How to arrest a killer

Prof Selim Cellek

More than 40% of all deaths are caused by a process called fibrosis. Professor Selim Cellek may have found a way to halt its progress.

“Fibrotic diseases are responsible for 42% of all deaths,” Professor Selim Cellek observes. Then, for clarification, he adds: “All deaths globally”. It sounds unbelievable. How could one group of diseases cause so many fatalities? Consider what these diseases really involve, however, and you realise how it can be true.

‘Fibrosis’ happens when our body’s remarkable, natural ability to heal wounds goes wrong. Whenever we are injured, the body sends cells called fibroblasts to the affected area. Fibroblasts normally provide a sort of protein scaffolding that maintains tissue structure. But when dispatched to a wound they transform into ‘myofibroblasts’, a super-charged version that builds this scaffolding in overdrive.

Myofibroblasts fill and close the wound, then usually die away. But this doesn’t always happen. Sometimes, instead of dying, myofibroblasts remain, ‘over-healing’ and producing scar tissue. This out-of-control healing is fibrosis, and it can also happen to damaged internal organs, with devastating consequences.

Fibrosis of the kidneys, for example, can lead to kidney failure. Fibrosis (cirrhosis) of the liver kills thousands of people in Britain every year. Fibrosis of the heart, or lungs, is usually fatal. Even nonfatal forms can be severe: the permanent scarring of burns victims, for instance, is caused by skin fibrosis.

“Pharma companies everywhere had been researching fibrosis for 50 years, but not one successful drug had emerged. I started wondering, why?”

Selim, who leads the Drug Discovery Group in our Medical Technology Research Centre, began studying fibrotic diseases years ago, having worked for a pharmaceutical company. “Pharma companies everywhere had been researching fibrosis for 50 years, but not one successful drug had emerged,” he says. “I started wondering, why?”

He developed a theory, which became the basis of his recent research at our University. These failed drugs had tried to target the diseases’ molecular structure. What if, instead, a drug could actually stop fibroblasts from becoming myofibroblasts?

Testing this required access to fresh fibroblasts from an active disease. Selim had previously worked on Peyronie’s disease, an unpleasant condition in which fibrosis of the penis creates a plaque that can cause erectile dysfunction and deformity. These plaques can be removed in surgery and, potentially, used for research.

Selim’s team with colleagues from University College London, painstakingly developed a method to turn fibroblasts into myofibroblasts in the lab, using these samples. Once they had perfected that process, they then set about testing chemical compounds that might stop the transformation.

They started with 25 approved drugs that had been developed for Peyronie’s disease, but had failed clinical trials. Selim fully expected them to fail again in his experiment. Instead, to everyone’s surprise, five of them (which belonged to two distinct groups – PDE5 inhibitors and SERMs) worked. Astonishingly, when combined in further tests, they synergised, inhibiting myofibroblast development even more. “That was a real eureka moment,” Selim says. “I realised we were on to something.”

“When I told one clinician about our results, he literally fell off his chair!”

Further tests in rats in collaboration with KU Leuven, Belgium, confirmed that these drugs can prevent fibrosis in Peyronie’s disease. So why had they failed clinical trials? Selim realised that doctors had focused on the wrong patients. In patients where fibrosis has not established itself, the drugs indeed stalled fibrosis. But the clinical trials had failed because the drugs were tested on patients who had had the disease for longer.

Selim’s method, in other words, does not reverse fibrosis, but it does seem to arrest its development if used early. He is now planning a full clinical trial with Peyronie’s disease patients, and seeking funding to test further drugs.

But on a much bigger scale, targeting myofibroblast development offers an entirely new method for stopping other fibrotic diseases in their tracks. Selim is now collaborating with Broomfield Hospital, to test potential compounds for burns patients, and Papworth Hospital, to study lung fibrosis.

“I am hopeful that our approach will work for other diseases,” he adds. “When I told one clinician about it, he literally fell off his chair! Another couldn’t contain his excitement. Those clinicians sometimes have to tell patients with fibrotic diseases that they have months to live and there is nothing they can do. When I see a clinician’s excitement, I feel we are on the right path.”




Drug Discovery Group at ARU

Our group focuses on drug discovery and development through phenotypic screening assays rather than single-target approach. We develop and validate in vitro and in vivo phenotypic screening assays. Our in vitro cell models are mostly based on human primary cells, rather than commercially available cell lines.

Currently our group has focused on the development of novel anti-fibrotic drugs using phenotypic assay approach. While fibrosis is the causative pathology of more than 40% of mortality globally, the treatment options are limited in numbers and efficacy. Our group aims to develop novel anti-fibrotic medicines through phenotypic screening. We have developed and validated phenotypic assays amenable to high throughput screening, as well as secondary functional assays. One of our workstreams has produced two hit compounds which have been further tested and validated in in vivo models and now being taken to clinical studies.

We offer these assays to external groups and organisations; we will be happy to test your lead/candidate compounds/molecules. We are also open to discussion around development of novel phenotypic assays for fibrosis or other indications with unmet need.

Please contact selim.cellek@aru.ac.uk for more information.