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Forging advances in the treatment of respiratory diseases

Forging advances in the treatment of respiratory diseases

In this issue of BioScience Today, we speak to Professor Martin Gosling, about the inspiration behind his work, what motivates him daily, and the advances in the treatment of respiratory diseases that he is working to bring about. Martin is Professor of Molecular Pharmacology at the University of Sussex and Chief Scientific Officer at Enterprise Therapeutics.

“As a child, I always found science interesting. My mother was a pharmacy technician and she’d talk to me about her work, which I found fascinating. For good or for bad, I always wanted to know how things worked.

“Spending a year working in the pharmaceutical industry before I went to university was a turning point and I knew then that developing new treatments that would benefit people was my ambition. Research that was translational rather than purely academic was what I wanted to focus on, developing drug treatments that could make a difference – so I read pharmacology at university.

“The action of drugs on physiological systems has always interested me and I soon found my niche researching ion channels – which I focused on for my PhD studies. Expressed by every cell of the body, ion channels are discrete holes in the membranes of cells that allow the flow of ions such as chloride and potassium into and out of cells. They are involved in many cellular processes such as nerve conduction and muscle contraction, and as such ion channels have long been explored as a conduit for new drug treatments.

“I researched the role of ion channels in bone cells for my doctorate and later I researched the role they play in blood vessels. In 2001, I joined Novartis specifically to research respiratory diseases – now nearly 20 years later, I’m looking at how ion channels could be used therapeutically to deliver new treatments for respiratory diseases including cystic fibrosis. I moved back into academia, joining the University of Sussex not long after Novartis moved their respiratory research centre to the United States.

“Academia can provide more latitude in terms of research area albeit grant funding is highly competitive. Working in the private sector resources may be more plentiful, but you have to put together a very strong commercial case for research to begin, plus companies can change strategic direction very quickly, like when there is a change of leadership for example.

“In the last 15 years drug discovery in the UK has changed dramatically and now very few major pharmaceutical companies have research facilities in the UK, with thousands of jobs which were once here now based abroad. This has to raise the question of how we train the next generation of drug discovery scientists and where talented UK scientists will progress their careers.

“At the same time, the model of research and development has changed dramatically and many smaller biotech companies are taking up the reins, but they simply don’t have the resources to train 

as many scientists as the large pharmaceuticals firms once did. At Novartis, for example, we had 15 apprenticeship places within the respiratory disease group alone, all of whom were studying for a degree part-time too.

“Before I returned to academia, I co-founded a biotech start-up, Enterprise Therapeutics, along with two former colleagues from Novartis, enabling me to carry out precisely the research that I wanted to. Ion channels had become much more tangible and feasible drug targets and were once again the focus of my research.

“Our biotech company is based at the university, within the Sussex Innovation Centre, and it is really beneficial to be working within a renowned research facility and to have such a close working relationship with the School of Life Sciences. Some of the postdoctoral research scientists from the university come and work with us too, so together we are doing our best to nurture the next generation of scientists.

“Our drug discovery research is entirely focused on respiratory diseases; with the hope of improving the quality of life, and reduce the susceptibility to infections of those with cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). We are working on new disease-modifying therapies with the aim of targeting the underlying mechanisms of mucus congestion.

“Mucus is a key part of the lung’s defence system, catching harmful particles and moving them up to the top of your lungs, thence to your stomach so they can be destroyed. Ideally, this mucus is a low viscosity gel of about 3% solids and 97% water. However, if there is too much mucus or too little fluid, it becomes sticky and can plug the airways. Patients with cystic fibrosis typically have mucus that is 15% solids; this causes their airways to become blocked and harmful pathogens, such as bacteria, are no longer cleared leading to infections and destruction of the lung.

“Though the genetic reason for cystic fibrosis was identified back in 1989, it took until 2012 for the first drug to be registered that addressed that genetic defect (Kalydeco). We are looking to tackle this and other respiratory diseases with two strategies. The first is to exploit the activity of ion channels that control the amount of fluid in the airways – this approach will increase airway hydration, reduce the stickiness of the mucus and make it easier to clear.

“We have discovery programs to find drugs which switch on the activity of a chloride channel (TMEM16A) and also to switch off the activity of a sodium channel (ENaC) in the lung – both effects will increase the amount of fluid available to thin mucus. Our second strategy is to reduce the number of mucus-producing cells, complementing these mucus hydration therapies,” explains Martin.

“The challenge in pharmacology is finding a drug that does what you want it to do and ideally only what you want it to do. You know what your target is, but finding the right molecule, that is the difficult part. You can look at hundreds of thousands of compounds to find a chemical starting point to switch your target on or off and that is precisely what we are working on now.”

To put this research into perspective, there are an estimated 70,000 patients worldwide with cystic fibrosis, and though their life expectancy is improving, it is currently around 40 years. COPD is reported to affect over 300 million people – in 2012 alone it was the world’s third highest killer and the estimated economic cost of COPD is in excess of $2 trillion.

In addition, there are an estimated 300 million asthma patients globally, of whom, 5% are classed as suffering from severe asthma, which is either refractory or poorly managed by current therapies (bronchodilators, steroids).

The novel therapies being explored by Martin and his colleagues are at an early stage, but these statistics show just how important research in this area is and what a huge impact, such research, could potentially have worldwide.

Enterprise Therapeutics has recently attracted £29 million in funding from an international consortium of top-tier venture capital investors to help develop these new drug therapies and fight respiratory diseases. The investment syndicate includes Versant Ventures, the Novartis Venture Fund, Forbion, Epidarex Capital and IP Group.

It is good to know the work of Martin and his colleagues has been given a huge vote of confidence and that hope is on the horizon for the development of new treatments for respiratory diseases.

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