Efficient Epigenome Editing Targets Alzheimer's Risk Gene

The American study introduces an optimised all-in-one AAV (adeno-associated virus) delivery system for CRISPR-based epigenetic editing, targeting the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), ApoE. Researchers engineered a small Staphylococcus aureus dCas9 fused to a repressor domain, capable of silencing gene expression in vitro and in vivo.

The platform utilises a compact CRISPR-dCas9 repressor system, including a fusion of dCas9 with the transcription repression domains from MeCP2 and KRAB. This system was delivered as a single AAV vector, overcoming the challenge of AAV's limited packaging capacity. The optimised AAV vector backbone included Sp1 and NF-kB enhancer elements to increase packaging efficiency and transcriptional repression.

The authors demonstrate successful repression of multiple target genes, including ApoE, in mouse models. Targeting the ApoE gene, a well-established risk factor for Alzheimer's, the system successfully repressed gene expression in mouse models, reducing ApoE expression by up to 71%. Notably, the repression was sustained, with significant gene expression reductions both in cultured cells and in vivo in mouse hippocampi, a critical brain region affected in Alzheimer's disease.

The study demonstrates the platform's ability to provide stable, long-term gene silencing across cell divisions without off-target mutations, marking it a promising candidate for therapeutic use in neurodegenerative diseases.

The study was conducted by a team from Duke University School of Medicine, including Boris Kantor and Ornit Chiba-Falek. It was published in Nature Communications on 23 August 2024.