期刊
SCIENTIFIC REPORTS
卷 10, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41598-020-66309-x
关键词
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资金
- Jurgen Manchot Stiftung
- Fortune Tuebingen [2412-0-0, 2485-0-0]
- Clinician Scientist Program [4400-0]
- Forderverein fur krebskranke Kinder Tubingen e.V.
- University Children's Hospital of Tubingen
- University of Tubingen
beta -hemoglobinopathies are caused by abnormal or absent production of hemoglobin in the blood due to mutations in the beta -globin gene (HBB). Imbalanced expression of adult hemoglobin (HbA) induces strong anemia in patients suffering from the disease. However, individuals with natural-occurring mutations in the HBB cluster or related genes, compensate this disparity through gamma -globin expression and subsequent fetal hemoglobin (HbF) production. Several preclinical and clinical studies have been performed in order to induce HbF by knocking-down genes involved in HbF repression (KLF1 and BCL11A) or disrupting the binding sites of several transcription factors in the gamma -globin gene (HBG1/2). In this study, we thoroughly compared the different CRISPR/Cas9 gene-disruption strategies by gene editing analysis and assessed their safety profile by RNA-seq and GUIDE-seq. All approaches reached therapeutic levels of HbF after gene editing and showed similar gene expression to the control sample, while no significant off-targets were detected by GUIDE-seq. Likewise, all three gene editing platforms were established in the GMP-grade CliniMACS Prodigy, achieving similar outcome to preclinical devices. Based on this gene editing comparative analysis, we concluded that BCL11A is the most clinically relevant approach while HBG1/2 could represent a promising alternative for the treatment of beta -hemoglobinopathies.
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