs when a type of liver cell known as the hepatic stellate cell is "activated" and overproduces the stringy network of proteins called the extracellular matrix that binds cells together. Being able to turn cirrhosis around, especially in its late stages, would be a great boon, because liver fibrosis and cirrhosis can be asymptomatic for decades. Many patients only seek treatment when their disease becomes very advanced, at which point liver transplant is their only option.

Scientists have known for more than a decade that a protein called tumor necrosis factor-related apoptosis-inducing ligand - TRAIL, for short - can specifically kill activated hepatic stellate cells that overproduce the extracellular matrix, sparing healthy cells in the liver. However, TRAIL has thus far proven unsuccessful for clinical use because in animal studies, enzymes in the bloodstream quickly degrade it before it has time to work. Seeking a way to extend TRAIL's half-life, or the time that it remains intact in the bloodstream, researchers coated TRAIL with polyethylene glycol (PEG), a synthetic polymer. Initial experiments showed that this "PEGylated" TRAIL had a half-life of between eight and nine hours in monkeys, compared to less than 30 minutes for the unmodified protein. When the scientists intravenously dosed rats that had liver fibrosis with the modified TRAIL for 10 days, the animals' activated hepatic stellate cells died off. By fighting these bad cells, signs of fibrosis began to diminish. Further investigation showed that multiple genes associated with fibrosis had reduced activity, and the proteins produced by these genes faded away.

Findings were similar in rats with advanced cirrhosis. Additionally, when the researchers examined the rodents' liver tissue under a microscope, they found that animals treated with PEGylated TRAIL had fewer deposits of collagen and other extracellular matrix proteins, offering some evidence that the disease had actually been reversed. The research team hopes to develop PEGylated TRAIL for clinical trials in human patients in the next two years. Some preliminary data suggest that the modified protein could also treat other fibrotic diseases as well, such as pancreatic or lung fibrosis, which also have no effective treatment.



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