In vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice

Hereditary Hemochromatosis (HH) is one of the most common genetic diseases in the Caucasian population, with a prevalence of 1:200/400. Among the four different types, the most common form is Type 1, a homozygous p.C282Y variant in the HFE gene, in which a guanosine is replaced by an adenosine (c.845 G>A). This variant results in the misfolding of the HFE protein, which can no longer reach the cell membrane of the hepatocytes, thereby losing its ability to work as a sensor for the iron content in the bloodstream. This ultimately causes the accumulation of iron in various organs, mostly in the liver, heart and pancreas, thus leading to the development of chronic diseases. A major complication represents the development of hepatocellular carcinoma.