Therapeutics
to advanced stages of NASH, such as inflammation and fibrosis. For example, the HDF-CDAA model combines a high fat diet and a modified version of the MCD diet (as methionine deficiency leads to hepatic injury, inflammation and fibrosis, and choline deficiency leads to macrovesicular steatosis). The STAM™ model first induces diabetes with streptozotocin treatment in mice at birth, followed by feeding a high fat diet for several months. The DIAMOND™ model7 takes a different approach. Rather than induce NASH by chemical intervention, this model relies on genetics and diet. It is a stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice, fed a high fat diet with ad libitum consumption of glucose and fructose. Impressively, this model is thought to mimic all the physiological, metabolic, histological and clinical endpoints of human NASH and it is now considered the most physiologically-relevant and predictive of all the available in vivo NASH animal models. Even though in vivo mouse models serve a valu-
able purpose in the quest for NASH therapeutics, scalability and time continue to be major limita- tions with animal models in general. Most mouse models employed for NASH research typically
require ~20 weeks to show the first hallmarks of NASH disease progression, while the appearance of severe fibrosis can take 30 weeks or longer. Considering that combination therapies are now the approach for most companies, and every new combination of drugs tested in mice requires this length of time, it might be years before the right combination makes it to the clinic.
Engineering better NASH models: human in vitro models pave the way for new therapies Due to high costs and time required for animal testing, there is growing interest in in vitro models of NASH, particularly for early preclinical screen- ing of single/combinatorial therapies. Historically, the predominant approach for modelling diseases in vitro has been limited to single cell types, such as cell lines (eg HepG2), hepatocytes, or stellate cells, cultured in a two-dimensional (2D) monolayer on a flat surface (see Figure 2). While these simple cell-based systems have advanced our understand- ing of the disease, cells placed in artificial 2D micro-environments do not reflect human biology. The lack of interactions between relevant cell types
Figure 2 The evolution of NASH models. Numerous in vivo mouse and in vitro human cell- based models have been used in NASH drug discovery. Although not an exhaustive list, this timeline highlights models that have influenced the field over the past 50 years. Since 2010, researchers have benefited from significant advances in both in vivo and in vitro models appropriate for NASH research
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