An opportunity for treatment of metabolic syndrome If you recall, RVX made this statement in their blog about the mechanism of action of RVX-208:
"RVX-208 acts on BET proteins, including BRD4, a member of the BET-protein family, leading to increased transcription of the ApoA-I gene followed by production of more ApoA-I protein." Much of their focus has been on the HDL/apoAI-mediated benefits to decrease atherosclerosis, diabetes, or alzheimers. But from mouse work (described below), there is good evidence that BRD2 inhibition has HUGE beneficial effects on the inflammation/metabolic complications of the metabolic syndrome. RVX hasn't highlighted this to the best of my knowledge and I think there is a great opportunity here.
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Metabolic syndrome (also referred to as insulin resistance syndrome) encompasses the myriad of complications that often result from obesity-induced enlargement of adipocytes (fat cells) showing a high amount of inflammation and these fat cells no longer able to stay healthy. These inflamed fat cells then cause whole-body insulin-resistance that often leads to diabetes. In their blog/program description, RVX has focused on the ability of RVX-208 to increase apoAI/HDL, and this apoAI/HDL to have some beneficial effects on the pancreas (hence, their diabetes clinical trial). These apoAI/HDL effects seem to be due to inhibition of BRD4. However, if RVX-208 also affects BRD2, or if RVX has other compounds that affect BRD2 alone or in conjunction with BRD4, then there is another huge population of people that could benefit from BET inhibitors. Some may argue that metabolic syndrome is an even bigger market than HDL raising therapies.
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If you have access to these articles, they are worth a read. But if you don't have access, then the abstracts pretty much summarize this BRD2 mouse model expresses low levels of BRD2. Cool stuff. I think it would be very timely for RVX to highlight some of this on their blog. Surely, RVX is aware of this. Its been out in the literature for a while now. But now especially with the idea of RVX Therapeutics, treatment of other diseases like the metabolic syndrome should be highlighted. Let me also remind everyone that Don made a statement in the latest CC that ALL compounds found to raise apoAI, not just RVX-208, would belong to RVX, not the RVX Therapeutics spin off. This might mean that only compounds that do not affect BRD4 would belong to RVX Therapeutics. It will be interesting to read what the information circular says about this. Anyways, here are the mouse BRD2 abstract links.
https://www.ncbi.nlm.nih.gov/pubmed/23374712
"In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from insulin resistance, glucose intolerance and pancreatic beta cell dysfunction, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible, innovative target to treat obesity and diabetes through modulation of the function of a chromatin code reader."
https://www.ncbi.nlm.nih.gov/pubmed/23420887
"we show that Brd2 and Brd4 physically associate with the promoters of inflammatory cytokine genes in macrophages......We propose that targeting BET proteins with small-molecule inhibitors will benefit hyperinflammatory conditions associated with high levels of cytokine production." This indicates that inhibition of either Brd2 or Brd4 is anti-inflammatory, but does simultaneous inhibition of Brd2 and Brd4 have even more anti-inflammation effects.
https://www.ncbi.nlm.nih.gov/pubmed/19883376
"In the present study, we show that wholebody disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated pro-inflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic beta-cells, where it normally inhibits beta-cell mitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-alpha (tumour necrosis factor-alpha)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans."