Epigenetic Therapy Demonstrates Efficacy in APOE Reduction for Alzheimer Disease

Ornit Chiba-Falek, PhD

In a recent study using an epigenome therapy strategy, the candidate demonstrated efficacy in editing of apolipoprotein (APOE) and APOE e4 expressions in human induced pluripotent stem cells (hiPSC) -derived neurons and the human isogenic APOEe4 organoids, ultimately reducing the levels of APOE-mRNA and the protein in both models.¹ These findings provided in vitro and in vivo proof-of-concept of the therapy’s efficacy and suggests the candidate's ability to fine-tune APOE expression is translational toward the development of a therapeutic approaches to prevent or delay late-onset Alzheimer disease (AD).

Using the e4 allele-specific therapy approach there were no detectable changes of the e3 allele in the isogeneic hiPSC-derived neurons, and organoids homozygous for the e3 allele. Adeno-associated- dCas9-KRAB-MeCP2 vector injected into the hippocampus of APOEe4 and APOEe3 mice, performed in vivo studies, demonstrated between a 50-70% decrease in the mRNA and protein. Researchers noted a similar effect using the lentivirus- CRISPR/Cas system to target ApoEe4 in the same allele-specific way.

“We developed a novel therapeutic platform for AD based on gene editing technologies. The platform reduces the expression of APOE, the strongest genetic risk factor for AD, by closing the genomic region surrounding the gene making it less accessible for the transcriptional machinery. This study provides proof-of-concept for our therapeutic strategy in both human based-cellular and rodent models, demonstrating the efficacy and beneficial effects related to AD pathology,” senior author Ornit Chiba-Falek, PhD, professor in neurology at Duke University, told NeurologyLive®.

In the study, Chiba-Falek and colleagues developed an epigenome therapy platform to reduce APOE gene and its e4 allele specifically by targeting the epigenome landscape in APOE locus, based on the CRISPR/dCas9-editing strategy. Presented at the 2023 Alzheimer’s Association International Conference, July 16-20, in Amsterdam, the Netherlands, investigators designed the therapy candidate to target the APOE e4 in an allele-discriminatory approach, making the targeted allele specific and precise.

A similar approach was developed for targeting the regulatory elements in the APOE promoter. The platform was then evaluated in vitro using human hiPSC-derived neurons and organoids, as well as in vivo through stereotactic injection of the developed system in the hippocampus of the APOE-humanized mice, fostering the human APOE loci substituted the mouse ortholog.

"APOE is a new emerging therapeutic target for AD. The outcomes of this study set the stage for gene therapy in AD and provide the foundation to advance this APOE-targeted epigenome therapy towards clinical studies and ultimately precision medicine in AD,” Chiba-Falek told NeurologyLive®.

All told, the system technology also provides the opportunity for refining the platform to the development of gene-specific and even allele- and cell-type- specific therapies. Thus, this approach could potentially enable the advancement of strategies for precision medicine in late-onset AD.

“Our next step is Investigational New Drug Application - enablement studies: safety, mode of administration and durability in animal models (nonhuman primates). Our vision is to advance the field of AD drug discovery towards precision medicine and prevent the production of the pathogenic form of APOE in the group of patients carriers of the APOEe4 allele,” Chiba-Falek told.

Recently, lead author Boris Kantor, PhD, associate research professor of neurobiology at Duke University, sat down in an interview with NeurologyLive® during AAIC 2023 to discuss the benefits of researching this innovative approach. He talked about how the epigenome editing approach is different from traditional gene editing methods in terms of DNA alterations and enzyme activity. He also about the advantages the activated Cas9 offers in terms of DNA damage, off-target effects, and early intervention. In addition, Kantor shared his thoughts on how epigenome editing might potentially pave the way for disease prevention and AD prophylactic treatment using genetic testing and biomarkers.

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REFERENCES
1. Kantor B, Rittiner J, Odonovan B, Chiba-Falek O. APOE-targeted epigenome therapy for late onset Alzheimer’s disease. Presented at: 2022 Alzheimer’s Association International Conference; July 16 to July 20; Amsterdam, the Netherlands. Abstract 80698.