Whether it’s from facial acne or a bad fall, scarring is a normal part of having skin that rarely results in anything serious. But scarring, or fibrosis, also happens internally in response to injury and inflammation, and it can lead to organ damage and even failure in systems such as the heart, lungs, and liver (1).
Based on the severity of a condition like idiopathic pulmonary fibrosis, it may seem surprising that there are only two approved antifibrotic drugs, both of which treat lung scarring rather than cure it. According to Michael Gerckens, a pneumology resident at the Helmholtz München Comprehensive Pneumology Center, a number of antifibrotic drugs look promising in mouse models only to fail to show efficacy in late-stage clinical trials. Gerckens recently used an alternate technique, called phenotypic screening, to identify a new class of antifibrotic drugs (2).
With the traditional model of drug discovery, scientists search for compounds that act on a specific pathway deemed relevant to a disease. Often, researchers use knockout mice for these studies. They consider a drug to be successful when it can restore function or prevent a negative outcome in the knockout model. Phenotypic screening works from the other end, identifying drugs of interest based on their ability to change an outcome. In Gerckens’ study, this outcome was the amount of extracellular matrix, a key component of scar tissue (3). Gerckens and his colleagues first developed a test for extracellular matrix deposition that measured proteins including collagen — a known key player in scarring (4) — as well as fibulin 1, which has not been studied in relation to fibrosis before.
Derek Lowe, the director of chemical biology therapeutics at Novartis Institutes for BioMedical Research who was not involved in the research, said that this discovery demonstrates one of the advantages of using phenotypic screening. The process leads to “looking at some stuff that you didn't know to look at.”
Gerckens searched through a library of 1,509 FDA-approved drugs and tested if any reduced the extracellular matrix proteins deposited by cultured human fibroblasts. These compounds were chosen with the intent of repurposing one and avoiding a lengthy process to regulatory approval; still, he confessed that this approach overlooked the vast majority of promising drugs.
“It was critical to prove that with such a complex assay on human primary cells, you can actually scale this up to thousands of compounds, and this was the proof of concept,” he said.
Nevertheless, the search identified the antiallergic drug tranilast as a candidate. In their cultured cells, the drug significantly decreased levels of collagen and fibulin. Further research is needed to understand how the drug works and whether it is safe and effective in patients. Since tranilast only produced an effect on the extracellular matrix proteins at high concentrations, future efforts should tinker with the chemical compound to increase its potency.
Lowe said that the phenotypic screening test used in the study was “perfectly good,” highlighting its use of fibrosis patient-derived cells, but he added that a useful process must be able to screen millions of compounds at once, rather than thousands.
“When we run a phenotypic screen, we try to set it up to cast the net as wide as possible,” he said. “I think that just running FDA-approved drugs is a tiny, little set of drugs.”
Even though their study highlighted idiopathic pulmonary fibrosis, extracellular matrix proteins play a role in a range of chronic conditions like cancer and heart disease that remain elusive targets for traditional drug discovery; Lowe said that with better models, phenotypic screening can accelerate drug discovery.
“You can actually create a ‘luck factory,’” he said. “You want the best, most relevant assay you can possibly come up with that casts the widest net and runs the most data in the shortest amount of time.”
- Friedman, S.L. et al. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5, 167sr1 (2013).
- Gerckens, M. et al. Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics. Sci Adv 7, eabb3673 (2021).
- Herrera, J., Henke, C.A., & Bitterman, P.B. Extracellular matrix as a driver of progressive fibrosis. J Clin Invest 128, 45-53 (2018).
- Tschumperlin, D.J. et al. Mechanosensing and fibrosis. J Clin Invest 128, 74-84 (2018).