Allele specific targeting of APOE‐E4 expression: The novel CRISRP/CAS9‐based platform for precision therapy for Alzheimer's disease: Nonhuman: Preclinical studies on APOE and neuroinflammation. (7th December 2020)

• Record Type: Journal Article
• Authors: Kantor, Boris; Moncalvo, Malik; Ilich, Ekaterina; Rittiner, Joseph; Dong, Wendy; Asmus, Natalie; Falek, Carmel; Yu, Young Jun; Gu, Jeffrey; Tringali, Dominic; Chiba‐Falek, Ornit
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 9
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.036578
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: APOEe4 is well‐established genetic risk factor for late onset Alzheimer's disease (LOAD). It has been demonstrated that DNA methylation plays an important role in controlling the levels of APOEe4 expression. Furthermore, the differential methylation levels were reported between disease‐ and naïve‐ individuals. It also has been shown that reduction of APOEe4 levels may alleviate LOAD pathology. Here we aimed to develop a novel approach for specific and accurate modulation of APOEe4 gene expression. Method: Here, we took advantage of a newly engineered VRER‐Cas9/gRNA system which specifically and accurately recognized a novel protospacer adjacent motif (PAM) created with SNP‐rs429358 T‐C transition in the APOEe4 gene. The system is based on an all‐in‐one lentiviral vector harboring gRNA/VRER‐dCas9‐DNMT3A. Using this vector, we were able to achieve an efficient enhancement in DNA methylation and the associated reduction in the expression of APOEe4 allele. The system has been validated on the isogeneic APOE‐human induced pluripotent stem cell (hiPSC)‐derived excitatory neurons. Result: We were able to specifically and efficiently downregulate expression of APOEe4 using isogeneic APOE‐human induced pluripotent stem cell (hiPSC)‐derived excitatory neurons as the experimental model. The reduction in the gene expression was linked to robust and specific DNA methylation. Conclusion: The developed epigenome‐editing platform highlights the novel approach towards the development of "smart" therapeutics for LOAD.