Brain-wide Genome Editing via STEP-RNPs for Treatment of Angelman Syndrome

Lu, X.; Xie, Y.; Bao, Y.; Yu, J.; Wang, Z.; Fan, J.; Sheu, W. C.; Long, G.; Tu, Z.; Tong, J.; Manquen, G.; Li, Y.; Katta, V.; Chow, R.; Chen, B.; Meng, Z.; Ma, Y.-h.; Qiu, C.; Chen, S.; Tsai, S.; Kumar, B. D.; Hendry, C. E.; Jiang, Y.-h.; Zhou, J.

doi:10.1101/2025.11.13.684643

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bioRxiv · 10.1101/2025.11.13.684643

Brain-wide Genome Editing via STEP-RNPs for Treatment of Angelman Syndrome

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Abstract

Brain-wide genome-editing remains a major hurdle for the treatment of neurogenetic disorders. Here, we report a non-viral, non-nanoparticle, chemical modification-based method, called Stimuli-Responsive Traceless Engineering Platform (STEP) that achieves highly efficient and brain-wide genome-editing of neurons in mice. Using cholesterol-based STEP as a lead, we show that a single administration of STEP-ribonucleoproteins (RNPs) results in functional genetic rescue with significant improvements across a battery of neurobehavioral domains in the Angelman syndrome (AS) mouse model. No significant off-target events or general toxicity effects are observed. STEP-RNPs are also highly efficient at editing human neurons and cortical brain organoids differentiated from AS patient-derived iPSCs. scRNA-seq analysis confirms functional genetic rescue via reactivation of Ube3a/UBE3A expression in human and mouse STEP-RNP-treated neuronal cells. Genome editing via STEP-RNPs has broad applications and the potential to treat many other neurogenetic disorders.

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Lu, X., Xie, Y., Bao, Y., Yu, J., Wang, Z., Fan, J., Sheu, W. C., Long, G., Tu, Z., Tong, J., Manquen, G., Li, Y., Katta, V., Chow, R., Chen, B., Meng, Z., Ma, Y.-h., Qiu, C., Chen, S., Tsai, S., Kumar, B. D., Hendry, C. E., Jiang, Y.-h., Zhou, J.. 2025-11-14. Brain-wide Genome Editing via STEP-RNPs for Treatment of Angelman Syndrome. https://doi.org/10.1101/2025.11.13.684643

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