A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic
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Abstract
Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo , Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.
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Excerpt
Two recent preprints indicate that Fostamatinib might help with severe COVID-19 symptoms and point to the importance of detailed examination of immune response to COVID-19 vaccines.
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SciScore for 10.1101/2020.06.30.180380: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Mesenteric Ischemia-Reperfusion (I/R): All animal procedures were performed in accordance with the guidelines and approval of the Institutional Animal Care and Use Committee (IACUC) of the BIDMC. Randomization Mice were randomly assigned to sham or I/R groups and were anesthetized by intraperitoneal injection of 72 mg/kg pentobarbital. Blinding not detected. Power Analysis not detected. Sex as a biological variable Mice: Adult, 7-week-old male C57BL/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME) and maintained in specific pathogen-free conditions at the Beth Israel Deaconess Medical Center (BIDMC) and allowed to acclimate for 1 week before use in … SciScore for 10.1101/2020.06.30.180380: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Mesenteric Ischemia-Reperfusion (I/R): All animal procedures were performed in accordance with the guidelines and approval of the Institutional Animal Care and Use Committee (IACUC) of the BIDMC. Randomization Mice were randomly assigned to sham or I/R groups and were anesthetized by intraperitoneal injection of 72 mg/kg pentobarbital. Blinding not detected. Power Analysis not detected. Sex as a biological variable Mice: Adult, 7-week-old male C57BL/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME) and maintained in specific pathogen-free conditions at the Beth Israel Deaconess Medical Center (BIDMC) and allowed to acclimate for 1 week before use in experiments. Table 2: Resources
Antibodies Sentences Resources 5g/L Blocking Reagent [Roche]), then incubated 90 min at RT with 1:2000, monoclonal mouse anti-MUC1 (214D4) antibody (Millipore) in Roche Blocking solution, followed by four PBS wash cycles. anti-MUC1 ( 214D4 )suggested: NoneThen the secondary antibody Alexa Fluor® 546 Goat anti-mouse IgG, Thermo Fisher Scientific and Hoechst 33342 stain, Thermo Fisher Scientific, were applied at a 1:1000 dilution in Roche blocking solution and incubated at RT for 45 min, followed by four PBS wash cycles. the secondary antibody Alexa Fluor® 546 Goat anti-mouse IgGsuggested: Noneanti-mouse IgGsuggested: NoneExperimental Models: Organisms/Strains Sentences Resources Mice: Adult, 7-week-old male C57BL/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME) and maintained in specific pathogen-free conditions at the Beth Israel Deaconess Medical Center (BIDMC) and allowed to acclimate for 1 week before use in experiments. C57BL/6Jsuggested: RRID:IMSR_JAX:000664)Software and Algorithms Sentences Resources All graphs were visualized using ggplot2. ggplot2suggested: (ggplot2, RRID:SCR_014601)For the MUC1 membrane prevalence, the images acquired during 10-dose screening were analyzed using the Harmony software STAR morphology feature, which calculates the signal distribution across different cell compartments. STARsuggested: (STAR, RRID:SCR_015899)Statistical analysis: Statistical analysis was performed and presented using Graphpad Prism version 7.0 software. Graphpad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT02112838 Completed Safety and Efficacy Study of Fostamatinib to Treat Immunoglo… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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