Nav: Home

Modified protein reverses cirrhosis in lab rats

March 03, 2016

A protein modified to increase the amount of time it circulates in the bloodstream appears to reverse liver fibrosis and cirrhosis in rats, according to results of a study led by Johns Hopkins researchers.

The investigators say the findings, reported ahead of print in the March 3 early view edition of Hepatology, advance the search for a potential cure for the thousands of patients worldwide living with these incurable diseases. At present, there is little effective treatment and no cure other than liver transplantation, which carries its own risks and often fails.

"Our findings demonstrate that the damaging effects of liver cirrhosis in laboratory rats can be effectively treated, and perhaps even reversed, using a protein therapeutic that has been modified to enhance its activity through site-specific conjugation of a polymer that greatly enhances its residence time in the body," says senior author Justin Hanes, Ph.D., director of the Center for Nanomedicine at the Wilmer Eye Institute at Johns Hopkins. "This approach has tremendous potential to help people with this devastating condition and may also be helpful to the millions of patients with other diseases where fibrosis plays an important role."

Liver fibrosis and its more severe form, cirrhosis, are caused by scar tissue that forms in the liver that is usually induced by chronic alcohol abuse, infections and autoimmune diseases. 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, says Seulki Lee, Ph.D., assistant professor in the Department of Radiology and Radiological Science at the Johns Hopkins University School of Medicine. "That's because liver fibrosis and cirrhosis can be asymptomatic for decades," Lee says. "Many patients only seek treatment when their disease becomes very advanced, at which point liver transplant is their only option."

Lee cautions, however, that his team's work is years from any possible application to patients.

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, Lee explains, 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, Lee and his colleagues coated TRAIL with polyethylene glycol (PEG), a synthetic polymer that's widely used as a preservative, lubricant and ingredient in skin creams, and is already being used to extend the bloodstream life of a handful of drugs that treat neutropenia, hemophilia and rheumatoid arthritis.

Lee says 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, Lee says. 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.

Further experiments showed that PEGylated TRAIL selectively killed human-activated hepatic stellate cells growing in petri dishes while leaving normal liver cells unharmed, suggesting that findings in these animal models could apply to damaged human livers with limited toxicity concerns.

Lee says the research team hopes to develop PEGylated TRAIL for clinical trials in human patients in the next two years. He adds that 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.

"Eventually," Lee says, "we might be able to develop PEGylated TRAIL into a universal anti-fibrotic agent that can treat many different conditions."
Other Johns Hopkins researchers who participated in this study include Yumin Oh, Ogyi Park, Magdalena Swierczewska, James P. Hamilton, Jong-Sung Park, Tae Hyung Kim, Panagiotis Mastorakos, Clark Zhang and Martin G. Pomper. Other investigators are from the National Institute on Alcohol Abuse and Alcoholism, Sungkyunkwan University, Pohang University of Science and Technology, Seoul National University, and Korea Institute of Science and Technology.

This research was funded by the National Institute of Biomedical Imaging and Bioengineering under grant number EB013450, National Institute on Alcohol Abuse and Alcoholism under grant number AA000369, Department of Defense under grant number CA130460, and the National Research Foundation of Korea under grant numbers NRF-2013R1A1A2062043, NRF-2013R1A1A2064165 and NRF-2013K1A1A2A02050115.

Relevant disclosures: TRAILPEG for the study described in this release was provided by Theraly Pharmaceuticals Inc. Lee and Pomper are co-founders of the company, and Lee serves as its chief scientific officer. Both Lee and Pomper hold ownership equity in Theraly. This arrangement has been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

Johns Hopkins Medicine

Related Cirrhosis Articles:

Family of patients with NAFLD and cirrhosis are at increased risk of liver fibrosis
Non-alcoholic fatty liver disease can progress to cirrhosis and eventual liver disease.
Is cirrhosis associated with increased risk of stroke?
Cirrhosis was associated with increased risk of stroke, especially hemorrhagic, in a study that included a representative sample of more than 1.6 million Medicare beneficiaries, according to an article published by JAMA Neurology.
Statins may benefit cirrhotic patients with hepatitis B or C infections
Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) can lead to cirrhosis as well as liver cancer.
Study: Genetic markers may predict which HCV, cirrhosis patients improve with treatment
Genotyping of patients with advanced cirrhosis from hepatitis C virus could help health-care professionals predict the likelihood of improvement after successful hepatitis C treatment, thus minimizing the need for liver transplants.
Statins may benefit cirrhotic patients with Hepatitis B or C infections
Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) can lead to cirrhosis as well as liver cancer.
Long-term treatment of decompensated cirrhosis with human albumin improves survival
Results from the ANSWER study showed that long-term administration of human albumin improves the survival rate of patients with decompensated cirrhosis.
Cold weather & fewer sun hours are associated with increased rates of alcoholic cirrhosis
New data presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, suggests that colder and less sunny regions of the world have higher rates of alcoholic cirrhosis, a disease caused by excessive drinking which results in irreversible scarring of the liver.
Severe gum disease strongly predicts higher mortality in cirrhosis
Results presented today from a prospective study in patients with irreversible scarring of the liver (cirrhosis) demonstrates that severe periodontitis (an inflammatory gum disease) strongly predicts higher mortality in this population, after adjustments for various risk factors.
Nutrient offers hope to stop deadly march toward cirrhosis, liver cancer
A new study suggests that one type of omega 3 fatty acid offers people who are obese or have a poor diet a chance to avoid serious liver damage.
Gold standard monitoring of HCC in patients with cirrhosis is cost-effective
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis.

Related Cirrhosis Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#530 Why Aren't We Dead Yet?
We only notice our immune systems when they aren't working properly, or when they're under attack. How does our immune system understand what bits of us are us, and what bits are invading germs and viruses? How different are human immune systems from the immune systems of other creatures? And is the immune system so often the target of sketchy medical advice? Those questions and more, this week in our conversation with author Idan Ben-Barak about his book "Why Aren't We Dead Yet?: The Survivor’s Guide to the Immune System".