期刊
BLOOD
卷 137, 期 19, 页码 2598-2608出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020008503
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资金
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [Z01-Al-00644, Z01-Al-00988]
Inhibition of p53-binding protein 1 (53BP1) significantly increased long-term homology-directed repair efficiency, leading to highly efficient long-term correction of X-CGD CD34(+) cells.
Lentivector gene therapy for X-linked chronic granulomatous disease (X-CGD) has proven to be a viable approach, but random vector integration and subnormal protein production from exogenous promoters in transduced cells remain concerning for long-term safety and efficacy. A previous genome editing-based approach using Streptococcus pyogenes Cas9 mRNA and an oligodeoxynucleotide donor to repair genetic mutations showed the capability to restore physiological protein expression but lacked sufficient efficiency in quiescent CD34(+) hematopoietic cells for clinical translation. Here, we report that transient inhibition of p53-binding protein 1 (53BP1) significantly increased (2.3-fold) long-term homology-directed repair to achieve highly efficient (80% gp91(phox+) cells compared with healthy donor control subjects) long-term correction of X-CGD CD34(+) cells.
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