Anti-fibrotic compound SD-208 reroutes cultured cells' outgoing vesicles to lysosomes

The strongest evidence in the study is a comparison between drugs. The paper's title identifies SD-208 as an ALK5 inhibitor ^[6], and the Surrey group tested other compounds acting on the same primary target ^[5]. Those compounds did not reproduce the fall in vesicle release ^[5]. If shutting down ALK5 were what cut secretion, a second ALK5 inhibitor should have cut it too. The researchers stop short of naming an alternative. They say the result suggests SD-208's influence on vesicles is distinct from its known antifibrotic activity ^[5].

The finding arrived by accident. "We were studying SD-208 in cardiac cells when we noticed a striking reduction in the tiny vesicles they release," said Rahul Sanwlani, the study's first author ^[11]. Those cells came from patients with hypertrophic cardiomyopathy, an inherited condition in which the heart muscle thickens and is often affected by fibrosis ^[7]. SD-208 reduced their signs of activation, as expected ^[8]. That left an obvious alternative explanation: less activated cells might simply release fewer vesicles. So the team tried several other cell types, and release still fell in cells without the fibrotic character of the originals ^[9].

The route is the second finding. SD-208 did not simply stop vesicles being made ^[4]. Using protein analysis and microscopy, the group followed the compartments that carry them, which the paper describes as CD63-positive ^[6][10]. Those compartments were increasingly sent to lysosomes, the cell's disposal system, where their contents can be broken down ^[4]. Otherwise they would have travelled to the cell surface and been released ^[4].

The phys.org report calls the reduction substantial but does not give its size, the number of cell types tested, or which comparison inhibitors were used and at what doses ^[1][5][9]. The dose question matters most. A comparator tested at a dose too weak to block ALK5 as fully as SD-208 would say little about whether ALK5 is involved.

I'd expect the nearer consequence to fall on laboratories. On this evidence, a study that used SD-208 to block ALK5 in cells that signal to their neighbours would also have cut those cells' vesicle release through some other route ^[5][9]. For medicine the distance is longer. The researchers caution that the results come from lab-grown cells and do not show SD-208 can treat disease in patients ^[14]. Changes in vesicle signalling can contribute to disease, including cardiovascular disease and cancer, according to the report ^[15].

Sanwlani said the result "opens up an interesting new way of thinking about how communication between cells might be controlled using drugs" ^[12]. Patrizia Camelliti, the senior author, set out what comes first. "Now we need to work out exactly how SD-208 does this, and whether we can eventually turn that mechanism into a treatment," she said ^[13].