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Updated: Aug 6, 2026
CRISPR/Cas9 Gene Editing of Hematopoietic Stem and Progenitor Cells for Gene Therapy Applications
Published on: August 9, 2022
Editing around the target: epitope engineering to protect stem cell grafts
Joanne Baek1,2, Gabriele Casirati3,4,5, Pietro Genovese3,4,5
1Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Abstract:
Targeted immunotherapies have transformed the treatment of hematologic malignancies, yet their clinical utility is often constrained by on-target, off-tumor toxicity arising from shared antigen expression between malignant cells and essential healthy tissues. An early approach to mitigate this limitation involved the knockout of the target antigen in donor hematopoietic stem and progenitor cells. However, this strategy is restricted to markers that are dispensable for normal hematopoietic function. Epitope engineering has emerged as an alternative paradigm to decouple therapeutic susceptibility from physiological function by modifying the target antigen on healthy cells while preserving biological activity. In this review, we discuss recent advances in base and prime editing approaches used for epitope editing. We examine recent preclinical and emerging translational studies of this strategy in both malignant and nonmalignant contexts. Finally, we discuss challenges related to editing efficiency, off-target effects, delivery strategies, and long-term safety in hematopoietic stem cells. Collectively, epitope engineering of hematopoietic stem cells represents a versatile platform to expand the therapeutic window of precision immunotherapies and may enable safer, more effective combinatorial treatment strategies for both nonmalignant and malignant hematologic conditions.
Insights
Epitope engineering modifies target antigens on healthy cells, enhancing precision immunotherapies for blood cancers. This approach aims to reduce side effects by preserving normal cell function while targeting malignant cells.
Area of Science:
- Hematology
- Immunotherapy
- Gene Editing
Background:
- Targeted immunotherapies show promise for hematologic malignancies but face challenges with on-target, off-tumor toxicity due to shared antigen expression.
- Previous strategies like antigen knockout in hematopoietic stem and progenitor cells (HSPCs) were limited to dispensable markers.
Purpose of the Study:
- To review advances in epitope engineering for hematopoietic stem cells (HSCs) using base and prime editing.
- To explore preclinical and translational studies of epitope editing in hematologic conditions.
- To discuss challenges and future directions for safe and effective HSC epitope editing.
Main Methods:
- Review of recent literature on base and prime editing techniques for epitope modification in HSCs.
- Analysis of preclinical and translational studies investigating epitope engineering in hematologic contexts.
- Discussion of challenges including editing efficiency, off-target effects, delivery, and long-term safety.
Main Results:
- Epitope engineering offers a way to modify target antigens on healthy cells, decoupling therapeutic susceptibility from physiological function.
- Base and prime editing are key technologies enabling precise antigen modification in HSCs.
- Emerging studies show potential for epitope engineering in both malignant and non-malignant hematologic conditions.
Conclusions:
- Epitope engineering of HSCs expands the therapeutic window for precision immunotherapies.
- This versatile platform may enable safer, more effective combinatorial treatments for hematologic disorders.
- Addressing challenges in editing efficiency, delivery, and safety is crucial for clinical translation.
