Mount Sinai researchers have found that widely available and inexpensive drug targeting inflammatory genes have reduced morbidity and mortality in mice infected with SARS-CoV-2. Following its publication in Cell, and reporting by DDW, Megan Thomas spoke to Dr Ivan Marazzi, co-author of the study and associate professor in the Microbiology Department at the Icahn School of Medicine at Mount Sinai, about what this means for drug discovery and the treatment of Covid-19.
MT: What is topotecan (TPT)? What is it usually used for?
IM: Topotecan is a naturally occurring chemical derivative of camptothecin extracted from the “Happy Tree” (Camptotheca acuminata) in China. TPT is a highly selective interfacial inhibitor for topoisomerase I (TOP1), as it binds specifically to the DNA-TOP1 complex, and not to either free TOP1 or free DNA. Because it acts on the molecular complex (TOP1+DNA), rather than on single molecules (DNA or TOP1 alone) it is extremely specific.
TPT is typically used as a chemotherapy drug, and used as treatment for small cell lung cancer, ovarian cancer as well as cervical cancer. It is given either intravenously or orally over several treatment cycles.
MT: How did your team determine that this cancer drug might be effective for the treatment of Covid-19?
IM: Previously, we had identified topoisomerase I as a positive regulator of inflammatory gene expression. We showed that treatment of Camptothecin (CPT; a Top1 inhibitor) prevented lethality in mice infected with Staphylococcus aureus and virus-bacteria co-infection. Similarly, this protective effect was also observed in models of LPS-induced inflammation, and acute liver failure triggered by administration of LPS and D-galactosamine. Importantly, all the survivor mice that had received the CPT treatment were monitored for up to two months and no adverse effects have been observed. (Rialdi et al. 2016)
Given that patients with severe Covid-19 were shown to have an exacerbated inflammatory responses, and that patient survival could be improved with immune modulating therapies (such as with dexamethasone), we hypothesised that the use of Top1 inhibitors would be highly relevant for severe Covid-19 treatment.
MT: What does this sort of drug repurposing mean for the future of drug development?
IM: Because we are using drugs that already have established safety profiles, the use of drugs like TPT will potentially reduce the timeframe, regulatory barriers and costs required to bring the drug to the clinic. In addition, for a drug like TPT, which is off-patent, and whose synthesis routes are very well established, scalability of synthesis and distribution are not limiting. This will be especially important, especially in times like the pandemic, where treatments should be distributed equitably across the world.
However, that being said, we advocate that drugs chosen for repurposing should undergo vigorous pre-clinical testing on as many biological assays of activity as possible prior to them entering the clinic. Experimental model design should be scrutinised as well as the molecular mechanism-of-action of the drug. The recent fiasco of Hydroxychloroquine should serve as a cautionary tale for drug repurposing. This drug was identified based on very limited in vitro data with SARS-CoV-2 and pushed into clinics rapidly thereafter. This choice resulted in hundreds of wasted randomised trials attempting to prove/disprove its effects, to the detriment of patients.
MT: This study was undertaken in mice. What are the next steps for finding potential implications for treatment for humans?
IM: In collaboration with hospitals in India and Singapore, we have recently successfully completed a phase one clinical trial for the use of topoisomerase I inhibitors COVID19. The trial has allowed us to establish the lowest dose of topoisomerase inhibitor that can safely administered in order to reduce inflammatory markers in patients with moderate Covid-19. We are currently setting up a Phase II clinical trial with several hospitals in Brazil.
MT: So far, in pre-clinical models of Covid-19, there are no therapies shown to improve SARS-CoV-2 infection outcomes when administered after more than one day post-infection. How does TPT affect this?
IM: Severe clinical manifestations of Covid-19 are driven by imbalanced, hyper-activation of the host immune system at later stages of the disease, rather than direct activity of the virus itself. Indeed, patients with severe COVID19 have been shown to have systemic high levels of cytokine activation, that eventually lead to hypercoagulation and multi-organ failure. This is similar to many other conditions associated with a pathological hyperinflammatory phenotypes, such as septic shock and cytokine release syndrome. It is very important to note that viral activity is much lower at this stage of the disease, compared to when patients are asymptomatic, or showing mild symptoms.
Therefore, since TPT inhibits inflammatory gene expression, its administration can help modulate the pathological inflammatory responses that occur as a result of SARS-CoV-2 infection and improve infection outcomes.
One other benefit of TPT is that it can broadly inhibit multiple inflammatory gene expression programs at once. Other studies have proposed the use of specific cytokine inhibitors to modulate the inflammatory response in SARS-CoV-2. However, since these drugs work on single targets, they may have limited efficacy in controlling inflammation in patients.
In addition, many other studies have tested antiviral drugs. Unfortunately, these work best at the very early stages of the disease, where viral activity is the greatest. In practical terms, this would mean that such drugs will have limited use in patients with severe Covid-19, or will only work prophylactically.
MT: 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. Why is an exaggerated immune system response negative, and how does this fit into what occurs in Covid-19 patients?
IM: Typically, the inflammatory response is important for localising and neutralising pathogens that invade our bodies. This response is usually very tightly controlled; Once the infection is resolved, the inflammatory response is shut down, allowing the host to return to homeostasis.
However, in certain conditions, such as septic shock, acute respiratory distress syndrome (ARDS), CAR T cell therapy, the inflammatory response is dysregulated, resulting in an overdrive in the production of inflammatory mediators. This can result in complement activation, compromised endothelial barriers, coagulopathies (also seen in Covid-19), cell death and organ failure. All these features have been observed in Covid-19 patients.
Treatments that are targeted to reduce host inflammatory state (e.g. dexamethasone treatment) have been shown to be beneficial to patients with severe Covid-19. This strongly suggests that the dysregulated host inflammatory response, rather than viral activity is driving disease severity during severe Covid-19. i.e Covid-19 is an immune disease. Therefore, there is definitely a need to re-align our focus to host, immune-modulatory treatments for this disease, as opposed to antivirals.
References
Rialdi A, Campisi L, Zhao N, Lagda AC, Pietzsch C, Ho JSY, Martinez-Gil L, Fenouil R, Chen X, Edwards M et al. 2016. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352: aad7993.
