Project

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder (UCD). It is an inborn error of liver metabolism, where a deficiency of the ornithine transcarbamylase enzyme leads to an accumulation of neurotoxic ammonia in the blood. There is no cure besides whole liver transplantation. Gene editing via targeted nucleases, such as CRISPR/Cas9, has been suggested as an approach to treat this disease. The system generates a site-specific DNA double-stranded break (DSB), which enables precise modification of the locus when repaired by homologous recombination (HR) from ectopic template DNA. However, recent attempts to apply this technology to mouse models of recessive liver disorders have failed, as in postmitotic hepatocytes the HR pathway is inactive and gene correction rates are low. Recently, a novel CRISPR tool, so-called base editors, have been established. Base editors enable direct conversion of C∙G to T∙A base pairs and vice versa via base deamination. They are therefore independent of DNA break formation and HR. When applied to mouse models of monogenetic liver diseases, the technology enabled gene correction rates above 50%.