Topotecan suppresses lethal SARS-CoV-2 inflammation
Mount Sinai and University of Hong Kong (HKU) researchers find topotecan to be protective against hyperinflammation and death in preclinical models of coronavirus disease 2019 (COVID-19).
“Topotecan is derived from camptothecin, a natural product found in the bark of Chinese Happy Tree. It is an inexpensive FDA-approved anticancer drug available in most countries,” said study lead co-author Dr Bobo Mok of the Department of Microbiology at HKU. “We demonstrated that topotecan can alleviate hyperinflammatory complications or cytokine storm of COVID-19 infection in hamsters and decreases mortality in infected mice.” [Cell 2021;doi:10/1016/j.cell.2021.03.051]
Although the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not yet been fully characterized, it has been observed that the infection triggers hyperactivation of proinflammatory cytokines and chemokines, whose increased levels have been shown to correlate with COVID-19 severity. [Lancet 2020;395:497-506; Nature 2020;584:463-469; Front Immunol 2020;11:1708; Nat Med 2020;26:1636-1643]
“Elevated inflammatory responses contribute to sepsis and multi-organ failure, which are major causes of death from COVID-19. Therefore, treatments that can suppress host inflammatory response might be effective against COVID-19,” postulated the researchers. [Lancet 2020;395;1054-1062]
The researchers performed a combined structural and epigenetic analysis of infected cells expressing human receptor angiotensin-I-converting enzyme 2 (ACE2) receptor, which serves as the entry point for SARS-CoV-2. “Our data suggest that SARS-CoV-2 imposes both global and local [gene-specific] effects on host chromatin, ultimately dictating gene induction and suppression, and the establishment of a gene expression programme in the infected cell,” they reported.
To determine whether chromatin factors can control the transactivation of SARS-CoV-2–induced genes, the researchers focused on TOP1, a factor known to activate bacterial and viral infection-induced genes. [Science 2016;352:aad7993] Upon introducing the virus to cells treated with small interfering RNA, which mediated selective TOP1 knockdown, suppression of many infection-induced genes was observed.
TOP1 inhibition was subsequently demonstrated to dampen inflammatory gene expression in vivo, in a golden Syrian hamster model of COVID-19 treated with topotecan, a TOP1 inhibitor. Unlike the lungs of the infected control animals, the lungs of topotecan-treated hamsters did not have conspicuous alveolar space infiltration, exudation, or haemorrhaging at days 4 and 6 post-infection. Furthermore, reduced lung-to-body weight ratios in topotecan-treated animals suggested reduced pulmonary oedema.
“In addition, we evaluated topotecan’s effects in transgenic human ACE2 receptor–expressing mice susceptible to SARS-CoV-2 infection, with a disease progression profile that shares many features of severe COVID-19,” wrote the researchers. [Nat Immunol 2020;21:1327-1335] “Strikingly, we found that late topotecan treatment provided significant survival benefit [p=0.0085] to infected mice vs controls. At the same time, levels of neutralizing antibody activity in the blood of controls and treated mice were similar at 5 weeks post-infection, suggesting that topotecan does not negatively impact adaptive immune responses.”
“To date, no therapy – whether antiviral, antibody, or plasma – was shown to improve SARS-CoV-2 infection outcomes when administered ≥1 day post-infection in preclinical models of COVID-19,” said senior author Dr Ivan Marazzi of the Microbiology Department at the Icahn School of Medicine. “This is very problematic, as people with severe COVID-19 often do not present symptoms until many days post-infection. However, topotecan given days after the infection could limit the expression of inflammatory genes in the lungs of infected animals and prevented hyperinflammation.”
The safety and efficacy of topotecan will be evaluated in two clinical trials that have been submitted for trial initiation.