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Cited by 33CRISPR and Genetic EngineeringVirus-based gene therapy researchDNA Repair Mechanisms

The p53 challenge of hematopoietic stem cell gene editing

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Dorset, Sofie R., Bak, Rasmus O.·2023·Molecular Therapy - Methods & Clinical Development
DOI 10.1016/j.omtm.2023.06.003PMC PMC10331021
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Abstract

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.

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Cited by

Sorted by citations

Authors
Dorset, S. R., & Bak, R. O.
Affiliations
Aarhus University (DK)
Corresponding author
Bak, Rasmus O.
ORCID
Bak, Rasmus O.
Venue
Molecular Therapy - Methods & Clinical Development
Publisher
Elsevier BV
Published
2023-09
Volume
30
Pages
83-89
ISSN
2329-0501 (ISSN-L)
DOI
10.1016/j.omtm.2023.06.003
PMC
PMC10331021
OpenAlex
W4380356485
Cited by
33
References
10
Citations by year
2026: 8 · 2025: 11 · 2024: 9 · 2023: 5
FWCI
0.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy — Methods & Clinical Development (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Aarhus Universitet (609033)
  • Innovationsfonden (8056‐00010B, 00009B)
  • European Commission (101057438, 609033)
  • Lundbeckfonden (R238‐2016‐3349)
  • Novo Nordisk
  • A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal
  • Riisfort Fonden
  • Novo Nordisk Fonden (NNF17OC0028894, NNF19OC0058238)
  • H. Lundbeck A/S
  • HORIZON EUROPE Framework Programme (101057438)
  • Aarhus Institute of Advanced Studies, Aarhus Universitet (609033)
  • HORIZON EUROPE European Research Council (101041231)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
hematopoietic stem and progenitor cells, genome editing, homology-directed repair, p53 activation, DNA damage response, adeno-associated virus vectors, DNA double-strand breaks, engraftment, clonogenicity, clinical translation

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