Therapeutic adenine base editing of human hematopoietic stem cells

Jiaoyang Liao, Shuanghong Chen (), Shenlin Hsiao, Yanhong Jiang, Yang Yang, Yuanjin Zhang, Xin Wang, Yongrong Lai, Daniel E. Bauer and Yuxuan Wu ()
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Jiaoyang Liao: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Shuanghong Chen: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Shenlin Hsiao: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Yanhong Jiang: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Yang Yang: The First Affiliated Hospital of Guangxi Medical University
Yuanjin Zhang: East China Normal University
Xin Wang: East China Normal University
Yongrong Lai: The First Affiliated Hospital of Guangxi Medical University
Daniel E. Bauer: Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School
Yuxuan Wu: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract In β-thalassemia, either γ-globin induction to form fetal hemoglobin (α2γ2) or β-globin repair to restore adult hemoglobin (α2β2) could be therapeutic. ABE8e, a recently evolved adenine base editor variant, can achieve efficient adenine conversion, yet its application in patient-derived hematopoietic stem cells needs further exploration. Here, we purified ABE8e for ribonucleoprotein electroporation of β-thalassemia patient CD34+ hematopoietic stem and progenitor cells to introduce nucleotide substitutions that upregulate γ-globin expression in the BCL11A enhancer or in the HBG promoter. We observed highly efficient on-target adenine base edits at these two regulatory regions, resulting in robust γ-globin induction. Moreover, we developed ABE8e-SpRY, a near-PAMless ABE variant, and successfully applied ABE8e-SpRY RNP to directly correct HbE and IVS II-654 mutations in patient-derived CD34+ HSPCs. Finally, durable therapeutic editing was produced in self-renewing repopulating human HSCs as assayed in primary and secondary recipients. Together, these results support the potential of ABE-mediated base editing in HSCs to treat inherited monogenic blood disorders.

Date: 2023
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DOI: 10.1038/s41467-022-35508-7

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