期刊
GENE THERAPY
卷 28, 期 1-2, 页码 105-113出版社
SPRINGERNATURE
DOI: 10.1038/s41434-020-00192-z
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资金
- National Institute of General Medical Sciences of the National Institutes of Health [P20GM109021]
- NIH NIGMS Institutional Development Award (IDeA) Program [P20 GM103446]
- State of Delaware
The study revealed that the efficiency and specificity of CRISPR are influenced by multiple factors, including the position of the cleavage site and variability among patient samples. Results showed a unique genetic profile generated based on attempts to correct the SCD single base mutation along the beta globin gene.
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and their associated CRISPR-associated nucleases (Cas) are among the most promising technologies for the treatment of hemoglobinopathies including Sickle Cell Disease (SCD). We are only beginning to identify the molecular variables that influence the specificity and the efficiency of CRISPR- directed gene editing, including the position of the cleavage site and the inherent variability among patient samples selected for CRISPR-directed gene editing. Here, we target the beta globin gene in human CD34+ cells to assess the impact of these two variables and find that both contribute to the global diversity of genetic outcomes. Our study demonstrates a unique genetic profile of indels that is generated based on where along the beta globin gene attempts are made to correct the SCD single base mutation. Interestingly, even within the same patient sample, the location of where along the beta globin gene the DNA is cut, HDR activity varies widely. Our data establish a framework upon which realistic protocols inform strategies for gene editing for SCD overcoming the practical hurdles that often impede clinical success.
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