The excessive production of collagen in cells, which leads to fibrosis and is one of the problems of aging, can be avoided by inhibiting the TANGO1 protein, as demonstrated by scientists from the Center for Genomic Regulation (CRG) in Barcelona. The research, which is presented today in Nature Communications, opens the way to slowing down some aspects of aging and treating serious diseases derived from excess collagen.
The first applications will probably be for the skin, since it may be easier to develop a topical treatment than a drug that has to reach internal organs, reports Vivek Malhotra, Icrea researcher at the CRG and director of the project.
Controlling proper collagen production could prevent scar formation, improve burn healing, and “could potentially rejuvenate the skin,” Malhotra states. What it could not do is eliminate already consolidated scars, although it might be possible to remove them and regrow better quality skin by controlling collagen production.
In the longer term, a drug that inhibits the TANGO1 protein could treat diseases in which there is abnormal collagen production. Among them, pulmonary fibrosis, liver cirrhosis or systemic sclerosis. “The problem with these diseases until now is that, once they start, there is no way to stop them,” explains the researcher.
Inhibiting the TANGO1 protein could also encourage surgical scars to form well, something that does not always happen, which is a cause of postoperative complications.
“For the first time we have the ability to control the quantity and quality of collagen secreted by cells,” says Malhotra. But he warns that “we have not yet reached the point where we have a treatment,” so we are still a few years away. that this advance reaches patients.
The CRG researchers have applied for a patent and plan to contact pharmaceutical companies now that they have published their results.
Previous attempts to develop anti-fibrosis therapies, focusing on inflammation or the activity of certain genes, have so far been unsuccessful. Malhotra decided to focus on the TANGO1 protein, which he himself had identified while working at the University of California in San Diego, because it is at the origin of excessive collagen accumulations, which in turn are at the origin of fibrosis.
Specifically, TANGO1 binds to another protein called cTAGE5 to export the collagen that is produced inside the cells to the outside. When excess collagen accumulates outside the cells, dysfunctional fibrous tissue, such as scar tissue, forms.
Based on the AlphaFold2 artificial intelligence system, Malhotra’s team has designed molecules that prevent TANGO1 and cTAGE5 from binding. This prevents collagen from being exported and accumulating outside the cells.
In experiments with zebrafish, researchers have shown that these molecules improve skin scar formation. In experiments with human cells from people with systemic sclerosis, they have shown that less collagen accumulates and less fibrosis forms.
“Our results suggest a promising strategy for therapeutic interventions (…) for fibrotic diseases that currently have no treatment,” the researchers conclude in Nature Communications.
To ensure that this advance reaches patients, the next step will be to test the treatment on pig skin, since it is very similar to human skin. “If it works on pigskin, then it will surely also work on people,” declares Malhotra, who highlights that “for now we have not seen any relevant side effects, although of course it is something that will have to be monitored.”
