Combinatorial base editing couples disease correction with lineage amplification in hematopoietic stem and progenitor cells

The introduction of a naturally occurring erythropoietin receptor truncation increased erythroid cell production without impairing viability.

• Genome-corrected hematopoietic stem and progenitor cells (HSPCs) gain little advantage in bone marrow due to late activation of globin genes.
• A multiplex base editing strategy was developed to link therapeutic genome edits to a fitness-enhancing allele, promoting erythroid lineage expansion.
• The combination of erythroid enhancer and promoters in HSPCs increased erythroid proliferation and fetal hemoglobin expression more than single editing methods.
• Multiplex base-edited HSPCs demonstrated long-term lineage repopulation and engraftment capacity.
• This approach may enhance therapeutic potency by pairing disease correction with lineage amplification.

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