Understanding and overcoming adverse consequences of genome editing on hematopoietic stem and progenitor cells

Hematopoietic stem and progenitor cell (HSPC) gene therapies have recently moved beyond gene-addition approaches to encompass targeted genome modification or correction, based on the development of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPRCas technologies. Advances in ex vivo HSPC manipulation techniques have greatly improved HSPC susceptibility to genetic modification. Targeted gene-editing techniques enable precise modifications at desired genomic sites. Numerous preclinical studies have already demonstrated the therapeutic potential of gene therapies based on targeted editing. However, several significant hurdles related to adverse consequences of gene editing on HSPC function and genomic integrity remain before broad clinical potential can be realized. This review summarizes the status of HSPC gene editing, focusing on efficiency, genomic integrity, and long-term engraftment ability related to available genetic editing platforms and HSPC delivery methods. The response of long-term engrafting HSPCs to nuclease-mediated DNA breaks, with activation of p53, isa significant challenge, as are activation of innate and adaptive immune responses to editing components. Lastly, we propose alternative strategies that can overcome current hurdles to HSPC editing at various stages from cell collection to transplantation to facilitate successful clinical applications.

Automated summary

Hematopoietic stem and progenitor cell (HSPC) gene therapies have advanced to include targeted genome modification techniques such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPRCas technologies. While promising, challenges related to adverse effects on HSPC function and genomic integrity remain. Targeted gene editing platforms have shown potential for therapeutic applications, but further research is needed to address these obstacles before widespread clinical use.