RUNX1 Inhibition Proposed for Prevention, Treatment of Lung Injury in Severe COVID-19
- Ro24-7429, a small-molecule inhibitor of the transcription factor RUNX1, was developed as an inhibitor of the HIV-1 Tat protein and proved safe for treatment of AIDS in a phase 2 trial, although it had no antiviral effect
- In a mouse model of bleomycin-induced lung injury, treatment with Ro24-7429 robustly abrogated inflammation and fibrosis
- RUNX1 inhibition reduced the expression of ACE2 and FURIN, two proteins that play critical roles in lung uptake of the SARS-CoV-2, in the mouse model and in human lung epithelial and vascular endothelial cells in vitro
- 78% of 113 genes previously found to be dysregulated in patients with COVID-19 contained binding sites for RUNX1 modulation, suggesting RUNX1 has an important role in the pathobiology of COVID-19
- Taken together, these findings suggest RUNX1 inhibition might treat or even prevent lung pathology in severe COVID-19
The most common effect of COVID-19 on the lung is diffuse alveolar damage, and pulmonary fibrosis can occur. In fact, pulmonary fibrosis develops in up to 30% of COVID-19 patients with acute respiratory distress syndrome.
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Leo A. Kim, MD, PhD, a clinician scientist at Mass Eye and Ear/Massachusetts General Hospital and assistant professor of Ophthalmology at Harvard Medical School, and Joseph F. Arboleda-Velasquez, MD, PhD, an assistant scientist at Schepens Eye Research Institute of Mass Eye and Ear and assistant professor of Ophthalmology at Harvard Medical School, and colleagues have found evidence that a transcription factor called RUNX1 is involved in the pathobiology of pulmonary fibrosis. In The American Journal of Pathology, they explain why RUNX1 inhibition shows promise as a new approach to treating COVID-19.
Antifibrotic Activity of Ro24-7429
Two small-molecule inhibitors of RUNX1 activity have been used in previous studies, mainly in cancer. One of them, Ro24-7429, was developed as an inhibitor of the HIV-1 Tat protein. It proved safe in a phase 2 trial but had no antiviral effect.
In this study, the researchers tested escalating doses of Ro24-7429 in a mouse model of bleomycin-induced lung injury. Treatment started one week before instillation of bleomycin because treatments for COVID-19 appear to be more effective at early stages.
In untreated mice, prominent fibrosis was detected two weeks after bleomycin instillation. In contrast, mice treated with Ro24-7429 displayed robust preservation of lung structures, similar to mice instilled with saline.
Anti-inflammatory Activity of Ro24-7429
RUNX1 blunted downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-β1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts and vascular endothelial cells.
Modulation of SARS-CoV-2 Uptake Proteins
- In the mouse model, Ro24-7429 treatment markedly reduced expression of ACE2 and FURIN, two proteins that play critical roles in lung uptake of the SARS-CoV-2 coronavirus
- RUNX1 inhibition also significantly blunted expression of ACE2 and FURIN in human-derived lung epithelial and vascular endothelial cells in vitro
The researchers analyzed 113 genes reported in The New England Journal of Medicine to be associated with angiogenesis in patients who died from COVID-19. Seventy-eight percent of them contained binding sites for RUNX1, suggesting RUNX1 plays an important role in the pathobiology of COVID-19.
A Novel Target
In the phase 2 trial of Ro24-7429 in patients with HIV infection, the only major adverse event during 12 weeks of treatment was a rash that appeared in a dose-dependent manner and resolved shortly after drug withdrawal. Because of this safety profile in immunocompromised patients, Ro24-7429 is likely to be safe to test in COVID-19 patients for prevention or treatment of life-threatening complications. Ro24-7429 should also be investigated for the treatment of pulmonary fibrosis in patients without COVID-19.
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