Failed HIV Therapy May Combat COVID-19-induced PF
An experimental therapy that proved ineffective in treating HIV infections now has shown promising potential at preventing or limiting pulmonary fibrosis (PF) caused by SARS-CoV-2, the virus that causes COVID-19.
That finding, from a mouse model of induced PF, was detailed in the study “Targeting RUNX1 prevents pulmonary fibrosis and reduces expression of SARS-CoV-2 host mediators,” published in The American Journal of Pathology.
Despite the recent development of medications to slow fibrosis, or tissue scarring, that characterizes idiopathic pulmonary fibrosis (IPF), there still are no widely accepted treatments that are able to lower IPF mortality. As a result, therapy developers continue their quest to design more effective therapies.
Drug repurposing is an alternative strategy that can be used in the development of new medications. It basically consists of finding new uses for old medications. Because the safety and pharmacological properties of these medications have already been established, drug repurposing has the potential to make the drug discovery process faster, less expensive, and safer.
Speeding therapy discovery may grow increasingly important as the incidence of IPF rises globally. The COVID-19 pandemic also could add to this, since the infection caused by SARS-CoV-2 has the potential to cause PF, in addition to raising the risk of severe cases of infection among those who already have IPF.
Ro24-7429 — a small molecule tested for the treatment of HIV, but then found to be ineffective — might be a promising candidate for drug repurposing.
The investigational therapy inhibits a protein called RUNX1, which recent studies suggest is involved in driving blood vessel abnormalities and fibrosis in response to COVID-19. Studies indicate the compound also might regulate the expression, or activity, of genes used to make two proteins — FURIN and ACE2 — that SARS-CoV-2 needs to interact with in order to infect cells.
Because of these findings, and since blood vessel abnormalities and fibrosis also are hallmarks of IPF, an international team of researchers set out to investigate the connection between RUNX1, FURIN, and ACE2 and the anti-fibrotic effects of Ro24-7429 in a mouse model of bleomycin-induced PF. Bleomycin is an agent often used to trigger PF in mice.
As a starting point, researchers examined post-mortem lung tissue samples from adult patients, ages 59–84, who died from COVID-19. In some samples RUNX1 was distributed abnormally throughout the tissue, highlighting its potential as a new therapeutic target.
Investigators then turned to mice to explore the therapeutic potential of Ro24-7429. The compound showed promising activity at reducing fibrosis and inflammation, and curbing RUNX1 expression — how much protein is being produced from its associated active gene.
Drops in RUNX1 expression also were accompanied by a decline in the levels of several fibrosis markers, including fibronectin and alpha-SMA.
In addition to RUNX1, Ro24-7429 lowered ACE2 and FURIN levels, as well as those of TNF-R1, another protein known to play a role in inflammation and immune responses.
Finally, researchers used computational methods to investigate the potential impact of reducing RUNX1 activity on blood vessel abnormalities associated with COVID-19. Of 113 genes reported to play various roles in blood vessel formation and regulation, 100 increased their activity in response to COVID-19 and were associated with higher mortality in severe cases.
Of these, 88 were targets of RUNX1, implying that by inhibiting RUNX1, Ro24-7429 also might reduce irregular blood vessel formation by limiting the activity of these genes.
Overall, these results point to a likely role for RUNX1 in how the body responds to COVID-19 infection and that it might affect PF progression through multiple biological pathways.
“We surmise that repurposing of Ro24-7429 for the treatment of PF in patients with or without COVID-19 should be examined in clinical trials,” the scientists wrote, adding that “because Ro24-7429 was already used in immunocompromised patients, it is likely to be safe to test in COVID-19 patients as [a] means to prevent or treat life-threatening complications.”