Researchers at the MRC Laboratory of Medical Sciences (LMS) and Mount Sinai 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 in 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 COVID-19, there are no therapies– either antiviral, antibody, or plasma – shown to improve SARS-CoV-2 infection outcomes when administered after more than one day post-infection,” says senior author Ivan Marazzi, PhD, Associate Professor in the Microbiology Department at the Icahn School of Medicine at Mount Sinai. “This is a huge problem because people who have severe COVID-19 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 topoisomerase 1 (TOP1) inhibitors given days after the infection can limit the expression of inflammatory genes in the lungs of infected animals to prevent an “hyper-inflammatory status” Moreover, says Dr. Marazzi, topotecan (TPT), an FDA-approved TOP1 inhibitor, as well as its derivatives, are inexpensive clinical-grade inhibitors available in most countries around the world for use as 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 UK, the US, 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 single inflammatory mediators, such as IL-6 or IL-1, or only specific gene expression programs. “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 the Icahn School of Medicine. “We demonstrated that TOP1 inhibitors were able to roadly dampen inflammatory gene expression in animal models, regardless of the gene or activation pathway.
Commenting on the contribution of the Functional Gene Control group at the MRC LMS, Group Head Mikhail Spivakov said:
“Our contribution to this study centred at the analysis of how the infected lung cells rewire their genome in 3D. We find that infection prompts extensive changes in the 3D connections between inflammatory genes and the “molecular switch” regions that control their expression, which 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. The World Health Organization (WHO) is expected to play an important role in these studies.
“Findings from our work suggest that repurposing TOP1 inhibitors could be a valuable global strategy for treating severe cases of COVID-19,” emphasizes Dr. Marazzi. “Particularly attractive is the fact 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 developed and developing countries across the world.”
‘TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation’ was published on 30 March 2021 in the journal Cell. Read the full article here.
