Base and prime editors promise to correct nearly all known pathogenic variants, but their therapeutic development is restricted to a handful of recurrent mutations owing to the high cost of bringing gene therapies to market. Writing in the New England Journal of Medicine, Musunuru et al. report on the rapid development of a customized base-editing therapy, provided to an infant born with a rare disease and delivered in vivo to hepatocytes through lipid nanoparticles.
The patient, who was diagnosed with a rare metabolic disease of the urea cycle known as carbamoyl phosphate synthetase 1 (CPS1) deficiency that prevents the proper breakdown of protein from food, received the first dose of base-editing therapy at just seven months of age. Within two months, the authors developed a cell line harboring two CPS1 variants identified in the patient’s genome and screened various adenine base editors with guide RNAs tiling one of those CPS1 variants. They selected the most efficient and precise base editor, called k-abe. Five months after birth, they assessed the in vivo efficiency of k-abe in a patient-specific mouse model, showing up to 42% whole-liver corrective editing. Safety studies in nonhuman primates and analyses of off-target editing in hepatocytes cleared the way for regulatory approval.
