Prime Editing of Alzheimer’s Disease High-Risk APOE4 Allele by Brain-Directed Adeno-Associated Virus Vectors

Dec 26, 2025Human gene therapy

Using Brain-Targeted Virus Vectors to Edit the High-Risk APOE4 Gene for Alzheimer's Disease

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Abstract

The APOE4 variant increases the risk of Alzheimer's disease by 15-fold in homozygotes compared to common E3 allele carriers.

Gene editing of the APOE4 variant to the E3 allele may reduce Alzheimer's disease risk in homozygous individuals.
Efficient editing was achieved in human APOE4-targeted replacement mice using optimized prime editing techniques.
The highest editing efficiency was observed with the APOE3/4-3_10 construct in both liver and brain tissues after specific delivery methods.
Different AAV capsids and administration routes showed comparable efficacy for brain-wide editing of the APOE gene.
Minor variations were noted in editing outcomes within the cerebellum, but overall results were consistent across brain regions.

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Common variants of the apolipoprotein E (APOE) gene have a major impact on the risk of developing Alzheimer's disease (AD). Relative to homozygotes with the common E3 allele, the APOE4 variant (C112R) increases risk by 3.5-fold in E3/E4 heterozygotes and 15-fold in E4 homozygotes. Since the E3 and E4 alleles differ only by a single nucleotide, gene editing of E4 to E3 is a potential strategy to reduce AD risk in E4 homozygotes. Because the APOE pool in the brain is separate from systemic APOE, editing to treat AD would ideally be directed to the brain. Followingoptimization of prime editing guide RNAs, efficient prime editing expression cassettes were inserted into the adeno-associated virus (AAV) split-intein system and packaged into pairs of AAV vectors forediting. The AAV vectors were administered to human homozygous APOE4-targeted replacement mice (TRE4), and APOE4 to APOE3 editing efficiency was assessed after 4 weeks. The prime editing construct designated APOE3/4-3_10 was the most efficient at APOE4 to APOE3 conversion, both in liver following intravenous delivery and in brain following intrahippocampal delivery. To assess brain-wide editing, two AAV capsids were compared, including AAVrh.10 with administration either directly to the hippocampus or to the cerebrospinal fluid via the cisterna magna and AAV-CAP.B10 administered intravenously. Other than minor differences in APOE4/3-3_10 mediated E4 to E3 editing in the cerebellum, the different capsids and routes yielded similar editing efficacy throughout the brain. This may represent a candidate treatment to reduce the risk of AD. in vitro in vivo

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Prime Editing of Alzheimer’s Disease High-Risk APOE4 Allele by Brain-Directed Adeno-Associated Virus Vectors

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