Professor Stuart Cook and IL-11

Professor Stuart Cook and IL-11 Mark Nicholls speaks to Stuart Cook MBBS MRCP PhD about research on the Interleukin 11 protein which advances the prospect of a new treatment for heart and kidney failure  It has remained something of a mystery for several years, a protein and its full impact apparently remaining unnoticed by cardiologists and researchers. But, now a team from Imperial College London (ICL) and Duke-National University of Singapore (NUS) may at last have unlocked some of these hidden facets and discovered the true impact of the interleukin 11 (IL-11) protein. It was thought that IL-11 was part of the immune system and that it may protect from organ damage, but it has now emerged that IL-11 is a cause of scarring and heart and kidney failure. And through this discovery, Stuart Cook feels the team have taken a step closer to a new treatment for heart and kidney failure. The findings focus on IL-11 after the team showed that it plays a significant role in the scarring process, which in turn can cause heart, kidney, and liver failure, with work conducted in mice models suggesting that by inhibiting IL-11, heart and kidney fibrosis could be prevented. The interleukins are a group of proteins that handle communication between cells, and regulate cell growth, differentiation, and movement and are particularly important in immune responses, inflammation, and fibrosis. Now, the research team is looking to assess whether drugs capable of blocking IL-11 can be developed, which may subsequently reduce the damage caused by a myocardial infarction and prevent the onset of heart or kidney failure. Stuart Cook, the head of the Cardiovascular Genetics and Genomics at the National Heart and Lung Institute (NHLI) at ICL and Professor at Duke-NUS and study’s author, said: ‘We’ve discovered that IL-11 is a critical fibrotic factor and required for fibrosis to occur. Scientists and pharmaceutical companies have been searching for such a factor for decades and this is a very exciting breakthrough’. Interleukin 11, he continued, is an essential ‘on switch’ in the fibroblast and without its activity the fibroblast is not able to make collagen in response to tissue injury. ‘IL-11 is only detectable in damaged tissue and does not appear to play a role in normal tissues’, he added. ‘When Interleukin 11 is activated for prolonged periods it causes “gumming up” of the tissue that destroys the normal architecture and function of that organ. We see this across organs in the mouse and have documented this clearly in the heart and kidney in our latest publication’. ‘It is really surprising that IL-11 has gone unnoticed for so long as it is clearly a master regulator of the fibrotic process. This discovery represents a major advance in our understanding of fibrosis and opens new doors for research into the processes underlying organ scarring’. For the study, published in Nature,1 the team hypothesized that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, they found that IL-11 up-regulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect. The researchers further showed that IL-11, and its receptor IL-11RA were expressed specifically in fibroblasts, where they drive the intracellular signalling pathway responsible for fibrogenic protein synthesis. They also demonstrated in mice that fibroblast-specific IL-11 transgene expression or the injection of IL-11 caused heart and kidney fibrosis and eventual organ failure, whereas genetic deletion of IL-11RA was protective against disease. Using genomic engineering techniques, Cook’s team created normal laboratory mice in which IL-11 in fibroblasts could be turned on when required. Also, when IL-11 was injected into healthy mice in separate experiments, their hearts and kidneys became fibrotic and failed within just 2 weeks. Professor Stuart Cook, a British Heart Foundation (BHF) funded researcher at ICL, who is also Tanoto Foundation Professor of Cardiovascular Medicine at Duke-NUS Medical School and a senior consultant at the National Heart Centre Singapore, added: ‘Its discovery gives us the opportunity to develop new ways of diagnosing, preventing, arresting and perhaps reversing tissue fibrosis and organ damage. It also shows how certain genes play a major role by regulating the levels of proteins only—that is, Interleukin 11 does not change levels of ribonucleic acid (RNA)—it only changes levels of protein. This may be another reason why it has gone unnoticed for so long’. A next stage of the research is to examine the effects of IL-11 in organs other than the heart and kidney. Preliminary data shows that this gene is important for fibrosis across tissues. The team hope to have approvals in place to proceed to a phase 1 clinical trial in 2020; and see significant possibilities of developing drugs capable of blocking IL-11. ‘We are developing molecules that will be used as drugs to block Interleukin 11’, he said. ‘We will particularly focus on antibody therapies as these have been proven to be safe and predictable and efficacious’. With some strong lead candidates that they are focusing on, the group is working with the UK-based CRO/CMO (Contract Research Organisation/Contract Manufacturing Organisation) Abzena to expedite this. It has also spun out a company from Duke-NUS (www.enleofen.com) that has licenced the intellectual property that has been developed to take forward the group’s inhibitors for therapeutic use. Conflict of interest: none declared. References References are available as supplementary material at European Heart Journal online. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Professor Stuart Cook and IL-11

