Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins

Giulia Pavani, Marine Laurent, Anna Fabiano, Erika Cantelli, Aboud Sakkal, Guillaume Corre, Peter J. Lenting, Jean-Paul Concordet, Magali Toueille, Annarita Miccio and Mario Amendola ()
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Giulia Pavani: Genethon
Marine Laurent: Genethon
Anna Fabiano: Genethon
Erika Cantelli: Genethon
Aboud Sakkal: Genethon
Guillaume Corre: Genethon
Peter J. Lenting: UMR_S1176, Inserm, Univ. Paris-Sud, Université Paris-Saclay
Jean-Paul Concordet: UMR_1154 Inserm, UMR_7196 CNRS, Univ Sorbonne
Magali Toueille: Genethon
Annarita Miccio: INSERM UMR 1163
Mario Amendola: Genethon

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Targeted genome editing has a great therapeutic potential to treat disorders that require protein replacement therapy. To develop a platform independent of specific patient mutations, therapeutic transgenes can be inserted in a safe and highly transcribed locus to maximize protein expression. Here, we describe an ex vivo editing approach to achieve efficient gene targeting in human hematopoietic stem/progenitor cells (HSPCs) and robust expression of clinically relevant proteins by the erythroid lineage. Using CRISPR-Cas9, we integrate different transgenes under the transcriptional control of the endogenous α-globin promoter, recapitulating its high and erythroid-specific expression. Erythroblasts derived from targeted HSPCs secrete different therapeutic proteins, which retain enzymatic activity and cross-correct patients’ cells. Moreover, modified HSPCs maintain long-term repopulation and multilineage differentiation potential in transplanted mice. Overall, we establish a safe and versatile CRISPR-Cas9-based HSPC platform for different therapeutic applications, including hemophilia and inherited metabolic disorders.

Date: 2020
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DOI: 10.1038/s41467-020-17552-3

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