Genome editing technology has immense potential for treating inherited diseases and is likely to supplant contemporary gene addition approaches already delivering exciting clinical success in multiple organ systems. Such progress has been underpinned by advances in adeno-associated virus (AAV) vector technology and the use of humanised preclinical models, however, challenges such as achieving therapeutically effective levels of editing in vivo remain to be resolved. In a previous study, we used the human ornithine transcarbamylase (OTC) gene as a therapeutic target and developed functionally validated dual AAV vectors for precise CRISPR/saCas9 cleavage and single nucleotide editing using AAV-mediated homology-directed repair (HDR). These reagents were evaluated in vivo on the native OTC locus in patient-derived primary human hepatocytes xenografted into the FRG (Fah-/-Rag2-/-IL2rg-/-) mouse liver. We observed an unprecedented level of in vivo editing, with up to 29% of alleles showing the expected single nucleotide change back to wild-type. These data demonstrated that targeted repair can be achieved in primary human hepatocytes in vivo at levels that would provide benefit for even the most therapeutically challenging liver disorders. Notably, however, HDR is inherently dependent on cell division which limits possible therapeutic targets. Here we describe a universal, homology-independent, approach designed to correct cells in both a dividing or non-dividing state. As initial proof-of-concept, we will focus on correcting the human OTC locus in vivo in a panel of OTC-deficient primary human hepatocytes engrafted into the FRG mouse.