Choice of template delivery mitigates the genotoxic risk and adverse impact of editing in human hematopoietic stem cells
Open accessAbstract
Long-range gene editing by homology-directed repair (HDR) in hematopoietic stem/progenitor cells (HSPCs) often relies on viral transduction with recombinant adeno-associated viral vector (AAV) for template delivery. Here, we uncover unexpected load and prolonged persistence of AAV genomes and their fragments, which trigger sustained p53-mediated DNA damage response (DDR) upon recruiting the MRE11-RAD50-NBS1 (MRN) complex on the AAV inverted terminal repeats (ITRs). Accrual of viral DNA in cell-cycle-arrested HSPCs led to its frequent integration, predominantly in the form of transcriptionally competent ITRs, at nuclease on- and off-target sites. Optimized delivery of integrase-defective lentiviral vector (IDLV) induced lower DNA load and less persistent DDR, improving clonogenic capacity and editing efficiency in long-term repopulating HSPCs. Because insertions of viral DNA fragments are less frequent with IDLV, its choice for template delivery mitigates the adverse impact and genotoxic burden of HDR editing and should facilitate its clinical translation in HSPC gene therapy.
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IDLV can detect off-target effects in cell types that are otherwise difficult to transfect.
“Empowered by the robust transduction ability of lentivirus in certain cell types, this method can detect off-target effects in cell types that are otherwise difficult to transfect (Ferrari et al., 2022).”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as Ferrari et al., 2022
The Results section on IDLV editing in LT-HSPCs (page unavailable) reports genome-wide retrieval of IDLV integration sites, including predicted nuclease off-target sites, supporting detection in the HSPCs studied. The paper does not establish that these cells are difficult to transfect or demonstrate that robust lentiviral transduction enables off-target detection across other difficult-to-transfect cell types. (LLM, conf=0.84)
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- Authors
- Ferrari, S., Jacob, A., Cesana, D., Laugel, M., Beretta, S., Varesi, A., Unali, G., Conti, A., Canarutto, D., Albano, L., Calabria, A., Vavassori, V., Cipriani, C., Castiello, M. C., Esposito, S., Brombin, C., Cugnata, F., Adjali, O., Ayuso, E., Merelli, I., Villa, A., Di Micco, R., Kajaste-Rudnitski, A., Montini, E., Penaud-Budloo, M., & Naldini, L.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- IRCCS Ospedale San Raffaele (IT)
- Inserm (FR)
- Corresponding author
- Naldini, Luigi
- ORCID
- Venue
- Cell stem cell
- Publisher
- Elsevier BV
- Published
- 2022-10
- Volume
- 29
- Issue
- 10
- Pages
- 1428-1444.e9
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC9550218
- OpenAlex
- W4302363821
- Cited by
- 133
- References
- 100
- Citations by year
- 2026: 22 · 2025: 40 · 2024: 33 · 2023: 37 · 2022: 1
- FWCI
- 16.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, cc-by-nc-nd)
- Funders
- New York Stem Cell Foundation
- Horizon 2020
- Fondazione Telethon
- Ministero della Salute (E-Rare-3 JTC 2017, PE-2016-02363691)
- Ministero dell’Istruzione, dell’Università e della Ricerca (20175XHBPN)
- Institut National de la Santé et de la Recherche Médicale (UMR1089)
- Fondation Louis-Jeantet
- Lady Tata Memorial Trust
- European Research Council (819815)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- hematopoietic stem and progenitor cells, homology-directed repair, genome editing, adeno-associated virus vectors, inverted terminal repeats, viral DNA persistence, MRN complex, lentiviral vectors, genotoxicity, clonogenicity, gene therapy
- MeSH terms
- Gene Editing, DNA Damage, DNA, Viral, Hematopoietic Stem Cells, Humans, Tumor Suppressor Protein p53, Integrases, CRISPR-Cas Systems
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