NatureJul 8, 2026

Safe cell transplantation and selection inside the body using targeted surface marker changes

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 9, 2026

Abstract

Amino acid changes in the extracellular domain of KIT may disrupt the binding of therapeutic monoclonal antibodies.

This disruption potentially allows for the preservation of transplanted hematopoietic stem/progenitor cells (HSPCs).
Introducing these mutations in HSPCs, combined with the disruption of the BCL11A erythroid enhancer, may enhance the expression of fetal hemoglobin (HbF).
The approach supports the in vivo co-selection of gene-engineered cells, which could meet therapeutic thresholds for sickle cell disease and β-thalassemia.
Progressive enrichment of multiplex-edited HSPCs occurs under selective pressure from KIT monoclonal antibodies both in vitro and in vivo.
Extended treatment with anti-KIT regimens may improve in vivo enrichment while avoiding clonal selection.
Epitope editing appears to overcome limitations of monoclonal antibody pharmacokinetics, enabling new hematopoietic replacement strategies without the need for chemotherapy or radiotherapy.

Simplified

The short-term and long-term effects of genotoxic pre-transplant conditioning remain barriers to the broader application of haematopoietic stem/progenitor cell (HSPC) transplantation and gene therapies^1-4. Although monoclonal antibodies targeting KIT have been proposed as alternatives to chemotherapy or radiotherapy^5-7, their pharmacokinetics hinder clinical applications owing to the risk of depleting transplanted HSPCs. Here, to address this issue, we identified amino acid changes in the extracellular domain of KIT that disrupt the binding of two therapeutic monoclonal antibodies^8,9, which impair stem cell factor (SCF)-mediated signalling without affecting KIT expression or functionality. We exploited adenine base editing¹⁰ or prime editing¹¹ to efficiently introduce these mutations in HSPCs and combined them with the disruption of the BCL11A erythroid enhancer to promote expression of fetal haemoglobin (HbF)^12,13, a therapeutic approach for several haemoglobinopathies. This strategy enables in vivo co-selection of gene-engineered cells to reach the threshold required to provide therapeutic benefit in patients affected by sickle cell disease and β-thalassaemia. We show progressive enrichment of KIT plus BCL11A multiplex-edited haematopoiesis under selective pressure with KIT monoclonal antibody, in vitro and in vivo. We report that extended treatment with anti-KIT regimens leads to superior in vivo enrichment while avoiding clonal selection, as assessed by a lentiviral barcoded library. Finally, by overcoming the limitations of monoclonal antibody pharmacokinetics, epitope editing enables novel haematopoietic replacement regimens that are not limited by on-target graft elimination, allowing prolonged immune-based conditioning that maximizes haematopoietic niche clearance without chemo-radiotherapy or monoclonal antibody wash-out.

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Safe cell transplantation and selection inside the body using targeted surface marker changes

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