"Because even with INCB054329 they were evaluating the potential of BET inhibition as a therapeutic in vivo, and they did find a decreased mortality rate, in direct contrast to the recent study's findings.....One found increased mortality with decreased viral fighting capacity in the lung.....The other found increased survival with improved cardiac results."
Not exactly a fair comparison. The recent Chen bioRxiv study used the K18-Ace2 trangenic mouse model infected with SARS-Cov2 to study how JQ1 and ABBV-744 affected outcomes. The Mills Cell 2021 used both the SARS-Cov2-infected K18-Ace2 mice as well as a lipopolysaccharide (LPS)-induced cytokine storm mouse model to study how INCB054329 affected outcomes. The treatment of SARS-Cov2-infected K18-Ace2 mice with INCB054329 did not increase survival; all mice experienced severe enough disease necessitating euthanasia. Despite observing no benefit of INCB054329 treatment on the lung pathology or viral load during the pre-euthanasia study period, they observed protective benefits on the heart transcriptional profile. But this is of minimal significance if the mice were dying anyways. In their other model, which did not use the K18-Ace2 mice or SARS-Cov2 infection, the LPS treatment induces pro-inflammatory cytokines TNF, IL-1β, and IFN-γ that led to increased mortality in control mice but reduced mortality in INCB054329 treated mice. But one cannot conclude that INCB054329 reduced mortality from SARS-Cov2 infection of K18-Ace2 mice.
Based upon Resverlogix's reply to Fuzzy's inquiry, I am now appreciating that the K18-Ace2 mouse model is a poor choice for evaluating the effect to BET inhibitors. If indeed reduction in ACE2 levels is a key component of the benefit of BET inhibitors, the trangenic K18-Ace2 mouse is going to drive strong and constitutive ACE2 expression that will not be amenable to silencing by the BET inhibitor epigenetic mechanisms.
"IF the cytokine storm wreaks havoc in part because it contines when there is little or no virus left to fight, then letting the virus run its course but administering BETi at a certain point toward the end of that course may (MAY) still save lives, mightn't it? In addition to potentially addressing long-term covid effects ? Could they look for viral load indicators and finesse the timing?"
Theoretically, yes. But it may be very difficult to identify that optimal window of time. For example, if viral load is still high and severe outcomes are setting in, then perhaps other therapies such as antibody therapies or antivirals would be the more appropriate go to. However, as stated above I share Resverlogix's concern about the appropriateness of the K18-Ace2 model to evaluate BET inhibitors. So there is a solid chance that the findings of the recent Chen bioRxiv paper are at least partially artifactual and not representative of how BET inhibitors would influence SARS-Cov2 infection/replication in a normal human without transgenic Ace2 overproduction.
BDAZ
