Molecular Therapy: Methods & Clinical Development (Sep 2018)

Disruption of the BCL11A Erythroid Enhancer Reactivates Fetal Hemoglobin in Erythroid Cells of Patients with β-Thalassemia Major

  • Nikoletta Psatha,
  • Andreas Reik,
  • Susan Phelps,
  • Yuanyue Zhou,
  • Demetri Dalas,
  • Evangelia Yannaki,
  • Dana N. Levasseur,
  • Fyodor D. Urnov,
  • Michael C. Holmes,
  • Thalia Papayannopoulou

Journal volume & issue
Vol. 10
pp. 313 – 326

Abstract

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In the present report, we carried out clinical-scale editing in adult mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs) using zinc-finger nuclease-mediated disruption of BCL11a to upregulate the expression of γ-globin (fetal hemoglobin). In these cells, disruption of the erythroid-specific enhancer of the BCL11A gene increased endogenous γ-globin expression to levels that reached or exceeded those observed following knockout of the BCL11A coding region without negatively affecting survival or in vivo long-term proliferation of edited HSPCs and other lineages. In addition, BCL11A enhancer modification in mobilized CD34+ cells from patients with β-thalassemia major resulted in a readily detectable γ-globin increase with a preferential increase in G-gamma, leading to an improved phenotype and, likely, a survival advantage for maturing erythroid cells after editing. Furthermore, we documented that both normal and β-thalassemia HSPCs not only can be efficiently expanded ex vivo after editing but can also be successfully edited post-expansion, resulting in enhanced early in vivo engraftment compared with unexpanded cells. Overall, this work highlights a novel and effective treatment strategy for correcting the β-thalassemia phenotype by genome editing. Keywords: hemoglobinopathies, BCL11a, genome editing, thalassemia, HbF reactivation, zinc finger nucleases