ArticleCell stem cell2022
Choice of template delivery mitigates the genotoxic risk and adverse impact of editing in human hematopoietic stem cells.
Article in Cell stem cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
What it found
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Who cites it
87 citing papers in PubMed, 120 citations in OpenAlex.
- Article
- Engineering hematopoietic stem and progenitor cells to generate red blood cells as viral traps against HIV-1.Molecular therapy. Advances · 2026Article
- In-depth characterization of stem cell potency and genotoxicity for clinical-scaleMolecular therapy. Advances · 2026Article
- Gene editing of hematopoietic stem cells: applications and advances.International journal of hematology · 2026Review
- Targeted lipid nanoparticles unlock in vivo human haematopoietic stem cell gene editing.Nature biomedical engineering · 2026Article
- The future of pediatric gene therapy: CRISPR-Cas9, AI, and personalized medicine.Pediatric research · 2026Review
- Selection of human hematopoietic stem cells bearing the intended functional edit by transient AND-gate reporters.Nature biotechnology · 2026Article
- Nickase NmCas9 unsilences paternal Ube3a in a mouse model of Angelman syndrome without causing AAV vector integration.Scientific reports · 2026Article
- ATP2B1 expression identifies human hematopoietic stem cells with superior repopulation and self-renewal.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- In vivo production of an anti-HIV antibody in mice by non-viral gene knockin in primate hematopoietic stem and progenitor cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- DNA-PKcs inhibitor AZD7648 reveals sgRNA cross-contaminants and enhanced sensitivity of genome engineering off-target activity in HSPCs.Nucleic acids research · 2026Article
- RAAVioli: A comprehensive approach to characterizing AAV vector integrations and rearrangements.Molecular therapy. Advances · 2026Article
- Emerging trends in gene and cell therapy: CRISPR in DNA editing and beyond.Cell reports. Medicine · 2026Review
- Gene therapy for hemoglobinopathies: Clinical trial results and biology of hematopoietic stem cell and the bone marrow niche.Cell reports. Medicine · 2025Review
- Harnessing DNA barcoding to enhance and sustain polyclonality in gene-edited hematopoietic stem cells.Molecular therapy. Methods & clinical development · 2025Article
- Orthogonal CRISPR systems for targeted integration and multiplex base editing enable nonviral engineering of allogeneic CAR-T cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- CRISPR-based therapeutic genome editing for inherited blood disorders.Nature reviews. Drug discovery · 2025Review
- Circular single stranded DNA potentiates non-viral gene insertion in hematopoietic stem and progenitor cells.Nature communications · 2025Article
- Unveiling the cut-and-repair cycle of designer nucleases in human stem and T cells via CLEAR-time dPCR.Nature communications · 2025Article
- Gene Correction of Wiskott-Aldrich syndrome iPS Cells Rescues Proplatelet Defects and Improves Platelet Size.Thrombosis and haemostasis · 2025Article
27 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
26 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.