Liver fibrosis inhibitor found by Salk researchers
Drug called JQ1 may promote liver healing, versions already in testing for cancer
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By Bradley J. Fikes | 2:12 p.m. Dec. 13, 2015
A drug that reverses liver fibrosis in animal studies has been identified by Salk Institute scientists. If the drug is brought to human clinical trials, it could prove of vast benefit in restoring liver function, avoiding the need for liver transplants and saving lives.
The drug, called JQ1, inhibits a scar-forming protein called BRD4. Its effects were reported in a study published in the Dec. 7 issue of PNAS. Ronald Evans was the senior author, Ning Ding the first author. Go to j.mp/fibrosisdrug for the study.
Evans' team tested the small molecule drug in a mouse model of liver damage caused by carbon tetrachloride, which also promotes fibrosis in human livers. The drug actually reversed or stalled fibrosis in previously liver-damaged mice.
The drug may also treat fibrosis outside the liver, such as in the lungs, pancreas and kidney. Moreover, new versions of the drug, with increased potency and safety are already being tested, in clinical trials for cancer.
"Beyond cancer, our interest is in re-purposing the cancer drug for chronic problems such as liver disease and tissue fibrosis," he said. "Because these new molecules are already in the clinic, we might be able to have a fast-track to get our trials up and running."
Evans said his team is now looking for a corporate partner to bring a drug to clinical trials.
"That's in the discussion phase right now," he said.
The liver possesses great regenerative powers, and is often able to completely repair damage, such as wounds or chemical injuries. But this ability has its limits. Extensive damage can lead to scarring called fibrosis that progressively and irreversibly destroys the liver. This can take place in cirrhosis, whether caused by alcohol abuse or non-alcoholic factors such as hepatitis virus infection. Fibrosis not only can cause liver failure, it's a major risk factor for liver cancer.
Companies testing treatments for liver fibrosis and related conditions include San Diego-based Conatus, which is in clinical trials for a drug called emricasan.
"To have a healthy liver, you need to have a repair switch going on when you need it, and off when you don't," Evans said. But in a chronic illness, the switch remains on for too long, resulting in persistent and progressive fibrosis.
Previous research by Evans' team found that molecules that target the vitamin D receptor can also turn off fibrosis. However, if the Vitamin D brake is overcome, the fibrosis switch remains jammed on.
"What we found is when vitamin D stops working, we can bypass the roadblock, by adding JQ1," he said. "We're excited as this suggest there are several different ways to treat liver disease. Having drugs that target genes is a real game changer. Indeed, we are in a new era in which genomic therapy treats complex diseases."
The work was funded by the NIH, the National Health and Medical Research Council of Australia Project Grants, the Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation and Ipsen/Biomeasure. 作者: StephenW 时间: 2015-12-15 08:52