March 31, 2021 -- A new study provides evidence that an inexpensive clinical-grade inhibitor that's already approved to treat cancer, called topotecan, can be used to treat severe COVID-19, even in the late stages of the disease. The findings were published in Cell on March 30.
Disease progression in severe COVID-19 is characterized by an initial phase of increasing viremia followed by a second phase of increased systemic inflammation where high levels of inflammatory molecules are correlated with risk of death due to infection. SARS-CoV-2 infection triggers hyperactivation of proinflammatory cytokines such as interleukin 6, interleukin 1 beta, and tumor necrosis factor alpha, as well as chemokines such as C-X-C motif chemokine ligand (CXCL) 8, 9, and 10 and C-C motif chemokine ligand 2.
"So far, in preclinical 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" explained senior author Ivan Marazzi, PhD, associate professor of microbiology at the Icahn School of Medicine at Mount Sinai, in a statement. "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."
Although the pathophysiology of SARS-CoV-2 infection is not fully understood, exaggerated immune system responses associated with increased expression of proinflammatory molecules can lead to inflammation, possible tissue damage, organ failure, and death in COVID-19 patients. Therefore, reducing the magnitude of the induction of gene expression during infection might be the key to therapeutics to treat infections that cause hyperinflammation.
A global group of researchers led by a team at Mount Sinai suspected that host-directed epigenetic therapies that address chemical modifications that influence gene expression could be used to treat COVID-19.
While little is known about how epigenetic modifications and genome structure are affected by infection, the authors have previously shown that chromatin factors play a key role in controlling the induction of inflammatory gene expression programs. Thus, targeting the activities of these proteins could lead to suppression of multiple genes during infection.
The researchers first sought to define the effect of viral infection on host chromatin modification and how those affect gene expression. To do this, they conducted Hi-C analysis, a chromosome conformation capture technique, to characterize chromatin structural changes during SARS-CoV-2 infection.
The team's data suggests that SARS-CoV-2 infection causes global and local changes in chromatin, leading to specific gene expression programs in infected cells. Specifically, chromatin immunoprecipitation (ChIP)-sequencing showed that histone 3 lysine 27 acetylation (K27ac), an epigenetic mark found at active regulatory regions (promoters and enhancers) undergo significant changes (gained and lost) during infection.
The researchers suggested that this dynamic restructuring of genome compartmentalization of regulatory regions control inflammatory responses via gene transcription.
"We found that infection prompts extensive changes in the 3D connections between inflammatory genes and the 'molecular switch' regions that control their expression," noted co-author, Mikhail Spivakov, PhD, head of the Functional Gene Control group at the Medical Research Council (MRC) London Institute of Medical Sciences. "This may partially explain why inhibiting topoisomerase, a protein that helps reshape DNA, helps dampen the cells' hyper-inflammatory response."
"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.
Next, to test whether chromatin factors can counteract SARS-CoV-2 infection, the team focused on host enzyme topoisomerase 1 (TOP1), which is required to fully transactivate infection-induced genes and controls the establishment of inflammatory gene programs during many viral and bacterial infections.
In animal studies, topotecan (TPT), a TOP1 inhibitor approved by the U.S. Food and Drug Administration, was able to reduce inflammatory gene expression in cells infected with the SARS-CoV-2 virus. In hamster models, TPT suppressed inflammatory gene expression in the lungs.
"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," explained Ho.
When TPT was given to mice four to five days following infection, the treatment significantly improved morbidity and mortality outcomes compared to control.
"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," Marazzi said.
The safety and efficacy of this TOP1 inhibitor treatment strategy in humans will soon be evaluated in global clinical studies.
"Findings from our work suggest that repurposing the TOP1 inhibitor could be a valuable global strategy for treating severe cases of COVID-19," Marazzi emphasized. "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."
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