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Multiplying models for NASH
SAN DIEGO—Crown Bioscience announced in June that it is developing four new preclinical translational nonalcoholic steatohepatitis (NASH) models. NASH is a degenerative liver disease that affects up to 12 percent of the adult population worldwide. If left untreated, NASH is expected to become the leading cause for liver transplant by 2020.
CrownBio calls itself steadfast in its commitment to the NASH drug development community.
“We continue to demonstrate our deep commitment to developing new and relevant preclinical models of NASH,” says Dr. Jim Wang, senior vice president cardiovascular and metabolic disease research at CrownBio. “The addition of these new models will establish a market-leading platform to accelerate NASH drug discovery.”
“First and most importantly, there are no approved therapeutics on the market for NAFLD/NASH. It is important to us as a company to help bring new treatments to patients faster. There is a very high unmet need for approved NAFLD/NASH therapeutics as fatty liver disease affects up to 40 percent of the population. While weight loss is currently the most effective option, it is not easily sustained, and ultimately, patients are waiting. That is our number one motivation,” notes Wang.
“Secondly, we place NASH as a top R&D priority because of our clients. They are working diligently to develop therapeutics and need better, more translatable preclinical models. Much of our internal research and new model development is client driven and we are committed to developing new and more relevant models of NAFLD/NASH,” he adds.
CrownBio’s dedication will result in the availability of four new models over the next 12 months. The models will include a chemically enhanced murine model using carbon tetrachloride, and modified diet models such as amylin, MCD or other choline-deficient diets which more closely mimic a Western diet and exacerbates fibrosis. There will also be an accelerated diet-induced murine model and an accelerated diet-induced non-human primate (NHP) model.
These models will join the existing CrownBio NASH platform, which includes the renamed MS-NASH model (formerly known as FATZO), a next-generation murine model of obesity, dysmetabolism and diabetes that exhibits accelerated and exacerbated liver fibrosis under administration of carbon tetrachloride. CrownBio also has a spontaneously obese, dysmetabolic and diabetic NHP model, which develops NAFLD/NASH similarly to humans.
“Our newest model, the MS-NASH (formerly FATZO) mouse model fed a Western diet plus fructose and administered low-dose carbon tetrachloride, is unique in that it is more translatable to the human condition than existing models,” Wang explains. “It is a spontaneous and polygenic model of obesity and type 2 diabetes (T2D) that develops NAFLD when fed a Western diet plus fructose. Disease progression/pathology is exacerbated and accelerated with a very low dose of carbon tetrachloride. Most preclinical NASH models require the researcher to choose between fast and severe fibrosis without dysmetabolism, or an appropriate dysmetabolic background with only mild NASH. Our model has both elements—spontaneous dysmetabolism with accelerated and exacerbated fibrosis.
“Additional modified diet models will be more translatable from existing models as they occur in animals with spontaneous obesity, diabetes and dysmetabolism. Our NHP models also have spontaneous obesity, diabetes and dysmetabolism, but there is a need to accelerate the development of NASH since disease progresses so slowly and similarly to humans. We are working with new diets to drive faster and more severe phenotypes to better serve the needs of our clients.”
“We [also] have a rat NASH model in development, which will be the first rat model on the market. Our accelerated murine model of NAFLD/NASH is available now, and the other rodent models are expected to be available this fall,” he adds. “The NHP models take longer to develop but are anticipated in 2020.”
When asked what he thinks is most exciting about the research, Wang replies, “The most exciting part of NASH research is helping our clients get closer to the clinic and being able to see promising preclinical data unfold. One recent example is working with Yale School of Medicine on a controlled-release mitochondrial protonophore (CRMP) for the treatment of NAFLD/NASH and T2D,” Wang mentions. “They had success safely reversing hypertriglyceridemia, fatty liver and hepatic inflammation/fibrosis in diet-induced rodent models of obesity, and worked with us to assess CRMP safety and efficacy in NHPs.”