What was it that drew you to this area of research?

I had an unconventional start in science. After my A’ Levels I spent four years in banking before deciding to switch. At my interview to study biology at Exeter University, I was told I ought to read up on some biochemistry, and was handed a textbook. Immersing myself in that was what got me hooked on physiology. During my PhD at the MRC Clinical Sciences Centre in the 1990s I become interested in the molecular mechanisms underlying disease. Most recently I’ve focused on nitric oxide (NO). It’s an interesting molecule because it displays “Goldilocks” qualities. In the cardiovascular system, too little NO causes constriction of blood vessels leading to the hypertension that increases the risk of cardiovascular diseases such as stroke, myocardial infarction and atherosclerosis. Too much NO causes profound vasodilation (dilation of the blood vessels) and hypotension, the low blood pressure that means organs simply don’t receive the throughput of blood they need, leading to multiple organ failure and often death. Getting the balance “just right” is what keeps us healthy. My group’s drug work has focused on sepsis, and understanding the role of NO is central to understanding sepsis.

Was it a good choice?

Yes. Sepsis is a potentially devastating condition that has been identified as a national priority in the UK. Government figures suggest that around 100 people a day die from sepsis, and that better diagnosis and treatment could save around half of these lives. Sepsis is caused by our body’s immune system over-reacting to infection, and its effects have proved intractable to medical advances for decades. In sepsis, our bodies produce too much NO from the walls of our blood vessels. We’ve discovered a novel regulatory pathway that can correct this.

Why has sepsis proved so intractable a condition? Is there hope on the horizon?

Treatments for sepsis have been difficult to find. Many approaches have attempted to dampen the initial immune response. These approaches have been unsuccessful, largely because by the time sepsis is diagnosed, the initial immune response is well established. Previous approaches to reduce the production of NO throughout the body did successfully raise blood pressure, but also reduced the ability of the immune system to kill bacteria – and had a negative impact on the heart. Our approach targets overproduction of NO by the blood vessels themselves, and does not affect cardiac or immune responses. This makes us hopeful that we have an effective new therapy for the treatment of sepsis.

What sort of problems confront those trying to develop new drugs for sepsis?

As an academic working in an MRC-funded institute, I’m in a position to undertake longer-term studies to understand in depth the role and therapeutic potential of specific molecular pathways. Developing treatments for sepsis has been called the “graveyard for pharmaceutical companies” because people with sepsis are often in a highly unstable condition. This can make it very difficult to detect whether a treatment is working. Therefore clinical trials for sepsis treatments often end up being very large and very expensive. This contributes to the perception that drug discovery in sepsis is “high risk”. But with the BHF’s support we should be able to reduce these risks, and make L-257 a very attractive product for taking into clinical trials.

How important a funder is the BHF to your research? How does that complement money you’ve had from the MRC?

I have received BHF funding, on-and-off, for more than 20 years. BHF funding underpins cardiovascular research in the UK and recognises the importance of understanding the disease at the molecular level, in order to design and develop novel therapeutics for patients. Without BHF funding I would not have been able to identify and understand the mechanism that can prevent blood vessels dilating in sepsis. In 2009, I moved back to the MRC Clinical Sciences Centre. This MRC Institute benefits from the security of funding that means researchers can take on longer term high-risk projects such as drug discovery.

Our new BHF Translational Award will allow us to do two things. Firstly, the medicinal chemistry to generate new patents to protect our novel compounds. This is important as clinical trials of new drugs take many years and cost hundreds of millions of pounds. Drug companies will not fund this process if they cannot make money on the finished drug. New patents will extend the time for which drug companies will have exclusive rights to sell these drugs.

The award will also allow us to talk to the regulatory authorities about how best to test these new therapeutics in people. Next month we’re meeting the US Food and Drug Administration to discuss how our clinical trials should be carried out. This discussion is important as the design of the clinical trial is a big factor in its cost and duration. If the FDA endorses our plans it will reduce the risk for drug industry investors and help ensure that our treatment reaches patients as quickly as possible. After over a decade of hard work in the lab, it’s exciting to see this promising drug is getting closer to helping thousands of people a year.

Find out more about sepsis from the UK Sepsis Trust.

For further information, get in touch:

Susan Watts
Head of Communications and Public Engagement
07590 250 652
0208 383 8247

A “highly promising” new approach to treating sepsis could enter human trials within 18 months, following an award to James Leiper of the MRC Clinical Sciences Centre.

Sepsis is a national priority in the UK, with thousands of lives a year lost to the condition in our hospitals. It’s a life-threatening condition caused by infection, and leads to more than 100,000 people being admitted to hospital in the UK each year. But over a third (around 37,000) of those people die. Antibiotics can effectively treat the infection but the body’s response to the infection can cause dangerously low blood pressure, organ failure and death. An effective treatment for this aspect of sepsis is urgently needed and many drugs have already failed to make it through clinical trials.

The BHF Translational Award, granted to Dr Leiper and his clinical collaborator Simon Lambden, of University College London, will cover the costs of further studies to find different forms of a drug candidate they’re developing to treat the dangerous effects of sepsis.

The results are “truly remarkable”

Early funding for the research, awarded back in 2002, also came from the BHF. This funding supported the laboratory animal research where the discovery was made of the potential of a drug called L-257. It works by reducing the production of the chemical nitric oxide. Healthy amounts of nitric oxide are needed for the normal function of blood vessels. However, during sepsis high nitric oxide levels can cause dangerously low blood pressure and ultimately organ failure.

In animals, L-257 improved survival from 0% to 15%, and reduced organ failure during sepsis. All of the animals that survived were on the new drug. What was especially notable was that the drug had been given alone, without the antibiotics and steroids that are usually used to treat patients. Dr Leiper said the results are “truly remarkable”. Here, Dr Leiper tells us more about his start in science, his hopes for this latest research and what it might mean for patients.