Topoisomerase 1 (Top1) Inhibition as a Novel Treatment Strategy for Sepsis and Cytokine Release Syndrome

Background

Sepsis is a life-threatening condition caused by an excessive host response to infection, which in turn leads to multi-organ failure and death. Estimates indicate that 250,000 to 500,000 people die from sepsis annually in the United States. To date there has been no targeted treatment for sepsis, or for other infections that promote this inflammatory storm. Researchers have discovered that chemical inhibition of Top1, an enzyme that unwinds DNA, also blocks a set of genes that are activated immediately by immune cells to combat an infection. In vitro, depletion or chemical inhibition of Top1 in epithelial cells and macrophages suppresses the host response against Influenza and Ebola viruses as well as bacterial products. In vivo, Top1 inhibition therapy rescued 70 to 90% mortality caused by exacerbated inflammation in three mouse models: acute bacterial infection, liver failure, and virus- bacteria co-infection.

Technology Overview

This technology is a novel therapeutic approach to the use of a topoisomerase inhibitor to suppress the inflammatory response to infection.

Stage of Development

• In vivo studies with novel formulation of Top1 inhibitor to test delivery and efficacy
• Optimizing dosing frequency, length of effect for clinical deployment

Further Details

• Rialdi A, et al Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation, Science. 2016

Benefits

• Significantly lower dose (1/50th the strength of normal chemotherapy) was enough to rescue 70-90 % of mice from an inflammatory storm
• Limits the cytokine response rather than directly targeting the virus or bacteria

Applications

• Treatment of sepsis, septic shock and cytokine release syndrome