Box 1. TRPV4 inhibition.


While the Boston team tested GlaxoSmithKline plc's transient receptor potential vanilloid 4 (TRPV4; VRL2) inhibitor GSK2193874 in a lung-on-a chip model, the pharma reported on the discovery and subsequent animal studies of the edema therapeutic.

TRPV4 is known to mediate Ca2+ flux across the plasma membrane and promote vascular relaxation when activated by mechanical activities such as enhanced pressure.5,6

Previous studies, including work at the University of South Alabama, showed that knocking out Trpv4 in mice prevented increased vessel permeability and pressure-induced pulmonary edema.7 Now, the group from South Alabama has teamed up with GSK to develop a TRPV4 inhibitor.

In a paper published in Science Translational Medicine,3 Kevin Thorneloe and colleagues used small molecule screening and chemical optimization to develop GSK2193874. Thorneloe is a senior scientific investigator at GSK.

In isolated mouse and rat lungs, GSK2193874 reversed pulmonary edema. The therapeutic had no effect on the lungs at low pressure, suggesting it acts specifically against pressure-induced vessel leakage.

GSK2193874 also normalized pressure and decreased pulmonary edema compared with vehicle control in mouse models of chronic and acute venous pressure elevation. In the chronic model, GSK2193874 given one week after myocardial infarction-induced increases in pressure reversed pulmonary edema.

"GSK2193874 is still a discovery effort. Safety and toxicology studies are the next steps," said Thorneloe.

"TRPV4 is expressed in most cells in the body. This is a potential problem for inhibitors, and they may therefore be doing things that you don't want them to do, but the authors of the paper did a good job addressing some of the potential problems," said Wolfgang Kübler, associate professor of surgery and physiology at the University of Toronto. "For example, they showed that heart rate, blood pressure and kidney function were not affected by the inhibitors. They also showed that the effects of diuretics, which you would still want to give patients, were not altered."

He added, "This proves that if you block the TRPV4 channel, you can inhibit the further effects on fluid leakage. It also may support another pathological mechanism for TRPV4 that we have found. TRPV4 may also stimulate a cascade that inhibits the removal of fluid from the air spaces, so inhibiting the channel may both prevent leakage and increase fluid removal, but the team would need to confirm the relevance of this mechanism."

Thorneloe said GSK has filed for patents covering GSK2193874.            -LM