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Drug repurposing

Drug Repurposing to Treat COVID-19 Induced Lung Injury

The rapid spread of COVID-19 during the global pandemic has led many scientists and researchers to look towards repurposing existing FDA-approved drugs, outside the scope of their originally designated purposes, to expedite the delivery of effective treatments on the shortened time-scale required to treat COVID-19 patients owing to their proven safe for human use in the original indication. In particular, researchers are focused on treating acute lung injury attributed to SARS-CoV-2 infection in patients with severe COVID-19.

Often in the initial feasibility studies, the first step uses in vitro assays to assess if there is any efficacy for the new intended application, which often involves the culture of primary cells or cell lines that can model in vivo responses. Having a well-characterized media system to support this is essential to obtaining clinically actionable data but not all cell culture media is equal. The composition of some media formulations can lead to alterations in cellular functionality that can limit their predictive power.

To facilitate scientists in these and other research goals, Lifeline® offers a diverse portfolio of cell culture media kits for the growth of many human primary cell types. Our media products do not contain antimicrobials and are phenol red-free to minimize confounding, off-target effects that may arise to ensure reproducible, consistent results.

Recent Research Using Lifeline Media Products

A recent publication by Kost-Alimova and Colleagues sought to identify FDA-approved compounds capable of reducing levels of mucin-1 (MUC1) protein as a treatment for SARS-CoV-2-induced acute lung injury (ALI). Elevated MUC1 levels correlate with poor clinical outcomes and is associated with ALI and acute respiratory distress syndrome (ARDS) onset. Additionally, a recent study identified elevated MUC1 and MUC5AC mucin levels in the airway mucosa of critically ill COVID-19 patients. Prompted by this strong connection between elevated MUC1 and ALI, the researchers looked to identify MUC1-reducing drugs for rapid repurposing to treat COVID-19 patients.

The authors mined a high-content screening library of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that met the following criteria: 1) Reduced MUC1-wildtype (WT) protein in a dose-dependent manner; 2) Mechanism of MUC1-WT reduction was not transcription-dependent since transcriptional suppressors have proven ineffective in the clinic, and 3) Has a favorable toxicity/safety profile. To execute their in vitro studies, they utilized an immortalized kidney tubular epithelial cell line (P cells) as well as primary human kidney epithelial cells from a patient with MUC1+ kidney disease; both maintained at 37°C with 5% CO2 in Lifeline’s RenaLife Renal Basal Medium supplemented with RenaLife LifeFactors.

The compound library was screened using high-content immunofluorescence (IF) imaging to assess MUC1 protein levels and viable cell numbers as measures of cellular toxicity. From this, the authors identified 203 promising compounds candidates, which were re-tested to determine dose-response curves (IC50) and perform transcriptomic profiling (qPCR) to narrow down the candidates based on the established criteria above. Ultimately, fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK), was identified as a repurposing candidate for the treatment of ALI. The authors used in vivo mouse models (induced to exhibit ALI) to confirm that R788 administration could ameliorate lung injury by reducing MUC1 levels from the plasma membrane in the lung epithelium. In comparison to the control mice (no R788 treatment), immunohistochemical staining of lung tissue stained with MUC1, phalloidin, and DAPI showed that MUC1 was significantly reduced in mice treated with a 10-day regimen of R7888.

Fostamatinib was approved in April 2018 by the FDA for the treatment of chronic immune thrombocytopenia (ITP), an autoimmune disease that results in low levels of circulating platelets. Multiple studies of SARS-CoV-2 and other similar respiratory infections indicate that SYK-mediated processes result in events contributing to ARDS and lung injury including inflammation, elevated cytokine and chemokine release, neutrophil activation, and endothelial cell stimulation causing vascular endothelium leakage and edema in the lungs. It stands to reason that treatment with SYK-inhibitors, like R7288 identified in this study, could counteract these hyper-inflammatory responses induced by anti-Spike IgG from patients with severe COVID-19. The scope of work is consistent with data presented by other groups, which provide a strong rationale to pursue clinical trials to test R788 treatment in patients suffering from acute COVID-19 lung injury.

Have you used Lifeline’s cell culture media products to facilitate your research? Let us know and your publication could be featured in our next blog!

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