European Heart Journal , Volume Advance Article (20) – May 21, 2018

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Publisher
Oxford University Press
Copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
ISSN
0195-668X
eISSN
1522-9645
D.O.I.
10.1093/eurheartj/ehy204
Publisher site
See Article on Publisher Site

Abstract

Mark Nicholls speaks to Stuart Cook MBBS MRCP PhD about research on the Interleukin 11 protein which advances the prospect of a new treatment for heart and kidney failure  It has remained something of a mystery for several years, a protein and its full impact apparently remaining unnoticed by cardiologists and researchers. But, now a team from Imperial College London (ICL) and Duke-National University of Singapore (NUS) may at last have unlocked some of these hidden facets and discovered the true impact of the interleukin 11 (IL-11) protein. It was thought that IL-11 was part of the immune system and that it may protect from organ damage, but it has now emerged that IL-11 is a cause of scarring and heart and kidney failure. And through this discovery, Stuart Cook feels the team have taken a step closer to a new treatment for heart and kidney failure. The findings focus on IL-11 after the team showed that it plays a significant role in the scarring process, which in turn can cause heart, kidney, and liver failure, with work conducted in mice models suggesting that by inhibiting IL-11, heart and kidney fibrosis could be prevented. The interleukins are a group of proteins that handle communication between cells, and regulate cell growth, differentiation, and movement and are particularly important in immune responses, inflammation, and fibrosis. Now, the research team is looking to assess whether drugs capable of blocking IL-11 can be developed, which may subsequently reduce the damage caused by a myocardial infarction and prevent the onset of heart or kidney failure. Stuart Cook, the head of the Cardiovascular Genetics and Genomics at the National Heart and Lung Institute (NHLI) at ICL and Professor at Duke-NUS and study’s author, said: ‘We’ve discovered that IL-11 is a critical fibrotic factor and required for fibrosis to occur. Scientists and pharmaceutical companies have been searching for such a factor for decades and this is a very exciting breakthrough’. Interleukin 11, he continued, is an essential ‘on switch’ in the fibroblast and without its activity the fibroblast is not able to make collagen in response to tissue injury. ‘IL-11 is only detectable in damaged tissue and does not appear to play a role in normal tissues’, he added. ‘When Interleukin 11 is activated for prolonged periods it causes “gumming up” of the tissue that destroys the normal architecture and function of that organ. We see this across organs in the mouse and have documented this clearly in the heart and kidney in our latest publication’. ‘It is really surprising that IL-11 has gone unnoticed for so long as it is clearly a master regulator of the fibrotic process. This discovery represents a major advance in our understanding of fibrosis and opens new doors for research into the processes underlying organ scarring’. For the study, published in Nature,1 the team hypothesized that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, they found that IL-11 up-regulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect. The researchers further showed that IL-11, and its receptor IL-11RA were expressed specifically in fibroblasts, where they drive the intracellular signalling pathway responsible for fibrogenic protein synthesis. They also demonstrated in mice that fibroblast-specific IL-11 transgene expression or the injection of IL-11 caused heart and kidney fibrosis and eventual organ failure, whereas genetic deletion of IL-11RA was protective against disease. Using genomic engineering techniques, Cook’s team created normal laboratory mice in which IL-11 in fibroblasts could be turned on when required. Also, when IL-11 was injected into healthy mice in separate experiments, their hearts and kidneys became fibrotic and failed within just 2 weeks. Professor Stuart Cook, a British Heart Foundation (BHF) funded researcher at ICL, who is also Tanoto Foundation Professor of Cardiovascular Medicine at Duke-NUS Medical School and a senior consultant at the National Heart Centre Singapore, added: ‘Its discovery gives us the opportunity to develop new ways of diagnosing, preventing, arresting and perhaps reversing tissue fibrosis and organ damage. It also shows how certain genes play a major role by regulating the levels of proteins only—that is, Interleukin 11 does not change levels of ribonucleic acid (RNA)—it only changes levels of protein. This may be another reason why it has gone unnoticed for so long’. A next stage of the research is to examine the effects of IL-11 in organs other than the heart and kidney. Preliminary data shows that this gene is important for fibrosis across tissues. The team hope to have approvals in place to proceed to a phase 1 clinical trial in 2020; and see significant possibilities of developing drugs capable of blocking IL-11. ‘We are developing molecules that will be used as drugs to block Interleukin 11’, he said. ‘We will particularly focus on antibody therapies as these have been proven to be safe and predictable and efficacious’. With some strong lead candidates that they are focusing on, the group is working with the UK-based CRO/CMO (Contract Research Organisation/Contract Manufacturing Organisation) Abzena to expedite this. It has also spun out a company from Duke-NUS (www.enleofen.com) that has licenced the intellectual property that has been developed to take forward the group’s inhibitors for therapeutic use. Conflict of interest: none declared. References References are available as supplementary material at European Heart Journal online. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

European Heart JournalOxford University Press

Published: May 21, 2018

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