{"id":"doi:10.1002/advs.76658","kind":"article","title":"Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7","authors":["Kim Y","Lee G","An S","Park H","Kim H","Kim J","Kang S","Kim S","Kwon D","Park J","Hwang Y","Yuan X","Jeong J","Lee H","Kim HK"],"author_count":15,"year":2026,"published":"2026-07-17","venue":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","cited_by":0,"doi":"10.1002/advs.76658","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1002/advs.76658","archive_url":"https://space-kitty.com/papers/doi:10.1002/advs.76658","updated":null,"pmid":"42467931","pmcid":"PMC13379251","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13379251/pdf","abstract":"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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7\" by Kim Y, Lee G, An S et al., https://doi.org/10.1002/advs.76658, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-editing-therapies","name":"CRISPR & Gene-Editing Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[]}