Epigenetic editing

Current anti-diabetic treatment approaches start at initial lifestyle adaptations, before progressing to–typically life-long–oral medications, including TZD and insulin therapies, whose use generally intensifies as the disease progresses and negative treatment effects start to manifest. Due to their reversible nature, epigenetic marks constitute an attractive target for novel therapeutic approaches. Accordingly, anticancer strategies that rely on the increased susceptibility of cancer cells to the rebalancing effects of small molecule inhibitors of epigenetic enzymes are being developed and clinically tested. The indisputable downside of such an intervention is that these so-called ‘epi-drugs’ lack both tissue- and sequence- specificity and are thus potentially inviting a myriad of unwanted side effects. While such imprecisions might be tolerated in life-threatening conditions like cancer, the cost likely outweighs the benefits in a chronic disease setting, like T2D, with a less fatal prognosis. We aim to identify and modify histone modification and DNA methylation events that occur at specific genomic sites and that can be linked to the development of obesity, insulin resistance and type 2 diabetes (T2D). Following the identification of such candidate epigenetic events, we intend to reverse their occurrence through site-specific recruitment of corresponding epigenetic modifiers (EMs) in vivo. EMs refer to a class of enzymes that are responsible for either adding (writers) or removing (erasers) histone/DNA modifications. We are currently developing new AAV-based tools and adapting already available methodologies for in vivo usage to recruit EMs to genomic target sites in a tissue-specific and time-restricted fashion, without having to rely on GMOs. Overall, we envision that targeting adverse epigenetic events at specific genomic loci, has the great potential of inducing and propagating long-lasting beneficial changes in gene expression and of reinstating normal physiology.