Human Enzyme Inhibitor Could Prove Vital for Treatment of Severe Dengue: Study

Mosquito-borne diseases like dengue, Zika and malaria affect millions of people every day as there is no concerted treatment available for these mosquito-borne diseases. But now researchers led by Duke-NUS Medical School have found that Tryptase, an enzyme in human cells, is responsible for blood vessel leakage in severe dengue hemorrhagic fever.

The discovery could pave the way for a possible new treatment strategy for severe cases of the mosquito-borne disease.

A small percentage of dengue patients experience dengue hemorrhagic fever (DHF), a more severe form of dengue, due to ruptured blood vessels

This can cause dengue shock syndrome (DSS), which can prove to be fatal without proper treatment, as the body is sent into bleeding and shock due to a failing circulatory system.

Targeted treatments have not been developed to prevent hemorrhaging or reverse shock because it was not clear how some dengue patients developed these severe conditions.

"We discovered that, in severe cases, a particular enzyme called tryptase cuts the proteins that act as seals between blood vessel cells, resulting in blood vessel leakage and shock during dengue infection," said Assistant Professor Ashley St. John, from Duke-NUS' Emerging Infectious Diseases Programme, corresponding author of the study.

To know if a drug specific to inhibiting tryptase could be used to treat the hemorrhaging, the researchers tested Nafamostat mesylate, a clinically-approved tryptase inhibitor.

Using preclinical models, they found that administration of Nafamostat mesylate, which is already used for the treatment of certain bleeding complications in some countries, prevented vascular leakage in the dengue model.

Even delayed treatment with the drug proved to be significantly effective in reducing dengue vascular leakage .

Tryptase levels were found to be very high in the blood of severe dengue patients who experienced DHF/DSS, compared to patients who easily recovered.

"Currently, only supportive care is available to patients suffering from severe dengue disease, with no targeted treatment for this potentially fatal condition. We believe our findings raise the possibility of developing new targeted treatments for dengue and, specifically, one that might be able to prevent shock," added Asst Prof St. John.

"We are currently experiencing a surge in dengue cases in Singapore," said Professor Patrick Casey, Senior Vice Dean for Research at Duke-NUS. "This timely study by our researchers not only holds out hope for a promising new strategy to treat severe dengue disease, but could also have broader implications for the treatment of other hemorrhagic diseases."

With the help of clinical trials, the researchers are now planning to test if tryptase inhibitors can reverse dengue vascular leakage and prevent shock in humans.