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<p>CRISPR/Cas9 genome editing has emerged as a promising treatment for genetic diseases like β-thalassemia. Editing γ-globin promoters to disrupt <i>ZBTB7A/LRF</i> or <i>BCL11A</i> binding sites has shown potential for reactivating fetal hemoglobin and treating sickle cell disease. However, its application to β<sup>0</sup>-thalassemia/HbE disease remains unclear. This study utilized CRISPR/Cas9 to disrupt these sites in mobilized CD34 + hematopoietic stem /progenitor cells from healthy donors and β<sup>0</sup>-thalassemia/HbE patients. The editing efficiency for the <i>BCL11A</i> site (75–92%) was higher than for the <i>ZBTB7A/LRF</i> site (57–60%). Both disruptions similarly increased fetal hemoglobin production in healthy donors (<i>BCL11A</i> 26.2 ± 1.4%, <i>ZBTB7A/LRF</i> 27.9 ± 1.5%) and β<sup>0</sup>-thalassemia/HbE cells (<i>BCL11A</i> 62.7 ± 0.9%, <i>ZBTB7A/LRF</i> 64.0 ± 1.6%). Off-target effects were absent in <i>BCL11A</i>-edited cells but observed at low frequencies in <i>ZBTB7A/LRF</i>-edited cells. Neither disruption significantly affected erythroid differentiation. These findings highlight the comparable contributions of <i>ZBTB7A/LRF</i> and <i>BCL11A</i> binding sites to γ-globin reactivation. CRISPR/Cas9 editing of either site may offer a potential therapeutic strategy for β<sup>0</sup>-thalassemia/HbE disease.</p>

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Disrupting ZBTB7A or BCL11A binding sites reactivates fetal hemoglobin in erythroblasts from healthy and β0-thalassemia/HbE individuals

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月15日

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  • Chokdee Wongborisuth,
  • Pawarit Innachai,
  • Chonticha Saisawang,
  • Alisa Tubsuwan,
  • Natee Jearawiriyapaisarn,
  • Pavita Kaewprommal,
  • Jittima Piriyapongsa,
  • Wararat Chiangjong,
  • Usanarat Anurathapan,
  • Duantida Songdej,
  • Amornrat Tangprasittipap,
  • Suradej Hongeng

摘要

CRISPR/Cas9 genome editing has emerged as a promising treatment for genetic diseases like β-thalassemia. Editing γ-globin promoters to disrupt ZBTB7A/LRF or BCL11A binding sites has shown potential for reactivating fetal hemoglobin and treating sickle cell disease. However, its application to β0-thalassemia/HbE disease remains unclear. This study utilized CRISPR/Cas9 to disrupt these sites in mobilized CD34 + hematopoietic stem /progenitor cells from healthy donors and β0-thalassemia/HbE patients. The editing efficiency for the BCL11A site (75–92%) was higher than for the ZBTB7A/LRF site (57–60%). Both disruptions similarly increased fetal hemoglobin production in healthy donors (BCL11A 26.2 ± 1.4%, ZBTB7A/LRF 27.9 ± 1.5%) and β0-thalassemia/HbE cells (BCL11A 62.7 ± 0.9%, ZBTB7A/LRF 64.0 ± 1.6%). Off-target effects were absent in BCL11A-edited cells but observed at low frequencies in ZBTB7A/LRF-edited cells. Neither disruption significantly affected erythroid differentiation. These findings highlight the comparable contributions of ZBTB7A/LRF and BCL11A binding sites to γ-globin reactivation. CRISPR/Cas9 editing of either site may offer a potential therapeutic strategy for β0-thalassemia/HbE disease.