Cardiovascular diseases, especially atherosclerotic disease and heart failure, affect more than 20% of the population aged 40 and over.
Vascular remodelling, which refers to changes that result in rearrangement of normal structures of the heart and blood vessels is a key pathological process in cardiovascular diseases such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease that remains a major cause of morbidity in the Western world.
Vein grafts are required in patients with multi-vessel coronary artery disease. For example, in coronary artery bypass graft (CABG) surgery, venous tissue taken from the patient’s leg is used to bypass the blocked region. Over time these grafts can narrow and eventually fail, partly due to damage to the vessel wall caused during surgery. Vascular smooth muscle cells are a predominant constituent of the blood vessel wall, and after undergoing damage, can become hyper-proliferative. This hyper-proliferation of smooth muscle cells in the graft causes narrowing of the luminal space, leading to neointima formation and eventual graft failure. Vein graft failure affects around 30-50% of patients within ten years of surgery, resulting in a need for further treatment, and significant additional costs to healthcare providers. Targeting, and limiting smooth muscle cell proliferation is considered a promising therapeutic target to prevent vein graft failure.
Edinburgh researchers have identified and characterised a long non-coding ribonucleic acid (RNA), called SMILR, which is up-regulated in proliferating vascular smooth muscle cells and plays a key role in regulating their proliferation. SMILR is present in the plasma of cardiovascular disease patients and found at increased levels in unstable regions of atherosclerotic plaques. Therapeutic targeting of SMILR could be a means to inhibit vascular remodelling and reduce or prevent vascular diseases. It is a very attractive target for anti-proliferative approaches with potential applications as a biomarker for detecting unstable atherosclerotic plaques, and it is also amenable to Ribonucleic acid interference, small molecule or gene therapy approaches.
As part of Professor Andy Baker’s research group at Centre for Cardiovascular Science, Dr Margaret Ballantyne identified SMILR and demonstrated that its expression is increased in response to pathogenic stimuli, which in turn drives proliferation specifically in smooth muscle cells. Further work from Dr Ballantyne and Dr Amira Mahmoud characterised SMILR’s mechanism of action and demonstrated precisely how it drives proliferation.
Currently there is a collaboration between Professor Baker’s group, led by Dr Simon Brown and the Nucleic Acid Therapy Accelerator (NATA), who are a Medical Research Council funded institute based near Oxford, and who are performing all the chemistry and siRNA synthesis. Together they are using current knowledge of SMILR to develop a state-of-the-art RNA therapeutic to block SMILR expression, which will be administered during cardiac surgery and could reduce heart bypass graft failure rates.
Professor Baker’s research group is interested in the mechanisms that control vascular damage, and how to influence repair and regeneration of the vascular system using innovative therapies, including gene-, cell- and RNA-based approaches. Focusing on vascular smooth muscle and endothelial cells, they are defining the non-coding RNA pathways and networks that influence cell function in healthy versus disease states and are developing interventions to increase repair and regeneration.
The translational research is being funded by the British Heart Foundation in collaboration with other academic experts at the Centre for Cardiovascular Science. Professor David Newby is a researcher who is heavily involved in the clinical aspect of the project and also has strong expertise in experimental medicine. Professor Scott Webster is a researcher who has strong expertise in translational research, drug discovery and small molecule medicines. Dr Amy Lam is a freelance intellectual property expert who is advising on new IP and disclosures and she works closely with Edinburgh Innovations.
Professor Baker’s lab is leading the way on gene therapy approaches to address cardiac failure using innovative gene therapy approaches to prevent pathological vascular remodelling associated with coronary artery bypass graft failure and its application at the clinical interface. One approach is the generation of endothelial cells from pluripotent stem cells for regeneration in ischaemic conditions, and developing an understanding in mechanisms that control endothelial cell commitment and specification.
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University of Edinburgh Centre for Cardiovascular Science: Andy Baker Research Group
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