Modeling an ultra-rare epilepsy variant in wildtype mice with in utero prime editing.

Generating animal models for individual patients within clinically relevant time frames holds the potential to revolutionize personalized medicine for rare genetic epilepsies. By incorporating patient-specific genomic variants into model animals, capable of replicating elements of the patient's clinical manifestations, a range of applications would be enabled: from preclinical platforms for rare disease drug screening, to bedside surrogates for tailoring pharmacotherapy without subjecting the patient to excessive trial medications. Here, we present the conceptual framework and proof-of-principle modeling of an individual epilepsy patient with an ultra-rare variant of the NMDA receptor subunit GRIN2A. Using in utero prime editing in the embryonic brain of wildtype mice, our approach demonstrated high editing precision and induced frequent, spontaneous seizures in prime editor-treated mice, reflecting key features of the patient's clinical presentation. Leveraging the speed and versatility of this approach, we introduce PegAssist, a generalizable 7-week workflow for bedside-to-bench modeling of patients using in utero prime editing. These individualized animal models can allow for widely-accessible personalized medicine for rare neurological conditions, as well as accelerate the drug development pipeline by providing an efficient and versatile preclinical platform for screening compounds against ultra-rare genetic diseases.