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| home > ebr > winter 2022 > a pressing need for accurate preclinical models of metabolic disease |
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European Biopharmaceutical Review
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Metabolic disease is a broad term to describe pathologies that disrupt normal metabolism and often centre around obesity and insulin resistance. Lifestyle choices, such as poor diets and inactivity, have largely been blamed for the increasing prevalence of obesity, high blood sugar, and diabetes, but genetic factors can also promote these diseases. Whatever the cause, there is no denying metabolic disorders are a modern epidemic. One example is non-alcoholic fatty liver disease (NAFLD), which occurs when there is excessive deposition of fat in the liver. NAFLD is currently the most common chronic liver disease worldwide, affecting around 25% of the general populace and over 50% of diabetics (1). Eventually, the increasing fat content becomes toxic, leading to liver inflammation, hepatic cell death, and potentially a buildup of scar tissue within the liver (cirrhosis). Advanced NAFLD, referred to as non-alcoholic steatohepatitis (NASH), can quickly lead to organ failure or cancer and is the second leading indication for liver transplants.
Despite its prevalence and severity, there is a lack of FDA-approved treatments. Over the past couple of years, a ‘first wave’ of at least ten different NASH pharmaceuticals, such as obeticholic acid, elafibranor, and selonsertib, hit clinical trials. While initially promising, all failed to meet efficacy targets and none made it to market. Such results are not uncommon; in general, nine in ten preclinical drug candidates are likely to fail. These failures occur for a myriad reasons, but within the field of metabolic disorders, more predictive preclinical models are required to improve the translatability of data between the laboratory and the clinic.
The Limitations of Conventional Methods
The standard in vitro liver model is the 2D monoculture of primary human hepatocytes. While these cells are human-relevant and maintain some in vivo metabolic activity, they are prone to dedifferentiation and remain viable for only a period of days in 2D. Unfortunately, this limits their use to short-term effect studies. Including non-parenchymal cells (NPCs), like hepatic stellate cells and/or Kupffer cells, improves these models, as they enable the maintenance of the differentiated status of hepatocytes for a longer period. Adding NPCs is also essential to reproducing diseased liver states. While NAFLD can be induced in 2D monoculture via the addition of free fatty acids (FFA), co-culture is required to recapitulate the inflammation associated with advanced NASH progression.
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