Preliminary report of in vitro and in vivo effectiveness of dornase alfa on SARS-CoV-2 infection

Abstract

Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). It is well known that novel Coronavirus disease 2019 (COVID-19) pneumonia progresses to ARDS and even multiple organ failure. High blood neutrophil levels are an early indicator of COVID-19 and predict severe respiratory diseases. Also it is reported that mucus structure of COVID-19 is very similar to cystic fibrosis due to the accumulation of excessive NET in the lungs. In this study, we showed the recovery of three COVID-19 patients after including Dornase alfa in their treatment. We followed clinical improvement in the radiological analysis (2-of-3 cases), oxygen saturation (SpO 2 ), respiratory rate, disappearing of dyspnea, coughing and a decrease in NET formation and SARS-CoV-2 viral load after the treatment. Also here, we share our preliminary results suggesting that Dornase alfa has an anti-viral effect against SARS-CoV-2 infection in a green monkey kidney cell line, Vero, and a bovine kidney cell line, MDBK without determined cytotoxicity on healthy peripheral blood mononuclear cells.

Vasculitis and Neutrophil Extracellular Traps in Lungs of Golden Syrian Hamsters With SARS-CoV-2

“…DNases can efficiently destroy NETs, and therefore clinical trials applying DNase treatment as potential therapeutic intervention in severe COVID-19 patients may be warranted (51). Furthermore, treatment strategies with dornase alfa to destroy NETs in COVID-19 patients with ARDS are already investigated in clinical trials (27,51). Here we confirmed in a control experiment, that ex vivo nuclease treatment of lung biopsies from SARS-CoV-2-infected hamster successfully degraded present NETs (Figure 5).…”

“…The detected microvascular injury during SARS-CoV-2-infections can at least partially be explained by these findings and is substantiated by recent observations of increased NET markers in the blood of SARS-CoV-2 patients (23). DNases can efficiently destroy NETs, and therefore clinical trials applying DNase treatment as potential therapeutic intervention in severe COVID-19 patients may be warranted (51). Furthermore, treatment strategies with dornase alfa to destroy NETs in COVID-19 patients with ARDS are already investigated in clinical trials (27,51).…”

Proteome Profiling of Recombinant DNase Therapy in Reducing NETs and Aiding Recovery in COVID-19 Patients

“…No evidence has so far been provided about the presence of NETs in the lungs and their involvement in causing ARDS in COVID-19. Two recent reports also found DNase to be beneficial in COVID-19 69 , 70 . Weber et.…”

Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

“… 135 ), reducing the risk for secondary infections and improving ventilation, and may also reduce the risk of progression towards ARDS, as shown in animal models 136 , 137 . Two case studies have shown that administration of dornase alpha is well tolerated in patients with COVID-19-associated ARDS 138 , 139 , and several trials are underway to determine the efficacy of this approach (NCT04402944, NCT04355364, NCT04432987, NCT04359654, NCT04445285, NCT04402970). Nebulizer administration of DNase provides direct access to NETs within the alveolar space, but there may be a barrier to reaching systemic efficacy owing to the high reported levels of platelet factor 4 (PF4) in severe COVID-19 (ref.…”