Ex vivo therapeutic base and prime editing using chemically derived hepatic progenitors in a mouse model of tyrosinemia type 1. Mus musculus

DNA base editors and prime editing technology that are capable of therapeutic base conversion enable ex vivo gene editing therapy for various genetic diseases. For such therapy, it is critical that the target cells survive well both outside the body and after transplantation. In this regard, chemically derived stem/progenitor cells are attracting attention as the most useful cell sources for clinical trials. Here, we generate chemically derived hepatic progenitors from the hereditary tyrosinemia type1 model mouse (HT1-mCdHs) and successfully correct the disease-causing mutation using both adenosine base editors (ABEs) and prime editors (PEs). After transplantation into HT1 mice, ABE- or PE- corrected HT1-mCdHs repopulated the liver with fumarylacetoacetate hydrolase-positive cells and dramatically increased the survival rate of HT1 model mice under a complete NTBC withdrawal condition, suggesting a safe and effective ex vivo gene editing therapy.