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Sickle Cell Disease (SCD) is a red blood cell disorder caused by a mutation in the β-globin gene, leading to sickle hemoglobin (HbS) polymerization under low oxygen conditions. CRISPR-Cas9 editing and lentiviral transduction have shown promising clinical outcomes, but it remains unclear which approach is superior. Alternatively, new editing tools such as base editing may also be promising and reduce risks of genotoxicity. To compare these approaches, we studied them in an immunocompromised mouse model. We optimized ex vivo conditions in CD34+ hematopoietic stem and progenitor cells (HSPCs) and infused edited SCD HSPCs into busulfan-conditioned NBSGW mice. Ex vivo analysis confirmed successful editing and transduction. At 16 weeks, bone marrow (BM) analysis showed similar human CD45+ cell engraftment across all groups (75-90%). In the competitive transplantation group, there was a lower amount of BCL11A enhancer editing compared to base editing and lentiviral transduction. A secondary transplantation model yielded similar results. An anti-sickling assay showed significantly higher RBC sickling reduction in the base editing, transduction, and competitive transplantation groups compared to CRISPR-Cas9. In conclusion, while all methods showed therapeutic potential, base editing and lentiviral transduction provided superior outcomes over CRISPR-Cas9-mediated editing in a competitive murine transplantation model.