Experimental antifibrotic drug shown to block a key form of cell-to-cell messaging

An experimental drug developed to fight scarring in the heart has been found, almost by accident, to shut down a different and largely unrelated cellular process: the release of tiny membrane-bound packages that cells use to communicate with one another. Researchers at the University of Surrey report that the compound, known as SD-208, sharply reduces the secretion of small extracellular vesicles from human heart cells, not by stopping the cells from making the vesicles but by rerouting them internally toward the cell's own disposal system.

The finding, published on Tuesday in the Journal of Extracellular Vesicles, emerged from laboratory work that was originally focused on fibrosis, the thickening and scarring of heart tissue seen in conditions such as hypertrophic cardiomyopathy. SD-208 blocks a receptor called ALK5, part of the signalling pathway that drives fibrotic scarring, and had been studied for its capacity to reverse the transformation of heart cells into scar-forming myofibroblasts. The vesicle effect, the researchers say, appears to run on a separate track entirely.

What the experiments showed

Extracellular vesicles are small, membrane-wrapped parcels that cells release to pass proteins, lipids and genetic material to neighbouring or distant cells. They are increasingly understood to play a role in a wide range of biological processes, including the progression of fibrosis and the spread of cancer. The Surrey team, led by Dr Rahul Sanwlani, a research fellow in cardiovascular medicine, and Dr Patrizia Camelliti, the university's head of cardiovascular science, was studying heart cells taken from patients with hypertrophic cardiomyopathy when it noticed a marked drop in the number of vesicles being shed after the cells were treated with SD-208.

Using tracking of a vesicle marker protein called CD63, the researchers found that the drug did not stop vesicles from forming inside the cell. Instead, it diverted CD63-marked compartments away from the cell surface and into lysosomes, the compartments cells use to break down and recycle unwanted material, marked by the protein LAMP1. The vesicles, in effect, were being intercepted and digested before they could be released. The effect held up not only in the diseased heart cells first studied but also in non-activated cardiac fibroblasts and in HEK293 cells, a standard laboratory cell line with no connection to cardiac disease or fibrosis, indicating the mechanism is not confined to sick or scarring tissue.

A mechanism apart from the drug's original purpose

The detail the researchers emphasise most is that other compounds which block the same ALK5 receptor, and which share SD-208's anti-fibrotic, TGF-beta-blocking activity, did not reproduce the vesicle-suppressing effect. That argues against the reduction being a simple side effect of blocking fibrosis signalling and points instead to a distinct, so far unexplained action of this particular molecule on the cell's internal trafficking machinery.

SD-208 is not a new compound. It has circulated in cardiovascular and fibrosis research for several years, including in earlier Surrey-led work examining whether it could revert cardiac myofibroblasts back to a quiescent state, and it sits within a broader family of antifibrotic strategies that includes pirfenidone, an approved drug for lung scarring that has also been trialled for hypertrophic cardiomyopathy in a National Heart, Lung, and Blood Institute study. What is new is the discovery that SD-208 has this second, apparently unrelated property, uncovered because the Surrey group happened to be measuring vesicle output as a secondary readout rather than looking for it directly.

"Finding a compound that can change cellular messages opens a completely new research line for us," said Dr Patrizia Camelliti, the study's senior and co-corresponding author.

Who stands to be affected

No patients are affected yet, and the researchers are careful to frame the work as fundamental cell biology rather than a therapeutic breakthrough. The experiments were carried out entirely in cultured cells, including cells derived from hypertrophic cardiomyopathy patients, and have not been tested in animals or people. The immediate audience for the finding is other laboratories working on extracellular vesicles, cardiac fibrosis and, more speculatively, cancer biology, where tumour-derived vesicles are known to help prepare distant tissue for metastasis and to blunt immune responses. A drug able to dial down vesicle traffic broadly, across cell types, would be of interest to researchers in both fields, independent of whatever role it eventually plays in treating fibrosis itself.

Dr Sanwlani, the study's first and co-corresponding author, said the result caught the team off guard. "The exciting part was that this effect emerged unexpectedly," he said. "We noticed a striking reduction in tiny vesicles released." That kind of incidental finding, turned up while investigating something else, is not unusual in cell biology, but the researchers say the consistency of the effect across different, unrelated cell types is what pushed them to pursue it as a study in its own right rather than a footnote.

Where the research goes from here

The Surrey team's next steps, according to the published paper, are to work out precisely which part of the cell's trafficking machinery SD-208 is acting on, since the drug's known target, the ALK5 receptor, does not appear to explain the effect. Identifying that mechanism would clarify whether the vesicle-blocking property can be separated from SD-208's anti-fibrotic activity, or engineered into a more selective compound, and whether it could eventually be steered toward diseases where excess vesicle traffic does harm, such as the spread of cancer or the progression of fibrotic disease in the heart, lungs or kidneys.

For now, the finding remains a laboratory observation, published through peer review but without clinical testing behind it. The authors' own caveat, echoed by outside coverage of the study, including a summary carried by Phys.org, is that results from cultured cells do not guarantee an effect in a living organism, let alone a treatment. What the study does establish, the researchers say, is that a known, previously characterised drug has a second pharmacological action that had gone unnoticed, a reminder that molecules already in the research pipeline can still hold undiscovered biology.