Insertion of the Icelandic Mutation (A673T) by Prime Editing: A Potential Preventive Treatment for Familial and Sporadic Alzheimer's Disease.

TitleInsertion of the Icelandic Mutation (A673T) by Prime Editing: A Potential Preventive Treatment for Familial and Sporadic Alzheimer's Disease.
Publication TypeJournal Article
Year of Publication2022
AuthorsTremblay, G, Rousseau, J, Mbakam, CHappi, Tremblay, JP
JournalCRISPR J
Volume5
Issue1
Pagination109-122
Date Published2022 02
ISSN2573-1602
KeywordsAlzheimer Disease, CRISPR-Cas Systems, Gene Editing, Humans, Iceland, Mutation
Abstract

Alzheimer's disease (AD) is the result of abnormal processing of the amyloid precursor protein (APP) by β-secretase and γ-secretase, which leads to the formation of toxic β-amyloid peptides. The toxic β-amyloid peptides induce neuron death, memory problems, and AD development. Several mutations increase the risk of developing early-onset AD. However, the A673T mutation identified in the Icelandic population prevents AD development by reducing the cleavage of APP by β-secretase. In this study, we inserted the A673T mutation in human cells using the CRISPR prime editing (PE) technique. Repeated PE treatments resulted in the insertion of the A673T mutation in up to 49.2% of genes when a second nick was induced in the other DNA strand. When the protospacer adjacent motif used for PE was also mutated, up to 68.9% of the genes contained the protective A673T mutation. PE is a promising approach to introduce the A673T mutation precisely without mutating nearby nucleotides.

DOI10.1089/crispr.2021.0085
Alternate JournalCRISPR J
PubMed ID35133877
Grant ListU24 AG021886 / AG / NIA NIH HHS / United States
/ / CIHR / Canada