University of Pittsburgh researchers have developed a novel in vitro model of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with genetic mutations (TM6SF2-167K). Using gene editing, human-induced pluripotent stem cells (iPSC) with TM6SF2-167K, known to increase the risk of MASLD, were developed and differentiated to hepatocytes. These hepatocytes can identify therapeutic targets and screen potential treatments. Using this novel model, a treatment has been shown to improve hepatic function in the hepatic cells, highlighting the potential of this model to identify novel treatments for MASLD.
Mutations to the transmembrane 6 superfamily 2 gene, TM6SF2 (rs58542926) at position 167 are associated with an increased risk of liver-related death. Gene edited iPSC containing a mutation (TM6SF2-167K) can be differentiated to hepatocytes. These hepatocytes can accurately model MASLD in humans with TM6SF2-167K mutations, improving the understanding of ESLD and development of treatments for chronic liver disease.
Description
Chronic liver failure with MASLD is an increasing global health problem where too much fat is present in the liver and affects 38% of people worldwide. MASLD can lead to fibrosis, cirrhosis, hepatocellular carcinoma and eventually liver failure-related death. Currently, no FDA-approved therapy exists for MASLD, in part due to the complexity of the disease and lack of suitable experimental models of patients with gene mutations. This novel in vitro model for MASLD could help researchers to better understand the role of these mutations in the development of end-stage liver disease (ESLD) and identify potential clinical targets and therapeutic options to improve patient outcomes.
Applications
• Chronic liver disease
• Hepatocellular carcinoma
• Metabolic dysfunction-associated steatotic liver disease
Advantages
Currently no suitable research model exists to understand the role of genetic TM6SF2-167K mutations on the development of ESLD. Mouse models show conflicting results, likely due to only 78% of human and mouse TM6SF2 proteins being identical.
This novel model, using iPSC from healthy humans genetically edited to include the TM6SF2-167K mutation and differentiated to hepatocytes mimics the behavior of hepatocytes from humans with the TM6SF2-167K mutation. This model could finally provide scientists with the tools needed to better understand and treat TM6SF2-167K induced liver dysfunction.
Invention Readiness
Hepatocytes were differentiated from gene edited healthy human iPSC. Compared to wildtype, induced hepatocytes demonstrated upregulation of genes in areas that included lipid and fatty acid accumulation. Lipidomics confirmed increased lipid classes associated with endoplasmic reticulum (ER) and mitochondria stress. ER stress often results in protein misfolding and cell death. Treatment of cells with 4-phenylbutyric acid, an FDA approved compound found to improve protein misfolding, mitigated the detrimental effect of the genetic mutation on hepatic lipid metabolism, alleviating ER stress.
IP Status
Patent Pending
