Prime editing of the beta-1 adrenoceptor in the brain reprograms mouse behavior

Boeck, D.; Tidecks, L.; Wilhelm, M.; Weber, Y.; Ioannidi, E.; Mumenthaler, J.; Rothgangl, T.; Schmidheini, L.; Janjuha, S.; Patriarchi, T.; Schwank, G.

doi:10.1101/2023.05.19.541410

bioRxiv · 10.1101/2023.05.19.541410

Prime editing of the beta-1 adrenoceptor in the brain reprograms mouse behavior

Boeck, D.·Tidecks, L.·Wilhelm, M.·Weber, Y.·Ioannidi, E.·Mumenthaler, J.·Rothgangl, T.·Schmidheini, L.·Janjuha, S.·Patriarchi, T.·Schwank, G.

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Abstract

Prime editing is a highly versatile genome editing technology that holds great potential for treating genetic diseases1, 2. While in vivo prime editing has recently been conducted in the brain, liver, heart, and retina3-6, application of this technology to modulate neural circuits in the brain has not been reported yet. Here, we employ adeno-associated viral vectors to deliver optimized intein-split prime editors into the brain of mice. Delivery into newborn pups via intracerebroventricular injection resulted in up to 44.0% editing at the Dnmt1 locus in the cortex (on average 34.8{+/-}9.8% after 6 months). In addition, we obtained up to 28.1% editing at the Adrb1 locus in the cortex (on average 14.7{+/-}11.6% after 6 months). The introduced Adrb1A187V mutation is a naturally occurring variant of the {beta}1-adrenergic receptor, which has previously been linked to increased activity and natural short sleep7. Similarly, we observed an increase in the activity and exploratory behavior of treated animals. This study demonstrates the potential of prime editing for treating genetic diseases in the central nervous system and for reprogramming molecular pathways that modulate animal behavior.

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Boeck, D., Tidecks, L., Wilhelm, M., Weber, Y., Ioannidi, E., Mumenthaler, J., Rothgangl, T., Schmidheini, L., Janjuha, S., Patriarchi, T., Schwank, G.. 2023-05-19. Prime editing of the beta-1 adrenoceptor in the brain reprograms mouse behavior. https://doi.org/10.1101/2023.05.19.541410

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