Cityslicker and Tada,

There is no one perfect animal model. Rabbits are not perfect models, and there or practical limitations to non-human primate studies. Normal mice are horrible models for cardiovascular disease due to some differences in cholesterol and lipoprotein metabolism. But genetically modified mice with mutations in the LDL receptor of ApoE (to make them susceptible to atherosclerosis) are commonly used as a first step in pre-clinical atherosclerosis studies. 

This Nature article that Barsax shared (https://www.nature.com/articles/s41467-020-17205-5) is interesting. It suggests (using the JQ1 pan-BET inhibitor) that there are different stages in the kidney injury and repair cycle that respond differently to BET inhbiition. Initiation of BET inhibition at the early stages of kidney injury worsened the outcome and increased mortality; whereas initiation of BET inhibition later in the injury/repair timeline showed benefits on fibrosis. So it seems that functional BET proteins are critically important for transcriptional changes that promote kidney repair in the early stages after acute injury; BET inhibition during this time has deleterious consequences on mortality. However, once the initial phase of post-injury transcriptional response had subsided (3-4 days after injury), BET inhibition did not increase mortality and showed some benefit on renal disease.

I would not dismiss these findings because it is in mice. Instead, I would caution readers to not read too much into the biological effects elicited by JQ1 (a pan-BET inhibitor). As is well established, apabetalone as a bromodomain-2 selective BET inhibitor elicits a very different transcriptional profile than does JQ1. It is well established that JQ1 elicits a lot of harmful side effects that prohibit it from being a therapeutic. However, apabetalone is relatively safe and well tolerated. It is too bad that this group did not also study apabetalone side by side with JQ1.

BDAZ