索尔克研究人员发现肝纤维化抑制剂

StephenW

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.

StephenW

通过索尔克研究人员发现肝纤维化抑制剂
药物称为JQ1可以促进肝脏愈合，在测试癌症已经版本
布拉德利J. Fikes的嫌疑犯照片
通过布拉德利J. Fikes |下午2点12二○一五年十二月十三日
可逆转肝纤维化动物实验的药物已被确定索尔克研究所的科学家。如果药物被带到人体临床试验，它可以在恢复肝功能，避免了需要肝脏移植和挽救生命证明的广阔益处。

这种药物被称为JQ1，抑制BRD4称为疤痕形成蛋白质。其影响报告发表在12月7日美国国家科学院院刊的研究。罗纳德·埃文斯的资深作者，宁鼎第一作者。转到j.mp/fibrosisdrug~~V为研究对象。

Evans的团队中引起的四氯化碳，它也促进纤维化人类肝脏肝损伤小鼠模型中测试的小分子药物。药物实际上颠倒或先前肝损伤的小鼠停滞纤维化。

该药物也可以治疗纤维化肝脏外，如在肺，胰腺和肾。此外，药物的新版本，具有增加的效力和安全性已被测试，在用于癌症的临床试验。

“除了癌症，我们的兴趣是在重新考虑对抗癌药物的慢性问题，如肝脏疾病和组织纤维化，”他说。 “由于这些新的分子已经在临床上，我们也许能有一个快速通道，让我们的试验和运行。”

埃文斯说，现在他的团队正在寻找企业合作伙伴带来了药物临床试验。

“这是在讨论阶段，现在，”他说。

肝脏具有巨大的再生能力，而且往往是能够完全修复损伤，如创伤或化学伤害。但是，这种能力也有其局限性。广泛的损害可导致疤痕称为纤维化是逐步和不可逆转地破坏肝脏。这可以发生在肝硬化，无论是由酒精滥用或不含酒精的因素，如肝炎病毒感染。纤维化不仅可引起肝衰竭，这是肝癌的主要危险因素。

公司检测治疗肝纤维化及相关条件包括圣地亚哥的科莱特斯，这是一个名为emricasan药物的临床试验。

“为了有一个健康的肝脏，你需要有一个维修开关会当你需要它，和关闭，当你不知道，”埃文斯说。但在一个慢性疾病，开关保持太久，造成持续性和进行性纤维化。

先前的研究由埃文斯的团队发现，针对维生素D受体分子也可以关闭纤维化。然而，如果维生素D制动器克服，纤维化开关保持卡住上。

“我们发现的是，当维生素D停止工作，我们可以绕过路障，加入JQ1，”他说。 “我们很高兴，因为这说明有几种不同的方法来治疗肝脏疾病，有药物靶基因是一个真正改变游戏规则。事实上，我们正处在一个新的时代，基因疗法治疗疑难杂症。”

该工作是由美国国立卫生研究院，国家卫生和澳大利亚的项目资助的医学研究理事会，利昂娜米和哈里B.赫尔姆斯利慈善信托，塞缪尔·韦克斯曼癌症研究基金会和易普森/ Biomeasure。

fs2002

谢谢！