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- W2562232830 abstract "Hemoglobinopathies such as sickle cell disease and β-thalassemia are both common and morbid inherited genetic disorders. Mutations in the β -globin (HBB) gene result in the expression of pathologic globin molecules or the reduction in expression of the wildtype allele. Despite the high prevalence of these disorders, current treatment options are limited. Patients with a hereditary persistence of fetal hemoglobin (HPFH) have disease modifying mutations that result in the compensatory expression of gamma or delta hemoglobin and these patients tend to have a much less severe phenotype. A previously reported unique 13bp deletion identified in the gamma hemoglobin promoter of two sickle cell patients with HPFH (HbF >30%) offers a novel target for gene editing using targeted endonucleases. This region contains known binding sites for multiple regulatory factors including the DRED repressor complex and the CAAT-box binding factor (CBF). TALENs designed to target this 13bp site have been generated and the mRNA successfully transfected into human peripheral blood CD34 cells. Genomic analysis of TALEN transfected cells reveals the introduction of INDELs by NHEJ in both the γ1 (HBG1) and γ2 (HBG2) genes (33% and 8% respectively). TALEN edited human peripheral blood stem cells were then differentiated into erythroid progeny that express increased levels of fetal hemoglobin detected by both flow cytometry (>50% increase over control) and HPLC (>5-fold increase over control). CRISPR guides (traditional and chemically modified RNA guides) targeting the same locus are currently being compared to TALENs. These data suggest that the introduction of INDELs in this locus is capable of de-repressing the gamma globin gene in human CD34 cells. In vivo mouse xenografts are underway to further assess this approach as a means for a functional cure of a wide array of hemoglobinopathies." @default.
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- W2562232830 date "2016-05-01" @default.
- W2562232830 modified "2023-10-02" @default.
- W2562232830 title "562. Fetal Hemoglobin Expression Can Be Increased by Targeted Disruption of the Gamma Hemoglobin Promoter in Human Peripheral Blood Stem Cells" @default.
- W2562232830 doi "https://doi.org/10.1016/s1525-0016(16)33370-6" @default.
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