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Focusing on fibrosis
SINGAPORE—Fibrosis is the theme of choice for some of the recent research out of the Duke-NUS Medical School, part of the National University of Singapore. The result of excess fibrous or scar tissue formation, typically in terms of internal scarring, fibrosis features in a variety of diseases and conditions. Two Duke-NUS teams recently shared the identification of new targets that play a role in fibrosis and could serve as therapeutic targets.
Beginning with their work on scarring of the heart, a Duke-NUS team—along with collaborators in Germany and the U.K.—generated the first genome-wide dataset on protein translation during fibroblast activation.
Cardiac fibrosis occurs when fibroblasts activate and turn into myofibroblasts, which leads to thickening, stiffening and development of scar tissue. That scarring plays a role in diseases such as atrial fibrillation, dilated cardiomyopathy and heart failure.
To narrow down the culprits behind this process, the researchers looked at the mechanisms behind the transcription of DNA into RNA, and the translation of RNA for protein synthesis in the process that turns fibroblasts into myofibroblasts.
“We found a staggering one-third of all genes undergo translational regulation during this pathogenic transition,” noted Sonia Chothani, first author of the study and a Ph.D. student at Duke-NUS. “All these gene expression changes are missed or misinterpreted in traditional RNA-based studies.”
By tracking the gene changes during this transition at different points of the process, and then analyzing the resulting data, the team pinpointed specific regulatory processes that affect RNA translation. After analyzing RNA found in the fibroblasts of patients with dilated cardiomyopathy, they identified many of the same processes in the tissue samples.
The key culprits in the transition of fibroblasts to myofibroblasts are RBPs, which target RNA and impact the translation of genetic data during protein synthesis, and inhibition of the RBPs PUM2 and QKI limited the transition of fibroblasts into myofibroblasts.
“There are more than 1,500 RBPs encoded in the human genome, but their role in the regulation of translation of target messenger RNAs remains largely unexplored. Our findings show the central importance of translational control in fibrosis, and highlight novel pathogenic mechanisms in heart failure,” explained Dr. Owen Rackham, corresponding author, computational geneticist and assistant professor in the Cardiovascular and Metabolic Disorders Programme at Duke-NUS. “Just as transcription factors are emerging targets in pharmacology owing to their centrality in the dysregulation of transcription, we show that RBPs may play a similar role in the dysregulation of translation.”
Prof. Patrick Casey, senior vice dean for Research at Duke-NUS, commented, “Our ability to understand disease is being revolutionized by the availability of new technologies, whose power can best be realized by interdisciplinary teams combined with the development of methods that can address previously intractable questions. As exemplified in this study, the best way to do this is by bringing together scientific and clinical expertise with cutting-edge technology.”
Moving to the work on lung fibrosis, a second Duke-NUS team found that blocking a protein known as Interleukin 11 (IL11) can prevent and even potentially reverse scarring in a preclinical model of idiopathic pulmonary fibrosis (IPF). The results appeared in Science Translational Medicine.
This research was another effort between multiple organizations, with Duke-NUS Medical School and the National Heart Center Singapore (NHCS) leading the collaboration and joined by collaborators in Germany, the United States and the U.K.
IL11 plays a role in cytokine signaling, and is present in abnormally high levels in IPF patients, with a greater concentration tied to a more severe disease state. Similar to the study done in heart fibrosis, lung fibrosis also results from myofibroblasts, which are dependent on IL11.
“IL11 contributes to lung fibrosis in a self-activating loop by stimulating myofibroblasts that, in turn, produce and release even more IL11,” said NHCS researcher Dr. Benjamin Ng, the study’s lead author. “We showed that IL11 is essential in causing lung fibrosis; in our lab experiments, we found that anti-IL11 therapy protects the lungs from damage.”
Prof. Stuart Cook, senior and corresponding author of the study, and the Tanoto Foundation Professor of Cardiovascular Medicine, also participated in this work, and has previously shown that IL11 is a key culprit in fibrosis of the liver, kidney and heart as well. Cook is also director of Duke-NUS Cardiovascular and Metabolic Disorders Programme; senior consultant at the Department of Cardiology, NHCS; director of the National Heart Research Institute Singapore; and deputy director (Clinical) of the SingHealth Duke-NUS Institute of Precision Medicine.
And as an added bonus beyond identifying a new therapeutic target for IPF, IL11 is also a target that can be targeted—with encouraging results. Cook and his team created what they call neutralizing antibodies, which target and block IL11 to prevent the activation of myofibroblasts. When tested in preclinical studies, these molecules not only inhibited lung fibrosis, they also reversed it and improved inflammation in the lungs as well.
The team has engineered the antibodies for human use and intends to evaluate them in safety trials late next year, with in-human clinical trials planned shortly after. They also plan to explore IL11's role in fibrosis of the skin, pancreas, eye and bone marrow, moving forward.
SOURCE: Duke-NUS press release