Yale Researchers Discover Old Drug Offers New Hope for Treating Liver Disease

As much as a third of the U.S. population has an unhealthy amount of fat in their livers, a condition that often goes undetected and can lead to devastating health issues. Some 80 to 100 million Americans suffer from Fatty Liver Disease which is linked to excess alcohol and obesity. “This is not only a disease of people who are morbidly obese or drink very large amounts of alcohol” says Dr. Wajahat Mehal, Professor of Medicine at Yale and Director of Yale Fatty Liver Disease Program. “Someone who is 5’9” and weighs 210 pounds can get fatty liver disease.”

Many won’t realize they have a problem until the disease progresses, forming damaging scar tissue in the liver over a 10- or 20-year period. A subsequent disease called NASH – short for nonalcoholic steatohepatitis – occurs as liver damage from excess fat leads to more serious liver inflammation. Some 30 million Americans have NASH. When this condition is caused by alcohol excess, it’s known as ASH (alcoholic steatohepatitis). There are currently no drugs approved to treat ASH or NASH, but the discovery of a new pathway by Dr. Mehal and his colleague Dr. Xinshou Ouyang may offer a first-of-its-kind solution. This pathway shows promise for the treatment of liver inflammation with a drug called digoxin which has been used for over 200 years to treat cardiac conditions. Their findings were recently published in Cell Metabolism.

Over the course of more than a decade of research that’s been supported in part by the National Institute on Alcohol Abuse and Alcoholism, Dr. Mehal’s lab identified that molecular pathways activated by HIF-1a are required for the liver inflammation seen in NASH and ASH. To prevent the inflammation from occurring, researchers needed to inhibit this pathway.

“We decided to test the cardiac drug digoxin,” says Mehal, “and we needed to answer two questions. One - ‘Would it work?’ And two – ‘How is it working?’” The recently published paper answers both, finding that digoxin is not only successful in treating a variety of liver injuries, but that it works through a pathway previously not known to be important in liver inflammation, by binding to the molecule pyruvate kinase M2 (PKM2), which is a key metabolic enzyme.

“In trying to find out how digoxin was working, we identified a completely new pathway of liver inflammation” Mehal says.

This has turned out to be extremely fortuitous. When digoxin is used to treat cardiac disorders, patients need to take levels just below toxic to be effective. A modest increase in dose could result in severe side effects. In its repurposed form for treating liver disease, only 1/10th-1/20th of the cardiac dose appears to be effective. And, says Mehal, because they have identified a new pathway for treating liver inflammation, it opens the door for other drug candidates with even better properties and less side effects to be developed.

This Yale-patented discovery has since been licensed by a small-sized biotech company in California with help from the Office of Cooperative Research (OCR). “OCR has been extremely helpful in making sure with have the IP in place, and to market the opportunity to potential industry partners,” says Mehal. “Without them, we wouldn’t have found this company, which has taken on the task of advancing this program for the benefit of millions of patients suffering from ASH and NASH.”  

Lolahon Kadiri, Business Development Associate at OCR, says drug repurposing programs such as this offer real opportunity to researchers to bring treatments to market much more quickly and cost effectively than discovering and developing novel compounds. “Academic researchers have deep expertise in the underlying biology of diseases,” Kadiri says, “which allows them to envision new uses for existing drugs, as well as open new avenues to discovery of new drugs. Over the years, Yale scientists have developed and contributed to commercialization of several drug repositioning programs, which resulted in novel treatments of cardio-vascular, retroviral, autoimmune, inflammatory, CNS diseases, and now, hopefully, NASH and liver fibrosis.”

CONTACT: Brita Belli, Communications Officer, Yale Office of Cooperative Research, (203)804-1911, brita.belli@yale.edu.