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Mount Sinai Researchers Discover Potential Treatment for Sepsis

Topoisomerase 1 inhibitors may blunt inflammatory storms

Researchers at the Icahn School of Medicine at Mount Sinai say that tiny doses of a cancer drug may stop the uncontrollable immune response to infection that leads to sepsis and kills up to 500,000 people a year in the U.S. The new drug treatment may also benefit millions of people worldwide who are affected by infections and pandemics.

Their study, conducted in cells and animals, demonstrated that a small dose of topoisomerase 1 (Top 1) inhibitor can blunt an acute inflammatory reaction to infection while still allowing the body’s protective defense to take place. The findings were published in Science.

Top 1 treatment may help control not only sepsis but also new assaults on human immunity, such as novel influenza strains and pandemics of Ebola and other singular infections, according to senior investigator Ivan Marazzi, PhD.

“Our results suggest that a therapy based on Top 1 inhibition could save millions of people affected by sepsis, pandemics, and many congenital deficiencies associated with acute inflammatory episodes—what is known as a cytokine, or inflammatory, storm,” Marazzi said.

“These storms occur because the body does not know how to adjust the appropriate level of inflammation that is good enough to suppress an infection but doesn’t harm the body itself,” he noted. “This drug appears to offer that life-saving correction.”

Sepsis is caused by an excessive host response to infection, which in turn leads to multiple organ failure and death. With an overall mortality rate between 20% and 50%, sepsis is the 10th leading cause of death in the U.S. It kills more people than human immunodeficiency virus (HIV) infection and breast cancer.

“To date, there has been no targeted treatment for sepsis or for other infections that promote this inflammatory storm,” Marazzi said. “Such treatment is desperately needed.”

For example, sepsis is a leading cause of death in infants and children. “Septic shock and lung destruction can occur when a child is suffering from a pneumonia caused by coinfection with a virus and a bacterium even when antibiotic therapy is being used. The elderly are also especially vulnerable to sepsis,” Marazzi remarked.

Following a challenge from the National Institutes of Health to repurpose existing drugs for new uses, the Mount Sinai team used a cellular screen to find candidate drugs that could slow rampant inflammation. They discovered that the Top 1 inhibitor class of cancer drugs—four have been approved for a variety of cancers—also blocks a set of genes that are activated immediately by immune cells to combat an infection. “These genes are the ones that have the strongest inflammatory effects,” Marazzi said.

The researchers found that the use of one to three doses of a Top 1 inhibitor that is 1/50th the strength of normal chemotherapy was enough to rescue 70% to 90 % of mice from an “inflammatory storm” death due to acute bacterial infection, liver failure, or virus/bacteria coinfection. The treatment did not have overt adverse effects.

The researchers also tested the Top 1 inhibitor in cells infected with influenza, Ebola, and other viral and bacterial microbes that overstimulate the immune system, and found that the drug blunted a dangerous immune reaction.

“Finding remedies for these infection-induced inflammatory storms is a global focus, and we look forward to testing the ability of Top-1 inhibitors to save lives,” Marazzi said.

Source: Mount Sinai Hospital; April 28, 2016.

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