Summary of research progress in the field of liver diseases (12.15)
December 15, 2017 Source: WuXi PharmaTech
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];1. NASH drugs receive 25 million euros in development funds
Recently, Dutch biotechnology company NorthSea Therapeutics announced the completion of a first round of fundraising of 25 million euros to develop the first of its kind of engineered engineered fatty acid (SEFA) "icosabutate" for the treatment of nonalcoholic fats. New oral therapy for hepatitis (NASH). Investors are led by Forbion and BGV, including Novo Seeds, the early investment arm of Novo Holdings A/S, and investment groups such as New Science Ventures.
NASH is a common liver disease unrelated to alcohol, characterized by accumulation of fat in the liver, inflammation and fibrosis, and persistent damage to the liver. The number of NASH cases worldwide continues to rise, with an estimated 15 million to 30 million new patients in the next few years. In the absence of effective treatment, NASH may induce severe liver problems, including cirrhosis, liver failure, and even liver cancer, allowing patients to undergo liver transplantation.
NorthSea Therapeutics' icosabutate is a designed omega-3 fatty acid molecule that has been structurally improved compared to traditional prescription omega-3 fatty acids to improve its triglyceride (TG) reduction. Improve drug efficacy and safety of drug preservation. Two previous Phase 2 clinical studies have shown that icosabutate is a safe and effective drug for the treatment of hypertriglyceridemia. The 25 million euro financing will be used for the phase 2b clinical study of icosabutate in NASH patients and will be advanced to the phase 3 clinical trials, including clinical and non-clinical toxicology studies and CMC (chemical chemistry) , production manufacture, quality control control) development.
â–² Mr. Rob de Ree (Source: NorthSea Therapeutics official website)
“At the beginning of the creation, NorthSea Therapeutics had all the elements to succeed in the highly competitive NASH field: we have a potential compound that has undergone clinical trial testing, a team of experienced drug developers. The world's leading experts in the field, easy access to clinical trial sites, and strong investment group support," said company CEO Rob de Ree. "We believe that icosabutate has the potential to affect the lives of millions of NASH patients worldwide. There are currently very few treatment options to choose from."
2. Professor Li Hongliang found the decisive factor of liver ischemia-reperfusion injury
Hepatic ischemia-reperfusion (IR) injury is a common clinical problem that is an important cause of liver damage during surgical procedures including hepatectomy and liver transplantation, which can result in 10% Liver failure after early liver transplantation, 45% acute and chronic tissue rejection and organ damage, greatly hindered the application and treatment of liver surgery. Liver IR injuries have long lacked effective therapies and medication targets. Recently, however, the team led by Professor Li Hongliang of Wuhan University, through a comprehensive analysis of transcriptomics, proteomics and metabolomics, found that the early decisive triggering factor of liver IR injury is “arachidonate 12-lipoxygenase (arachidonate). 12-lipoxygenase, ALOX12)"- "12-hydroxyeicosatetraenoic acid (12-HETE)" - "G-protein coupled receptor 31 (GPR31)" signal axis, nearly sixty In the past years, the treatment dilemma in the field of liver IR injury has found a new breakthrough. The paper was published in Nature, a supplement to Nature Medicine.
â–² Professor Li Hongliang (Source: Wuhan University official website)
Professor Li found that during ischemia, ALOX12 was up-regulated in hepatocytes and promoted the accumulation of 12-HETE. 12-HETE could then directly bind to GPR31, triggering an inflammatory response and aggravating liver damage. In animal models of mice and pigs, the inhibition of 12-HETE production by the small molecule inhibitor ML355 of ALOX12 inhibits IR-induced liver dysfunction, inflammation and cell death.
In addition, the researchers also established the world's first liver IR model of non-human primates, which reproduces clinical liver dysfunction after liver resection and allows researchers to detect ML355 in the liver for a long time and systematically. During the protection of the liver during the process, it was found that suppressing the accumulation of 12-HETE effectively attenuated all pathological features of liver IR in this model.
This study suggests that the underlying cause of hepatic IR injury is the reorganization of the metabolic signaling network during the ischemic phase and is regulated by the ALOX12-12-HETE-GPR31 signaling axis, as well as the prevention and treatment of 12-HETE by inhibition. IR-induced liver injury, a highly promising therapeutic strategy, is expected to bring great benefits to patients who need liver surgery in the future.
3. Professor Li Hongliang's team found important factors regulating the development of NASH
Nonalcoholic steatohepatitis (NASH) is an extreme form of development of nonalcoholic fatty liver disease (NFALD) that causes persistent damage to the liver. In recent years, the number of NASH cases worldwide has continued to increase. In the United States, the number of NASH patients has reached 16 million; in China, the prevalence of NASH in some areas can be as high as 27%. Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the development of NASH and has potential as a target for the treatment of this disease. However, the regulatory mechanism of ASK1 activation is not clear. Recently, the team led by Professor Li Hongliang of Wuhan University found that tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is an important negative regulator of ASK1 activation. The paper was published in Nature, a supplement to Nature Medicine.
Professor Li's team in the screening of NASH pathological state of protein interaction with ASK1, through high-throughput screening and a large number of experimental biological experiments, found that TNFAIP3 is a key endogenous inhibitor of ASK1 activation. TNFAIP3 is a deubiquitinating enzyme. The researchers found that it can directly act on ASK1 and deubiquitinate it in hepatocytes, thereby inhibiting the activity of ASK1 and downstream P38/JNK, effectively preventing the development of NASH and its complications. .
Animal experiments have shown that specific removal of the Tnfaip3 gene in mouse hepatocytes aggravates non-alcoholic fatty liver disease (NFALD) and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation, in an ASK1-dependent manner. Symptoms such as enhanced inflammation; in contrast, in mice and non-human primate models with NASH, the use of transgenic or adenovirus-mediated delivery of TNFAIP3 to the liver substantially blocks the onset and progression of the disease.
These findings by Professor Li showed that TNFAIP3 is an important endogenous inhibitor of ASK1 activation in the pathogenesis of NASH and suggests the possibility of TNFAIP3 as a potential new molecular target for NASH therapy. The new therapies generated by this may prevent the direct inhibition of the toxic side effects of ASK1 enzyme activity, thus bringing new hope to the majority of NASH patients.
Reference materials:
[1] NorthSea Therapeutics Scores €25M for Phase II NASH Trial
[2] An ALOX12–12-HETE–GPR31 signaling axis is a key mediator of hepatic ischemia–reperfusion injury
[3] The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis
Original Title: Summary of Research Progress in the Field of Liver Diseases (No. 31)
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