SINGAPORE — In a major medical breakthrough, researchers from the Duke-NUS Medical School and the National Heart Centre Singapore have discovered a protein that is primarily responsible for fibrosis, which causes widespread organ damage such as heart and kidney failure.
The findings published in Nature Medicine, a major medical journal, debunk established literature that the protein, known as interleukin 11, was harmless and dormant.
Since the 1990s, scientists have known that another protein — transforming growth factor beta 1 — was the major cause of fibrosis, but treatments targeting it with drugs or antibodies caused severe side effects such as chest infections or skin cancer.
However, the research team behind the breakthrough discovered that interleukin 11 is even more important. It is the “master switch”, which means turning off interleukin 11 will stop the production of collagen and proteins that contribute to fibrosis.
Speaking to reporters on Monday (Nov 13), Professor Stuart Cook, who led the 20-man research team, said that they have found out how to prevent the growth of fibrosis with antibodies that they developed to target interleukin 11.
More work has to be done to find out if the antibodies can stop fibrosis in its tracks or even reverse it. This might depend on the affected organ, he said. For example, fibrosis in lung tissue could be stopped, but not reversed.
The director of the Duke-NUS Medical School’s Cardiovascular and Metabolic Disorders Programme added: “This could really help people who have advanced fibrosis (where the treatment can reverse the damage), and the organ can be healthy again. There is a precedent that that can work, particularly in the liver.”
Prof Cook and his team will be applying to the authorities in mid-2019 for the antibodies to be approved as a drug, with plans to begin human clinical trials with about 20 to 30 people by 2020.
SCARRING OF ORGANS
Fibrosis — the formation of excessive connective tissue, which causes scarring and failure of organs and the skin — is a leading cause of common life-threatening conditions such as heart, lung, kidney and liver failure.
This is important because Singaporeans are at greater risk of heart failure than their Asian counterparts, as they have a higher prevalence of developing coronary artery disease, hypertension and diabetes.
Prof Cook said that the team’s finding could potentially impact millions of people worldwide.
More than 225 million people globally suffer from heart and kidney failure, with no treatment to prevent fibrosis.
Research work began in 2012 and two years later, in a bid to find new genes which are important for fibrosis, the team sequenced the genes found in fibroblasts. Fibroblasts are cells in connective tissue that produce collagen and other fibres.
This was accomplished through a collaboration with the National Heart Centre Singapore, which provided them with 84 samples of heart tissue from their patients. The researchers were then able to grow fibroblasts in the tissue and study the genes.
The breakthrough came when they found that interleukin 11 was linked to the activation of these fibroblasts, and that the protein could be inhibited by drugs. The team then spent a few more years conducting the study on the heart tissue samples and mice, as well as developing the antibodies.
Tests done on mice showed that the antibodies can prevent the growth of fibrosis.
In terms of potential side effects, Prof Cook noted that when the interleukin 11 receptor was “deleted” in one of the mice, it remained “very very well”.
“This discovery is significant because people like me, in the science laboratories and pharmaceutical companies, have been looking for something like this for 10 years,” he added.
In April, Prof Cook and another research team member, Assistant Professor Sebastian Schafer, co-founded a biotechnology startup, Enleofen Bio. Five patents relating to the research and the antibodies they developed have been licensed to Enleofen Bio.