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Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin.


ABSTRACT: ?-hemoglobinopathies are caused by abnormal or absent production of hemoglobin in the blood due to mutations in the ?-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 ?-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 ?-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 ?-hemoglobinopathies.

SUBMITTER: Lamsfus-Calle A 

PROVIDER: S-EPMC7311455 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34<sup>+</sup> HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin.

Lamsfus-Calle Andrés A   Daniel-Moreno Alberto A   Antony Justin S JS   Epting Thomas T   Heumos Lukas L   Baskaran Praveen P   Admard Jakob J   Casadei Nicolas N   Latifi Ngadhnjim N   Siegmund Darina M DM   Kormann Michael S D MSD   Handgretinger Rupert R   Mezger Markus M  

Scientific reports 20200623 1


β-hemoglobinopathies are caused by abnormal or absent production of hemoglobin in the blood due to mutations in the β-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 γ-globin expression and subsequent fetal hemoglobin (HbF) production. Several preclinical and clinical studies have been perform  ...[more]

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