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Contact: Wilhelm Schwaeble
ws5@le.ac.uk
44-116-252-5674
University of Leicester

Simple injection could limit damage from heart attacks and stroke

'Milestone achievement' also has potential applications in transplant surgery

IMAGE: This is professor Wilhelm Schwaeble of the University of Leicester.

Click here for more information.

Medical researchers today held out promise that a simple injection is being developed to limit the devastating consequences of heart attacks and strokes.

Described by the lead researcher as 'a fascinating new achievement', work has already begun to translate the research into novel clinical therapies.

The University of Leicester led an international team whose research has been published today in the Early Online Edition of the Proceedings of the National Academy of Sciences (PNAS).

Professor Wilhelm Schwaeble of the Department of Infection, Immunity and Inflammation at the University of Leicester, initiated and co-ordinated research collaborations with King's College London, the Medical University of Fukushima, Japan and the State University of New York, to achieve the present breakthrough findings, which were published today in PNAS.

Professor Schwaeble and collaborators identified an enzyme, Mannan Binding Lectin-Associated Serine Protease-2 (MASP-2), that is found in blood and is a key component of the lectin pathway of complement activation, a component of the innate immune system.

The lectin pathway is responsible for the potentially devastating inflammatory tissue response that can occur when any bodily tissue or organ is reconnected to blood supply following ischaemia a temporary loss of that blood supply and the oxygen that it carries. This excessive inflammatory response is, in part, responsible for the morbidity and mortality associated with myocardial infarction (heart attack) and cerebrovascular accidents (CVAs or strokes). Moreover, the work succeeded in finding a way to neutralise this enzyme by raising a therapeutic antibody against it. A single antibody injection in animals has been shown to be sufficient to disrupt the molecular process that leads to tissue and organ destruction following ischaemic events, resulting in significantly less damage and markedly improved outcomes.

"This is a fascinating new achievement in the search for novel treatments to significantly reduce the tissue damage and impaired organ function that occur following ischaemia in widespread and serious conditions such as heart attacks and strokes," said Professor Schwaeble. "This new potential therapy was also shown in animals to significantly improve outcomes of transplant surgery and may be applicable to any surgical procedure where tissue viability is at risk due to temporary interruption of blood flow.

"The main focus of our work was to identify a key molecular mechanism responsible for the overshooting inflammatory response that can cause substantial destruction to tissues and organs following their temporary loss of blood supply, a pathophysiological phenomenon called ischaemia/reperfusion injury," added Professor Schwaeble. "Limiting this inflammatory response in oxygen-deprived tissues could dramatically improve outcomes and survival in patients suffering heart attacks or strokes."

For more than seven years, the University of Leicester team has been working closely with a commercial partner, Omeros Corporation in Seattle (USA), to develop therapeutic antibodies for research and clinical applications. Omeros holds exclusive worldwide intellectual property rights to the MASP-2 protein, all therapeutic antibodies targeting MASP-2 and all methods for treating complement-mediated disorders by inhibiting MASP-2. The company has already begun manufacturing scale-up of an antibody for use in human clinical trials.

Professor Schwaeble's team and Omeros are also working with Professor Nilesh Samani, the British Heart Foundation Professor of Cardiology and Head of the Department of Cardiovascular Sciences at the University of Leicester. It is anticipated that the first clinical trials evaluating Omeros' human antibody in myocardial infarction patients will be conducted in the Leicester Biomedical Research Unit , at Glenfield Hospital, Leicester.

The development of this new technology was made possible through substantial and long-term grant support of the Wellcome Trust and the Medical Research Council, as well as through funding provided to Omeros Corporation by the U.S. National Institutes of Health.

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NOTES TO EDITORS

For more information, please contact Professor Wilhelm Schwaeble, University of Leicester:

Tel: +44 (0)116 252 5674
Fax: +44 (0)116 252 5030
E-mail: ws5@le.ac.uk

Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury

Wilhelm J. Schwaeble, Nicholas J. Lynch, Nilesh J. Samani, Youssif Mohammed Ali, Russell Wallis, Cordula M. Stover University of Leicester

James E. Clark, Michael Marber, Conrad A. Farrar, Steven Sacks King's College London

Youssif Mohammed Ali
University of Mansoura

Thomas Dudler, Brian Parent, Clark E. Tedford Omeros Corporation

Karl Lhotta
Landeskrankenhaus Feldkirch

Haekyung Lee, Ming Zhang
State University of New York-Downstate Medical Center

Daisuke Iwaki, Minoru Takahashi, Teizo Fujita Fukushima Medical University

About the Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk

ABOUT THE MRC:

For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk.

A more detailed summary of the research is available here::

This weeks Early Edition of the Proceedings of the National Academy of Sciences (USA) (PNAS), an internationally leading Science Journal, will publish a fascinating new milestone achievement in the search for novel clinical therapies to significantly reduce the loss of tissue and organ-functions following the loss of blood supply in widespread and serious human pathologies such as heart attacks (myocardial infarction) and strokes (cerebral ischemia). This new therapy was also shown to significantly improve the outcome of transplant surgery and of any surgical procedure that involves the temporary loss of blood supply.

An international team lead by Professor Wilhelm Schwaeble of the Department of Infection, Immunity and Inflammation in the College of Medicine, Biological Sciences and Psychology of the University of Leicester has identified that the inflammatory response that follows the loss of blood supply of organs and tissues is the main factor in determining the subsequent loss of tissue and organ functions. Limiting this inflammatory response in oxygen-deprived tissues dramatically improves the outcome of ischaemic pathologies in terms of disease severity and survival. PNAS reports that the University of Leicester research team has now identified the molecular mechanism leading to the devastating inflammatory tissue response to the temporary loss of oxygen supply and succeeded in disrupting that specific mechanism using a therapeutic antibody against a key component of this system, known as the lectin pathway of complement activation. In experimental models of myocardial infarction and infarction of the small intestine, the absence of lectin pathway functional activity resulted in a dramatic reduction of tissue loss with significantly lower infarct sizes than in animals that retained lectin pathway functional activity. Mice treated with a therapeutic antibody that blocks the function of this lectin pathway, the severity of ischaemic injury to the small intestine following transient occlusion of the vessel responsible for the blood supply of the small intestine was dramatically reduced. The therapeutic depletion of lectin pathway functional activity is long-lasting and easily achieved by a single dose antibody injection. In addition to the mouse-specific lectin pathway inhibitors used in models of ischaemic disease, the University of Leicester team has joined up with a commercial partner, Omeros Corporation in Seattle (USA) and developed a set of recombinant therapeutic antibodies that efficiently block the human lectin activation pathway of complement. The first institution to translate this exiting new medical research into clinical applications will be the Biomedical Research Centre of the Department of Cardiovascular Sciences, at Glenfield University Hospital, where Professor Nilesh Samani will lead a clinical team of cardiologists to assess the clinical efficacy of this new therapy in protecting the heart after heart attacks.

The development of this technology was made possible through substantial and long-term grant support of the WELLCOME TRUST and the MEDICAL RESEARCH COUNCIL



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