In Vivo Base Editing for Neonatal Inborn Errors of Metabolism: Clinical Progress, N-of-1 Therapy, and the Ethics of Bespoke Genetic Medicine

Abstract

Severe neonatal-onset inborn errors of metabolism (IEMs), such as urea cycle disorders including carbamoyl phosphate synthetase 1 (CPS1) deficiency and the classic organic acidemias, present within days of birth with metabolic decompensation that carries high early mortality and, in survivors, a substantial burden of neurologic injury despite optimal medical management. Because most cases arise from defined point mutations, these disorders are conceptually well suited to one-time genetic correction. Base editing, which installs precise single-base changes without generating double-strand DNA breaks, and its companion technology, prime editing, have moved rapidly from laboratory description to in vivo demonstration in animals and, most recently, to a single human patient. In 2025, an infant with CPS1 deficiency ('KJ') received a bespoke lipid nanoparticle-delivered base-editing therapy designed and manufactured for that individual's specific variant, becoming the first reported recipient of a customized in vivo gene-editing medicine. This review synthesizes the clinical rationale for genetic correction of neonatal IEMs, the mechanistic basis and delivery strategies (lipid nanoparticles and adeno-associated virus) that make in vivo base editing feasible, and the preclinical evidence that preceded the first human case. We then examine the ethical dimensions of bespoke 'N-of-1' genetic medicine: the somatic versus germline distinction; consent for a non-autonomous neonate; equity, cost, and scalability; and the evolving regulatory pathway for individualized therapies. We conclude by distinguishing what has been proven in a single patient and in preclinical models from what remains speculative and by outlining what would need to generalize for a single case to become a platform.