Therapeutics
Figure 1 NAFLD and NASH: a global
public health epidemic. Non- alcoholic fatty liver disease
(NAFLD) and its most severe form, non-alcoholic
steatohepatitis (NASH), are
closely associated with obesity and type 2 diabetes epidemics. Prevalence of these chronic
liver diseases are on the rise throughout the world, but particularly in Western populations1. NASH is
expected to be the primary cause of liver transplants by
20203. There is an enormous untapped market for NASH- targeting therapies, and as of 2019, no approved drugs are available4
inflammation, are responsible for excessive extra- cellular matrix deposition, leading to fibrosis and eventually cirrhosis. Signalling interactions between hepatocytes, Kupffer cells and stellate cells are critical
drug discovery was the carbon tetrachloride (CCl4) model, introduced in the 1970s. CCl4 treatment in mice causes significant fibrosis within a relatively
for NASH pathogenesis.
Successfully modelling all the key physiological events (from steatosis to inflammation and fibro- sis) evident in clinical NASH has been extremely challenging – in both in vivo animal models and in vitro cell-based ones. Meanwhile, researchers are realising it is unlikely that a single, ‘one-size-fits- all’ wonder drug will be discovered. Many phar- maceutical companies are shifting their R&D efforts toward combination therapies, making an extremely expensive bet that their preclinical mod- els will accurately predict the best combinations to test in the clinic.
In vivo animal models – predictive or just poorly-treated mice? To date, most NASH therapeutics have been tested for efficacy and toxicity in mouse models prior to being advanced to clinical trials. Why mice? Their short lifespan, relatively low cost (compared to other laboratory animals) and ease of genetic manipulation. More than 20 different mouse mod- els have been used to study NASH6 and it is clear that these models have come a long way over the past 50 years (see Figure 2). One of the first animal models used for NAFLD
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short treatment period, and it is still occasionally utilised for testing drugs that target the fibrotic aspect of NASH. Understandably, this highly-toxic chemical model does not truly reflect the manifes- tation of NASH in humans. More appropriate in vivo mouse models have
since been developed for NASH drug discovery and development, each with advantages and limi- tations. These models range from chemical- induced, high fat diet-induced, Methionine Choline Deficient (MCD) diet, genetically-altered, or some combination/adaptation thereof. To better mimic the major human risk factors associated with NASH, most of these mouse models are at least partially diet-based and the animals typically become obese. However, genetically identical mice do not have identical eating habits, and a confir- matory surgery and liver biopsy is typically required prior to the initiation of drug treatment (at ~week 20-30, depending on the model), to prove that they truly developed NASH. For this reason, a significant percentage of diet-induced NASH mice are subsequently excluded from the remainder of the experiment. Many dietary-only mouse models progress only
as far as steatosis, with or without mild inflamma- tion, and require additional stimulation to progress
Drug Discovery World Fall 2019
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