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...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123000931 |
| _version_ | 1797797174166159360 |
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| author | Sofie R. Dorset Rasmus O. Bak |
| author_facet | Sofie R. Dorset Rasmus O. Bak |
| author_sort | Sofie R. Dorset |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T03:44:12Z |
| format | Article |
| id | doaj.art-0b88949a62f74f55ad37f8f99b180bc1 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-13T03:44:12Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-0b88949a62f74f55ad37f8f99b180bc12023-06-23T04:43:13ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-09-01308389The p53 challenge of hematopoietic stem cell gene editingSofie R. Dorset0Rasmus O. Bak1Department of Biomedicine, Aarhus University, Aarhus C, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus C, Denmark; Corresponding author Rasmus O. Bak, Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, Bldg. 1115, 8000 Aarhus C, Denmark.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.http://www.sciencedirect.com/science/article/pii/S2329050123000931p53p21GSE56DDRDNA damage responseCRISPR-Cas |
| spellingShingle | Sofie R. Dorset Rasmus O. Bak The p53 challenge of hematopoietic stem cell gene editing Molecular Therapy: Methods & Clinical Development p53 p21 GSE56 DDR DNA damage response CRISPR-Cas |
| 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 | p53 p21 GSE56 DDR DNA damage response CRISPR-Cas |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123000931 |
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