Liver fibrosis and cirrhosis are largely incurable diseases. Existing treatments have little effectiveness and the only cure is liver transplantation. Even then, transplantation has its own risks and occasional fails.
However, a modified protein has renewed hopes in the treatment of both diseases and possible reverse effects in a research conducted by researchers at John Hopkins.
As the disease progress, a characteristic progressive stiffening of the liver occurs. This is the hallmark of the disorders. This occurs because of the “activation” of certain liver cells called hepatic stellate cells. The “activated” hepatic stellate cells then overproduce the stringy network of proteins—extracellular matrix—that binds cells together.
Usually, the diseases would have progressed to this very advanced stage before many patients seek treatment and at which point a liver transplant becomes the only option available. This is because sufferers of both diseases may not notice symptoms for decades. Thus, a therapeutic way to reverse cirrhosis at its late stages would have maximum impact.
For a long time, over a decade to be exact, scientists have identified a protein that could attack and eliminate activated hepatic stellate cells thus sparing the healthy cells in the liver. This protein is called tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
However, the major drawback why TRAIL has not crept into clinical use is that enzymes in the bloodstream break it down before it has time to work. Therefore, the goal for the team of researchers was to devise a means to extend how long TRAIL can remain intact in the bloodstream.
To this end, they explored the use of a synthetic polymer that has seen extensive use in extending the life span of a handful of drugs in the bloodstream. This polymer called polyethylene glycol (PEG) used to coat drugs needed to treat hemophilia, neutropenia and rheumatoid arthritis is also widely used as a lubricant, preservative and ingredient in skin creams.
Initial experiments to compare the half-life of “PEGylated” TRAIL to unmodified TRAIL showed impressive results. The half-life of the modified TRAIL stood at 8 to 9 hours in monkeys, while unmodified TRAIL had a half-life of less than 30 minutes.
In rats with liver fibrosis, the scientists found out the intravenous use of modified TRAIL for 10 days killed off activated hepatic stellate cells in the diseased rats.
Furthermore, the scientists noticed that fighting these bad cells caused reduction in the signs of fibrosis. In fact, multiple genes associated with fibrosis had reduced activity, and proteins associated with these genes faded away.
Similar experiments conducted on diseased rats with advanced cirrhosis also led to similar findings. However, the icing on the cake was that on examining the liver tissue of the diseased rodents, animals treated with PEGylated TRAIL had fewer deposits of collagen and other extracellular matrix proteins. Thus, prompting the notion that the modified protein had actually reversed the disease.
The scientists then conducted experiments to compare the activity of PEGylated TRAIL in the activated hepatic stellate cells of humans. The activated hepatic stellate cells were grown in a petri dish and were together with normal liver cells.
Interestingly, the modified TRAIL selectively killed the activated hepatic stellate cells while sparing the normal liver cells. This finding suggests that the experimental conclusions in the animal models could apply to damaged human livers with limited toxicity concerns.
The research team looks forward to developing PEGylated TRAIL for human clinical trials within the next two years. They have also expressed optimism in using the modified protein to treat other fibrotic diseases, such as lung or pancreatic fibrosis.
Findings of the study are published in the journal Hepatology.