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1.
Front Immunol ; 12: 714833, 2021.
Article in English | MEDLINE | ID: covidwho-1506100

ABSTRACT

Background: The most severe cases of Coronavirus-Disease-2019 (COVID-19) develop into Acute Respiratory Distress Syndrome (ARDS). It has been proposed that oxygenation may be inhibited by extracellular deoxyribonucleic acid (DNA) in the form of neutrophil extracellular traps (NETs). Dornase alfa (Pulmozyme, Genentech) is recombinant human deoxyribonuclease I that acts as a mucolytic by cleaving and degrading extracellular DNA. We performed a pilot study to evaluate the effects of dornase alfa in patients with ARDS secondary to COVID-19. Methods: We performed a pilot, non-randomized, case-controlled clinical trial of inhaled dornase for patients who developed ARDS secondary to COVID-19 pneumonia. Results: Improvement in arterial oxygen saturation to inhaled fraction of oxygen ratio (PaO2/FiO2) was noted in the treatment group compared to control at day 2 (95% CI, 2.96 to 95.66, P-value = 0.038), as well as in static lung compliance at days 3 through 5 (95% CI, 4.8 to 19.1 mL/cmH2O, 2.7 to 16.5 mL/cmH2O, and 5.3 to 19.2 mL/cmH2O, respectively). These effects were not sustained at 14 days. A reduction in bronchoalveolar lavage fluid (BALF) myeloperoxidase-DNA (DNA : MPO) complexes (95% CI, -14.7 to -1.32, P-value = 0.01) was observed after therapy with dornase alfa. Conclusion: Treatment with dornase alfa was associated with improved oxygenation and decreased DNA : MPO complexes in BALF. The positive effects, however, were limited to the time of drug delivery. These data suggest that degradation of extracellular DNA associated with NETs or other structures by inhaled dornase alfa can be beneficial. We propose a more extensive clinical trial is warranted. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT04402970.


Subject(s)
COVID-19/drug therapy , Deoxyribonuclease I/therapeutic use , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2/physiology , Administration, Inhalation , Adult , Aged , Aged, 80 and over , Case-Control Studies , DNA/metabolism , Extracellular Traps/metabolism , Female , Humans , Male , Middle Aged , Oxygen Consumption/drug effects , Peroxidase/metabolism , Pilot Projects , Recombinant Proteins/therapeutic use , Young Adult
3.
Biomaterials ; 267: 120389, 2021 01.
Article in English | MEDLINE | ID: covidwho-898508

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/drug therapy , DNA/blood , Deoxyribonuclease I/therapeutic use , Drug Carriers/administration & dosage , Nanoparticles/administration & dosage , Neutrophils/drug effects , SARS-CoV-2 , Sepsis/drug therapy , Animals , COVID-19/blood , COVID-19/immunology , Cytokine Release Syndrome/etiology , Deoxyribonuclease I/administration & dosage , Dexamethasone/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Extracellular Traps/drug effects , Humans , Indoles , Male , Mice , Mice, Inbred C57BL , Multiple Organ Failure/blood , Multiple Organ Failure/etiology , Multiple Organ Failure/prevention & control , NF-kappa B/blood , Neutrophils/enzymology , Peroxidase/blood , Polyethylene Glycols , Polyglactin 910 , Polymers , Sepsis/etiology , Sepsis/immunology
4.
Mol Med ; 26(1): 91, 2020 09 29.
Article in English | MEDLINE | ID: covidwho-803281

ABSTRACT

BACKGROUND: Mechanically ventilated patients with COVID-19 have a mortality of 24-53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. METHODS: Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19-including three requiring veno-venous extracorporeal membrane oxygenation-treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. RESULTS: The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. CONCLUSIONS: Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered.


Subject(s)
Albuterol/administration & dosage , Coronavirus Infections/drug therapy , Deoxyribonuclease I/administration & dosage , Pneumonia, Viral/drug therapy , Respiration, Artificial , Adult , Aged , Albuterol/therapeutic use , Bronchodilator Agents/administration & dosage , Bronchodilator Agents/therapeutic use , COVID-19 , Coronavirus Infections/therapy , Deoxyribonuclease I/therapeutic use , Female , Humans , Intubation, Intratracheal , Male , Nebulizers and Vaporizers , Pandemics , Pneumonia, Viral/therapy , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use
5.
Clin Sci (Lond) ; 134(12): 1295-1300, 2020 06 26.
Article in English | MEDLINE | ID: covidwho-599624

ABSTRACT

We demonstrate that the general clinical conditions, risk factors and numerous pathological and biological features of COVID-19 are analogous with various disorders caused by the uncontrolled formation of neutrophil extracellular traps and their by-products. Given the rapid evolution of this disease's symptoms and its lethality, we hypothesize that SARS-CoV2 evades innate immune response causing COVID-19 progresses under just such an amplifier loop, leading to a massive, uncontrolled inflammation process. This work allows us to propose new strategies for treating the pandemic.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Extracellular Traps/physiology , Host-Pathogen Interactions/immunology , Pneumonia, Viral/immunology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Deoxyribonuclease I/therapeutic use , Humans , Immunity, Innate , Multiple Organ Failure/immunology , Multiple Organ Failure/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , SARS-CoV-2
6.
Physiol Genomics ; 52(5): 217-221, 2020 05 01.
Article in English | MEDLINE | ID: covidwho-47305
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