编者按：近年来，随着肝纤维化发生的细胞和分子机制研究逐渐深入，人们已逐渐认识到识别肝纤维化过程中的关键细胞及因子有助于设计新药，并改变其治疗策略。本届AASLD年会上，肝纤维化 Special Interest Group (SIG) 邀请了国际著名肝纤维化研究专家、德国美因茨大学医学中心Detlef Schuppan教授做了两场关于肝纤维化转化医学应用的专题报告。会后，本刊对Schuppan教授进行了专访，请他介绍目前抗肝纤维化治疗取得的最新进展。
We realize that fibrosis in the liver and in other organs is a very complex process. It is not just a single target cell or a single target molecule, but a multicellular process. We have many different cells and molecules that can be addressed to treat fibrosis and the bottom line is that it is very likely we have to address several of these targets to have an efficient and side effect-free therapy. In the first-line, we think about myofibroblasts and stellate cells as the major effector cells of fibrosis that deposit most of the connective tissue or scar tissue. We also have to think about the immune modulator cells especially the macrophages. Macrophages have a very important role in the progression of fibrosis and in inducing regression of advanced fibrosis, so we have a special interest in addressing these cells too. We have other targets like the damaged hepatocytes especially in diseases like fatty liver disease where damaged hepatocytes also play significant roles. Other examples are hepatocytes damaged by viral infection. We know that when we treat the viral infection (such as hepatitis B and C), we can also significantly reduce the fibrosis. So we are realizing the multicomponent etiology of fibrotic liver disease.
There are several examples. The problem with the validation in animal (rat and mouse) models is that, in the past, many of these models have not been performed to best standards. We are trying to establish best standards and how to preclinically best test potential antifibrotic agents. This is something that still has to be done. Apart from that, a few compounds have been tested based on such preclinical data and most of these studies were very small and not really representative but there was at least one larger study testing the PPAR gamma agonist, farglitazar, in a large number of hepatitis C patients who were non-responsive to treatment and this study was negative. It was published in Gastroenterology in 2010 and was a >400-patient study that turned out negative based on not terribly well performed preclinical studies.
Now we have the ongoing studies with the LOXL2 inhibitor antibody which is supposed to block the cross-linking of collagen, and we expect the data to be released (at least in part) within one year from now. So there will be first data from these large trials using fairly good study design for controlling the efficacy of the drug (mainly biopsy-based) soon.
There has been a revolution in the last couple of years in both antisense and siRNA technologies. They had essentially been abandoned ten years ago. Now we have reagents that are highly efficacious without significant side effects on the immune system or epithelial cells, for example, and which intrinsically target the liver. When injected (and most of them need to be injected intravenously or peripherally), there is a high targeting efficiency to the liver and both antisense and siRNA technologies have been proven in clinical studies and are currently being evaluated in clinical studies, mainly for hepatocyte-based diseases like lipid metabolism abnormalities (hypercholesterolemia, for example). They are very efficient drugs in intercepting certain central RNAs that work in pathologies like hyperlipidemias and coagulation disorders and hepatocyte damage as seen with NASH. We are also getting closer to siRNA drugs now that interfere directly with the scar tissue molecules like collagen type 1. These are still dependent on nanoparticle delivery systems. There are also some naked antisense oligonucleotide and siRNA technologies that are also directed at the liver. There is a lot happening now in this field. We have the first clinical proof-of-concept studies from phase I up to phase III to show that in fibrosis-related or unrelated diseases, they are effective in humans. We have very detailed data on both antisense and siRNA approaches in disorders of hepatocyte lipid metabolism. It is very convincing data showing high efficiency where patients are not treatable with conventional drugs such as in familial hypertriglyceridemia or cholesterol overproduction syndromes or LDL receptor deficiency. We have first data in coagulation disorders and I think we will get closer to direct antifibrotic therapies and therapies that modulate the macrophages that have a very important role in the progression and resolution of fibrosis as I mentioned before. I believe we will see further clinical data apart from the emerging preclinical data that is being presented at this conference.
This is a discussion that my colleagues and I increasingly have with biotech and also larger industry because there is a growing interest in developing so-called indirect and direct antifibrotic agents and how to design the trials. Most companies and investigator-initiated trials like to get proof-of-concept before they start phase III trials that will be of long duration and very expensive and potentially pose a risk to patients. We are talking more and more about relatively short proof-of-concept trials where we use as many biomarkers or surrogate markers that are not necessarily biopsy-based; to get positive signals of a certain drug or drug combination that would indicate that we should dare to go into a larger biopsy-based phase III clinical study. We will have a lot of studies coming up that target fibrosis as a primary or secondary endpoint with novel drugs or drug combinations which will use these biomarkers to get as many favorable signals as possible in terms of fibrosis progression or regression.
专家简介： Detlef Schuppan, PhD, MD，德国美因茨大学医学中心分子及转化医学教授，美国哈佛大学医学院Beth Israel Deaconess 医疗中心肝病专家，国际著名肝纤维化研究学者，Gastroenterology, Journal of Hepatology等杂志副主编，已发表文章467篇。