Simon Brown

Image

Coronary artery disease is one of the largest causes of death worldwide, and in 2019 was the single largest cause of death worldwide, accounting for 9.1 million deaths. The British

Heart Foundation estimate that there are over 200 million people living with coronary artery disease worldwide. In patients with advanced coronary artery disease, heart bypass grafting is commonly performed, with around 17,000 surgeries performed annually in the UK, and more than 2 million worldwide. In this procedure, a vein is taken, most commonly from the patient’s leg, and used to bypass blocked arteries in the heart, thus restoring blood-flow. The failure rates of these procedures remain high, with 25% failing in the first 12-18 months, and 50% failing 5-10 years post-surgery. Heart bypass graft failure is a complex process, but excessive proliferation of a particular cell type, smooth muscle cells, is recognised as central to graft failure. This excessive smooth muscle cell division leads to a narrowing of the grafted vein, which eventually will occlude the vein and prevent blood flow. Repeated interventions in these patients are difficult, and if left untreated, patients can have a heart attack or develop heart failure.

We have developed an advanced RNA therapeutic which blocks the expression of a gene called SMILR. SMILR has been shown through our published work to be a key driver of smooth muscle cell division, and thus of heart bypass graft failure. Blocking SMILR expression is considered to be a realistic means of reducing heart bypass graft failure rates. Crucially, we can administer our therapeutic specifically, and only to, the vein immediately prior to grafting in the heart, preventing off-target effects. We propose to conduct a first-in-human clinical trial to assess the safety and efficacy of our therapeutic in real-world heart bypass surgeries. If this trial is successful, we would look to expand to larger phase II clinical trials, with the eventual aim of introducing our therapeutic into the market for wider use.

The Team 

Simon Brown

Professor Andy Baker

Professor David Newby

Professor Scott Webster

Mr Mark Cunningham

Dr Anna Malinowska

About  Us

I am a research fellow based at the Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh. My main research focus is the development of gene and RNA therapies for cardiovascular disease, with particular focus on heart bypass graft surgery. During heart bypass graft surgery, a vein is taken, usually from the patients leg, and used to bypass blocked arteries in the heart. As part of our team, we are developing novel therapeutics to improve the outcome of these surgeries.

Problem 

Heart bypass grafting is one of the most common surgical interventions performed on patients with severe, multi-vessel coronary artery disease. In this procedure, a vein is taken, most-commonly from the patient’s leg, and used to bypass the blocked arteries in the heart. As the vein is placed into the higher blood pressure environment in the heart (i.e. the arterial circulation), the vein often becomes injured when adapting to its new environment. This leads, in up to 50% of cases, long term failure of the graft and reoccurrence of symptoms in the patient. Re-interventions in these patients are difficult, and most often other cardiovascular complications, such as heart attacks and heart failure, arise. In the wall of the vein, certain cells become activated after grafting and lead to this detrimental effect. We have shown that these cells are involved in this process and that they divide too quickly leading to the pathology. We have shown a way to block this excess cell division by reducing the levels of a key gene that we have identified and characterised called SMILR (smooth muscle cell-induced lncRNA). We have shown that SMILR expression increases when these cells become proliferative, and that SMILR itself helps drive this proliferation. Blocking SMILR expression is thus a promising approach to prevent this excessive cell proliferation that drives vein graft failure.

Solution 

We have developed an advanced therapeutic which targets SMILR, blocks its expression and reduces cell proliferation in the vein tissue. During heart bypass graft surgery, the patient’s vein is often removed entirely, and sits outside the body while the heart is prepared for grafting. This provides us with a unique opportunity to deliver our therapeutic specifically to the target tissue, with little change to surgical practice. Delivering only to the target tissue prevents any unwanted side-effects from delivering our therapeutic systemically.

Market

Our market would be the NHS and private healthcare providers, both in the UK and eventually worldwide. We have already engaged with cardiac surgeons to discuss our proposal and our therapeutic approach, which does not propose any changes to surgical practice; and this has been received enthusiastically. We have made initial contacts with representatives of the Medicines and Healthcare products Regulatory Agency (MHRA) to establish precise clinical end-points and requirements to design and begin a clinical trial. 

Contact

Simon Brown LinkedIn