Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7

초록

The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), driving Aβ accumulation, tau pathology, and synaptic dysfunction. Allele-specific correction of APOE4 represents a promising therapeutic strategy to mitigate disease progression. In this study, we developed an APOE4-specific prime editing strategy based on an optimized APOE4-targeting pegRNA, enabling precise and efficient conversion of the APOE4 allele to the lower-risk APOE3 variant. We found that PE7 targeting the APOE4 allele achieved robust and specific editing without detectable off-target effects. This correction reduced ApoE4 protein levels and attenuated key AD-related pathologies, including Aβ42 accumulation, tau phosphorylation, and activation of the ERK1/2 pathway in APP/APOE4 knock-in (KI) mice. Notably, PE7 treatment enhanced neuronal survival and improved cognitive performance in these mice. Furthermore, in human induced neurons derived from APOE3/4 heterozygous AD patient fibroblasts, PE7 consistently corrected the APOE4 allele and suppressed both amyloid- and tau-associated pathologies. These findings establish PE7-mediated APOE4 correction as a precise and efficient therapeutic genome-editing strategy with translational potential for sporadic AD. © 2026 The Author(s). Advanced Science published by Wiley-VCH GmbH.

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