Excessive production of collagen in cells, leading to fibrosis and being one of the issues related to aging, can be prevented by inhibiting the protein TANGO1, as shown by scientists from the Center for Genomic Regulation (CRG) in Barcelona. The research, presented today in Nature Communications, paves the way to slow down certain aspects of aging and treat serious diseases resulting from collagen excess.
The first applications will probably be for the skin, as it may be easier to develop a topical treatment than a drug that has to reach internal organs, reports Vivek Malhotra, an Icrea researcher at the CRG and project director.
Controlling the proper production of collagen could prevent scar formation, improve burn healing, and "potentially rejuvenate the skin," declares Malhotra. What it could not do is eliminate already established scars, although it might be possible to remove them and regrow skin by controlling collagen production.
Longer term, a drug that inhibits the TANGO1 protein could treat diseases in which there is an abnormal production of collagen. Among these are pulmonary fibrosis, liver cirrhosis, and systemic sclerosis. "The problem with these diseases so far is that, once they start, there is no way to stop them," explains the researcher.
Inhibiting the TANGO1 protein could also promote the proper formation of surgical scars, 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 the collagen produced by cells," Malhotra states. However, he warns that "we have not yet reached the point where we have a treatment available," so it will be a few more years before this breakthrough reaches patients."
Researchers at the CRG have applied for a patent and plan to contact pharmaceutical companies now that they have published their results.
Previous attempts to develop therapies against fibrosis, focused on inflammation or the activity of certain genes, have not borne fruit so far. Malhotra decided to focus on the TANGO1 protein, which he had identified while working at the University of California in San Diego, because it is at the root of excessive collagen buildup, which in turn is at the root of fibrosis.
Specifically, TANGO1 joins another protein called cTAGE5 to export the collagen produced inside the cells to the outside. When an excess of collagen accumulates, a dysfunctional fibrous tissue is formed, such as scars.
Based on the AlphaFold2 artificial intelligence system, the Malhotra 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 scar formation on the skin. In experiments with human cells from individuals with systemic sclerosis, they have demonstrated 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," conclude the researchers in Nature Communications.
To ensure that this breakthrough reaches patients, the next step will be to test the treatment on pig skin, as it is very similar to human skin. "If it works on pig skin, then it will likely work on humans as well," says Malhotra, emphasizing that "so far we haven't seen any significant side effects, although of course this is something that will need to be monitored."
