CRISPR/dCAS9 Shows Promise in Editing APOE ε4 to Treat Late Onset Alzheimer Disease

Results presented at the 2023 meeting of the Alzheimer’s Association International Conference (AAIC) demonstrate the potential of a novel CRISPR/dCas9-editing strategy to treat late onset Alzheimer disease (LOAD) by targeting the ε4 allele of the APOE gene. This technique showed efficacy in human induced pluripotent stem cell (hiPSC)-derived neurons, human isogenic organoids, and a mouse model, demonstrating the strategy’s promise as a potential future epigenome therapy.

The novel CRISPR/dCas9-editing strategy utilizes the recently developed bipartite repressor platform to specifically and precisely target APOE ε4, without affecting the neutral APOE variant, ε3. With a similar approach that uses an adeno-associated-dCas9-KRAB-MeCP2 vector, the researchers also developed a method to target and edit the APOE promoter. The efficacy of the strategy was assessed in vitro using hiPSC-derived organoids and neurons, which both showed reduction in APOE-mRNA and apolipoprotein E (APOE), with no detectable editing of the ε3 allele. In vivo, researchers conducted stereotactic injection of the system into murine models that were modified to express the human APOE gene. This method yielded a 50% to 70% reduction in APOE mRNA and associated protein levels, with similar results for the APOE ε4 allele-targeting method. Both the in vitro and in vivo results are indicative of this gene editing system’s potential for APOE-targeted epigenome therapy.

The protein encoded by APOE ε4 is implicated in Alzheimer disease (AD), including LOAD, as well as cardiovascular diseases. The research was presented by Boris Kantor, PhD, Associate Research Professor of Neurobiology at the Duke University Center for Advanced Genomic Technologies.