The therapeutic implications of all-in-one AAV-delivered epigenome-editing platform in neurodegenerative disorders

Boris Kantor (), Bernadette O’Donovan, Joseph Rittiner, Dellila Hodgson, Nicholas Lindner, Sophia Guerrero, Wendy Dong, Austin Zhang and Ornit Chiba-Falek ()
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Boris Kantor: Duke University School of Medicine
Bernadette O’Donovan: Duke University School of Medicine
Joseph Rittiner: Duke University School of Medicine
Dellila Hodgson: Duke University School of Medicine
Nicholas Lindner: Duke University School of Medicine
Sophia Guerrero: Duke University School of Medicine
Wendy Dong: Duke University School of Medicine
Austin Zhang: Duke University School of Medicine
Ornit Chiba-Falek: Duke University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Safely and efficiently controlling gene expression is a long-standing goal of biomedical research, and CRISPR/Cas system can be harnessed to create powerful tools for epigenetic editing. Adeno-associated-viruses (AAVs) represent the delivery vehicle of choice for therapeutic platform. However, their small packaging capacity isn’t suitable for large constructs including most CRISPR/dCas9-effector vectors. Thus, AAV-based CRISPR/Cas systems have been delivered via two separate viral vectors. Here we develop a compact CRISPR/dCas9-based repressor system packaged in AAV as a single optimized vector. The system comprises the small Staphylococcus aureus (Sa)dCas9 and an engineered repressor molecule, a fusion of MeCP2’s transcription repression domain (TRD) and KRAB. The dSaCas9-KRAB-MeCP2(TRD) vector platform repressed robustly and sustainably the expression of multiple genes-of-interest, in vitro and in vivo, including ApoE, the strongest genetic risk factor for late onset Alzheimer’s disease (LOAD). Our platform broadens the CRISPR/dCas9 toolset available for transcriptional manipulation of gene expression in research and therapeutic settings.

Date: 2024
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DOI: 10.1038/s41467-024-50515-6

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