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Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing.
There is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD (Jonsson et al. Nature 2012). This single nucleotide mutation in APP exon 16 reduces the cleavage of the A...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8681611/ http://dx.doi.org/10.1093/geroni/igab046.2511 |
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author | Tremblay, Jacques Guyon, Antoine Rousseau, Joël Tremblay, Guillaume Begin, Francis-Gabriel Lamothe, Gabriel |
author_facet | Tremblay, Jacques Guyon, Antoine Rousseau, Joël Tremblay, Guillaume Begin, Francis-Gabriel Lamothe, Gabriel |
author_sort | Tremblay, Jacques |
collection | PubMed |
description | There is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD (Jonsson et al. Nature 2012). This single nucleotide mutation in APP exon 16 reduces the cleavage of the APP protein by the beta-secretase by 40% thus preventing the development of AD even in persons more than 95 years old. Our research group has initially shown that the presence of the A673T mutation in an APP gene reduced the secretion of beta-amyloid peptides even if there is also a FAD mutation in the gene. This is the case for 14 different FAD mutations. We have used CRISPR/Cas9 base editing and PRIME editing technologies to insert the A673T mutation in the APP gene. We have compared several different cytidine base editor complexes to achieve the most effective and accurate genome modification possible in HEK293T cells and in SH-SY5Y neuroblastomas. The insertion of the A673T mutation in cells containing the London mutation reduced the secretion of beta-amyloid peptides. We are currently using lentiviral vectors to infect neurons from a mouse model and human neurons induced from fibroblasts of a patient with the London mutation. The insertion of the protective Icelandic mutation in the APP gene using these editing technologies opens a new potential therapeutic avenue not only for Familial Alzheimer’s diseases but also for sporadic Alzheimer’s disease. |
format | Online Article Text |
id | pubmed-8681611 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86816112021-12-17 Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing. Tremblay, Jacques Guyon, Antoine Rousseau, Joël Tremblay, Guillaume Begin, Francis-Gabriel Lamothe, Gabriel Innov Aging Abstracts There is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD (Jonsson et al. Nature 2012). This single nucleotide mutation in APP exon 16 reduces the cleavage of the APP protein by the beta-secretase by 40% thus preventing the development of AD even in persons more than 95 years old. Our research group has initially shown that the presence of the A673T mutation in an APP gene reduced the secretion of beta-amyloid peptides even if there is also a FAD mutation in the gene. This is the case for 14 different FAD mutations. We have used CRISPR/Cas9 base editing and PRIME editing technologies to insert the A673T mutation in the APP gene. We have compared several different cytidine base editor complexes to achieve the most effective and accurate genome modification possible in HEK293T cells and in SH-SY5Y neuroblastomas. The insertion of the A673T mutation in cells containing the London mutation reduced the secretion of beta-amyloid peptides. We are currently using lentiviral vectors to infect neurons from a mouse model and human neurons induced from fibroblasts of a patient with the London mutation. The insertion of the protective Icelandic mutation in the APP gene using these editing technologies opens a new potential therapeutic avenue not only for Familial Alzheimer’s diseases but also for sporadic Alzheimer’s disease. Oxford University Press 2021-12-17 /pmc/articles/PMC8681611/ http://dx.doi.org/10.1093/geroni/igab046.2511 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Abstracts Tremblay, Jacques Guyon, Antoine Rousseau, Joël Tremblay, Guillaume Begin, Francis-Gabriel Lamothe, Gabriel Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing. |
title | Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing. |
title_full | Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing. |
title_fullStr | Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing. |
title_full_unstemmed | Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing. |
title_short | Insertion of the protective APP A673T mutation by CRISPR/Cas9 base editing or PRIME editing. |
title_sort | insertion of the protective app a673t mutation by crispr/cas9 base editing or prime editing. |
topic | Abstracts |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8681611/ http://dx.doi.org/10.1093/geroni/igab046.2511 |
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