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“Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins”
Mario Amendola
Research scientist INSERM, Leader of the team ” genome editing’ group, UMR_S951, Evry, FR.
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. Therefore, we developed 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 integrated 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. Finally, additional optimization of therapeutic transgene, CRISPR-Cas9 tools and donor DNA delivery further improve efficiency and safety of the approach.
Overall, we establish a safe and versatile CRISPR-Cas9-based HSPC platform for different therapeutic applications, including hemophilia and inherited metabolic disorders.
You can find more information on Mario Amendola on his Biosketech.
