Researchers from the Icahn School of Medicine at Mount Sinai (New York), in collaboration with those from other institutions, including Luis Martínez-Gil, from the University of Valencia, have reported that small doses of a cancer drug could control the immune response to sepsis, a condition that currently kills hundreds of thousands of people worldwide. The research was published in the prestigious magazine Science this Thursday.

The study "Topoisomerase 1 inhibition suppresses the transcriptional activation of innate immune responses and protects against inflammation-induced death", demonstrates both in the laboratory and in animal models that small doses of a topoisomerase I inhibitor (Top I) can decrease the acute inflammatory response that occurs against certain infections, which allows at the same time a normal immune response in the body to fight the disease. The new treatment could benefit millions of people affected by infections and pandemics.

Luis Martínez-Gil, currently Juan de la Cierva researcher at the University of Valencia and co-author of the work, explains: "The development of a new approach was key to finding an alternative use to Top1 inhibitors and our work demonstrates the value of pioneering and risky research". The researcher, who participated in the study during his postdoctoral stay at the Icahn School of Medicine at Mount Sinai and who completed it at the University of Valencia, details that it is "the first specific treatment of the uncontrolled inflammatory response that produces against infections with certain pathogens".

The researcher responsible for the published work, Ivan Marazzi, a professor in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai, explains that the treatment could control not only sepsis – a product of hospital infections in patients with a weak immune system –, but also new attacks on the immune system, which are the result of infections by new strains of influenza or pandemics such as Ebola. "Our results suggest that a therapy based on a Top1 inhibitor could save millions of people affected by sepsis, pandemics and congenital deficiencies associated with acute episodes of inflammation, which is known as an inflammatory storm. These storms occur when the body does not know how to adjust the appropriate level of inflammation to, on the one hand, repress the infection, but also not to damage the organism itself”.

Sepsis is caused by an excessive response of the host to an infection, which causes multi-organ failure and subsequently death. With a mortality rate of 20-50%, sepsis is the tenth leading cause of death in the United States and is responsible for more deaths than AIDS and breast cancer.

"Until now, there was no specific treatment against sepsis beyond the treatment of the infection that causes the inflammatory storm", points out Dr. Marazzi. "This treatment is desperately needed," he says. For example, sepsis is one of the leading causes of death in newborns and children. "Septic shock and destruction of lung tissue can occur when a child suffers from pneumonia caused by coinfection with a virus and bacteria, even when antibiotic therapy is used. The elderly are also particularly vulnerable to sepsis.”

Following the challenge launched by the National Institutes of Health of the United States to find new uses for existing medicines, the research team, which also included the now researcher at the University of Valencia, Luis Martínez-Gil, used a cellular trial to find candidates that could decrease the inflammatory response. What they discovered is that cancer drugs from the group of Top1 inhibitors – four of which have already been approved for use in various types of cancer – are able to block a group of inflammatory genes that are activated in immune cells to fight infection.

Dose 50 times lower than that used in chemotherapy

The research team found that using a Top1 inhibitor at a dose 50 times lower than that used in chemotherapy was enough to bring 70-90% of the mice back from an inflammatory storm fatal due to bacterial infection, liver failure, or virus-bacteria co-infection. The treatment apparently produced no side effects. The treatment was also tested in cells infected with influenza, Ebola and other microbial infections (viruses and bacteria) that overstimulate the immune system to find that the compound is able to modulate the dangerous inflammatory response.

This study, which has resulted in the work published in the journal Science, has been funded by the National Institutes of Health of the United States Department of Health and the Department of Defense.

Researcher at the University of Valencia

Luis Martínez-Gil's research focuses on the study of interactions between viruses and their hosts, and their application in the development and improvement of antivirals and vaccines. His doctoral thesis, at the University of Valencia, was directed by Ismael Mingarro, professor of Biochemistry and Molecular Biology. He is currently working on the identification of protein-protein interactions between the Nipah virus and its host (human cells) with the aim of identifying new targets for the design of antivirals.

The article's co-authors are  Alex Rialdi, Laura Campisi, Nan Zhao, Arvin Cesar Lagda, Luis Martínez-Gil, Megan Edwards, Giorgi Metreveli, Nicole Bouvier, Chris Basler, Adolfo García-Sastre, Zuleyma Peralta, Romain Fenouil, Stefan Jordan, Harm vanBakel, Miriam Merad and Jian Jin (of the Icahn School of Medicine at Mount Sinai). Colette Pietzsch and Alex Bukreyev of the University of Texas Medical Branch, Galveston; Jessica Sook Yuin Ho of the Institute of Molecular and Cell Biology, Singapore; Xiaoting Chen and Matthew Weirauch of the Cincinnati Children’s Hospital Medical Center; Cesar Munoz-Fontela of the Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Sven Heinz of the University of California, San Diego; and Chris Benner of the Salk Institute for Biological Studies, La Jolla, CA.

Article:

«Topoisomerase 1 inhibition suppresses the transcriptional activation of innate immune responses and protects against inflammation-induced death». A. Rialdi et al., Science 10.1126/science.aad7993 (2016)

Photo caption:

Luis Martínez-Gil, currently researcher Juan de la Cierva at the University of Valencia