Globally Accessible Therapy Is Found to Protect Against Lethal Inflammation from COVID-19 in Animal Models
Mount Sinai researchers have found that a widely available and inexpensive drug targeting inflammatory genes has reduced morbidity and mortality in mice infected with SARS-CoV-2, the virus that causes COVID-19. In a study published today in the journal Cell, the team reported that the drug, Topotecan (TPT), inhibited the expression of inflammatory genes in the lungs of mice as late as four days after infection, a finding with potential implications for treatment of humans.
“So far, in pre-clinical models of SARS-CoV-2, there are no therapies—either antiviral, antibody, or plasma—shown to reduce the SARS-CoV-2 disease burden when administered after more than one day post-infection” says senior author Ivan Marazzi, PhD, Associate Professor of Microbiology at the Icahn School of Medicine at Mount Sinai. “This is a huge problem because people who have severe COVID19 and get hospitalized, often do not present symptoms until many days after infection. We took a different approach, and sought to find a potential therapy that can be used during later stages of the disease. We found that the TOP1 inhibitors given days after the infection can still limit the expression of hyper-inflammatory genes in the lungs of infected animals and improve infection outcomes.” Moreover, says Dr. Marazzi, topotecan (TPT), an FDA-approved Topoisomerase I (TOP1) inhibitor, as well as its derivatives, are inexpensive clinical-grade inhibitors available in most countries around the world for use as antibiotic and anti-cancer agents.
Although the pathophysiology of SARS-CoV-2 is not yet fully understood, scientists have observed that the virus triggers excess production of cytokines and chemokines—chemicals which are secreted by cells of the immune system to help fight infection. An exaggerated immune system response, which characteristically occurs in the lungs of COVID-19 patients, can flood the infected area with white blood cells, resulting in inflammation, possible tissue damage, organ failure, and death. Reduction of the inflammatory state in such patients could therefore improve their clinical outcomes.
In a previous study published in Science in 2016, the same group at Mount Sinai found that inhibiting the activation of inflammatory genes could help prevent animal deaths from viral and bacterial infections and suggested this could be a potent strategy against future pandemics. The current study, led by Mount Sinai along with partners from Singapore, Hong Kong, the United Kingdom, the United States, and other global sites, expands on that earlier work to show how epigenetic therapy (which addresses the chemical modifications that influence gene expression) could be harnessed against severe cases of COVID-19.
The team’s research suggests that many other anti-inflammatory agents are less effective against COVID-19 because they target only a single inflammatory mediators, such as IL6 or IL1, or a specific gene expression program. “The fact is, a multitude of inflammatory genes and signaling pathways are dysregulated during a SARS-CoV-2 infection,” explained lead author Jessica Sook Yuin Ho, PhD, a postdoctoral researcher at Icahn Mount Sinai. “We demonstrated that TOP1 inhibitors were able to broadly or systemically dampen inflammatory gene expression in animal models, regardless of the gene or activation pathway.”
Co-author Mikhail Spivakov, PhD, head of the Functional Gene Control group at the MRC London Institute of Medical Sciences added, “We found that infection prompts extensive changes in the 3D connections between inflammatory genes and the ‘molecular switch’ regions that control their expression. This may partially explain why inhibiting topoisomerase, a protein that helps reshape DNA, helps dampen the cells’ hyper-inflammatory response.”
The safety and efficacy of this treatment strategy in humans will soon be evaluated at clinical sites around the world, including India, where a trial recently began and Singapore, where the National Medical Research Council of Singapore has also funded a phase 1 clinical trial of topoisomerase 1 inhibition in COVID-19. The World Health Organization (WHO) is also expected to play an important role in subsequent studies.
“Findings from our work suggest that repurposing the TOP1 inhibitor could be a valuable global strategy for treating severe cases of COVID-19,” emphasizes Dr. Marazzi. “Particularly attractive is the fact that TPT is already FDA-approved and that its derivatives are inexpensive, with generic formulations existing throughout the world. This makes these drugs readily accessible and available for immediate use in both developing and developed countries across the world.”
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.