AI Article Synopsis
- Scientists studied how gene editing works in special cells called HSPCs using a virus called AAV.
- They found that AAV can stick around longer than expected and can cause DNA damage in those cells, which is not good for their health.
- Using a different type of virus called IDLV instead, helps reduce the DNA damage and makes gene editing more effective, which is better for using this method in medical treatments.
Article 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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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550218 | PMC |
| http://dx.doi.org/10.1016/j.stem.2022.09.001 | DOI Listing |
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