Prime editing of the beta-1 adrenoceptor in the murine brain restores physiological REM sleep in Alzheimer disease

Prime editing is a highly versatile genome editing technology with potential for treating genetic diseases. In this study, we used adeno-associated viral vectors to develop in vivo prime editing approaches in the murine brain, achieving up to 61.2% editing at the Dnmt1 locus in the cortex 10 weeks after intracerebroventricular (ICV) injection. We further targeted the beta-1 adrenergic receptor to introduce the naturally occurring Adrb1-A187V variant, which is associated with short sleep in humans and mice. We observed up to 28.1% editing in the cortex of wildtype animals 6 months after ICV injection. Treated animals showed increased home cage activity, locomotion, exploration, and recognition memory during awake phases as well as a decrease in slow wave activity during non-rapid eye movement (NREM) sleep. Furthermore, introducing the Adrb1A187V mutation into a mouse model of Alzheimer disease improved REM sleep disturbances and reduced NREM sleep slow wave activity after bouts of prolonged spontaneous activity. Together, our data demonstrate the potential of prime editing for reprogramming genetic circuits in the central nervous system, and suggests a beneficial effect of the Adrb1-A187V variant on various activity- and sleep-related behaviors.