The Menlo Roundtable

Developing an siRNA Therapy to Fight Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is more common than one might expect, affecting about 25% of the global population.

Those with preexisting conditions, such as obesity, metabolic syndrome, or Type 2 Diabetes are much more likely to develop NAFLD, though it can develop in anyone. NAFLD is a spectrum disease consisting of stages: the first stage is fatty liver, also known as steatosis. This is when excessive fat, or triglyceride, builds up in the hepatocytes. Diet and exercise can typically help reduce liver fat at this stage. The second stage is nonalcoholic steatohepatitis, or NASH. This is when the excessive fat starts to cause cell bloating, cell degeneration, and infiltration of inflammation cells into the liver. This is the stage when most people are diagnosed. It is also the stage where a tipping effect can occur where it is hard to reverse the disease state.

Some individuals with NASH will progress to a more serious stage where collagen builds up in the liver, causing fibrosis. This stage is called “cirrhosis.” Individuals with cirrhotic livers typically need a liver transplant to survive. It has also been shown that diabetes is a major factor in one’s progression from NAFLD to cirrhosis; those with diabetes were seen to develop cirrhosis almost three times more frequently than those without, according to the study performed by Porepa et al (Li et al., 2018). A small subset of individuals with NASH may progress to hepatocellular carcinoma (HCC). Currently, it is estimated that about 80 million adults in the United States fall somewhere on the NAFLD spectrum; 16 million of these individuals are predicted to have NASH. At this time there are at least 70 programs being evaluated to treat NAFLD; however, there are still no approved therapies for NASH/cirrhosis.

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