Cargando…

The p53 challenge of hematopoietic stem cell gene editing

Ex vivo gene editing in hematopoietic stem and progenitor cells (HSPCs) represents a promising curative treatment strategy for monogenic blood disorders. Gene editing using the homology-directed repair (HDR) pathway enables precise genetic modifications ranging from single base pair correction to re...

Descripción completa

Detalles Bibliográficos
Autores principales: Dorset, Sofie R., Bak, Rasmus O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331021/
https://www.ncbi.nlm.nih.gov/pubmed/37435043
http://dx.doi.org/10.1016/j.omtm.2023.06.003
_version_ 1785070174081122304
author Dorset, Sofie R.
Bak, Rasmus O.
author_facet Dorset, Sofie R.
Bak, Rasmus O.
author_sort Dorset, Sofie R.
collection PubMed
description Ex vivo gene editing in hematopoietic stem and progenitor cells (HSPCs) represents a promising curative treatment strategy for monogenic blood disorders. Gene editing using the homology-directed repair (HDR) pathway enables precise genetic modifications ranging from single base pair correction to replacement or insertion of large DNA segments. Hence, HDR-based gene editing could facilitate broad application of gene editing across monogenic disorders, but the technology still faces challenges for clinical translation. Among these, recent studies demonstrate induction of a DNA damage response (DDR) and p53 activation caused by DNA double-strand breaks and exposure to recombinant adeno-associated virus vector repair templates, resulting in reduced proliferation, engraftment, and clonogenic capacity of edited HSPCs. While different mitigation strategies can reduce this DDR, more research is needed on this phenomenon to ensure safe and efficient implementation of HDR-based gene editing in the clinic.
format Online
Article
Text
id pubmed-10331021
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Society of Gene & Cell Therapy
record_format MEDLINE/PubMed
spelling pubmed-103310212023-07-11 The p53 challenge of hematopoietic stem cell gene editing Dorset, Sofie R. Bak, Rasmus O. Mol Ther Methods Clin Dev Review Ex vivo gene editing in hematopoietic stem and progenitor cells (HSPCs) represents a promising curative treatment strategy for monogenic blood disorders. Gene editing using the homology-directed repair (HDR) pathway enables precise genetic modifications ranging from single base pair correction to replacement or insertion of large DNA segments. Hence, HDR-based gene editing could facilitate broad application of gene editing across monogenic disorders, but the technology still faces challenges for clinical translation. Among these, recent studies demonstrate induction of a DNA damage response (DDR) and p53 activation caused by DNA double-strand breaks and exposure to recombinant adeno-associated virus vector repair templates, resulting in reduced proliferation, engraftment, and clonogenic capacity of edited HSPCs. While different mitigation strategies can reduce this DDR, more research is needed on this phenomenon to ensure safe and efficient implementation of HDR-based gene editing in the clinic. American Society of Gene & Cell Therapy 2023-06-12 /pmc/articles/PMC10331021/ /pubmed/37435043 http://dx.doi.org/10.1016/j.omtm.2023.06.003 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Review
Dorset, Sofie R.
Bak, Rasmus O.
The p53 challenge of hematopoietic stem cell gene editing
title The p53 challenge of hematopoietic stem cell gene editing
title_full The p53 challenge of hematopoietic stem cell gene editing
title_fullStr The p53 challenge of hematopoietic stem cell gene editing
title_full_unstemmed The p53 challenge of hematopoietic stem cell gene editing
title_short The p53 challenge of hematopoietic stem cell gene editing
title_sort p53 challenge of hematopoietic stem cell gene editing
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331021/
https://www.ncbi.nlm.nih.gov/pubmed/37435043
http://dx.doi.org/10.1016/j.omtm.2023.06.003
work_keys_str_mv AT dorsetsofier thep53challengeofhematopoieticstemcellgeneediting
AT bakrasmuso thep53challengeofhematopoieticstemcellgeneediting
AT dorsetsofier p53challengeofhematopoieticstemcellgeneediting
AT bakrasmuso p53challengeofhematopoieticstemcellgeneediting