Paper of the field n°11
Click here to learn more about the novel strategy to select cells for gene therapy!
Abstract for General public
Ex vivo genome editing of hematopoietic stem and progenitor cells (HSPCs) through homology-directed repair (HDR) represents a promising strategy for the treatment of genetic blood disorders such as sickle cell disease (SCD). By correcting the disease-causing mutation, edited cells can restore the production of functional proteins and potentially provide long-term therapeutic benefit. However, achieving sufficiently high levels of precise editing in the primitive cells remains challenging and unintended editing outcomes remain an important concern, that may affect the safety and long-term functionality of edited cells.
In this study, the authors developed a novel strategy called SMArT (“Selection by Means of Artificial Transactivators”), designed as a molecular “quality-control” system to identify and enrich correctly edited cells. The system uses transient reporter elements that become activated only after successful gene correction, allowing selective enrichment of properly edited HSPCs while reducing the presence of unedited or aberrantly edited cells.
To optimize this approach, the researchers designed three progressively more advanced SMArT configurations functioning as transient synthetic AND-gate systems, enabling increasingly accurate selection of correctly edited cells: SMArT-1 established the proof of concept for transient identification of corrected cells; SMArT-2 and SMArT-3 further improved selection specificity, enrichment efficiency, and preservation of long-term stem cell properties.
In laboratory experiments, SMArT-2 achieved approximately 30% overall functional correction, with around 20% of the most primitive hematopoietic stem cells carrying the desired HDR-mediated edit. Importantly, the editing and selection workflow preserved HSPCs viability and stem cell properties, while showing limited evidence of genotoxicity. The approach was further validated in humanized mouse models, where edited HSPCs successfully engrafted and repopulated the bone marrow with a high proportion of correctly edited cells displaying long-term repopulating capacity. Notably, the optimized SMArT-3 configuration, combined with improved culture conditions, enabled the generation of highly enriched grafts reaching up to 80% HDR-edited cells, while maintaining stem cell fitness and lowering the genotoxic burden associated with genome editing
Overall, this work represents an important step toward safer and more efficient genome-editing therapies for inherited blood disorders, potentially facilitating the clinical translation of HSPC-based gene editing approaches
Abstract written by Giulia Scalisi from Institut national de la santé et de la recherche médicale (France)
Canarutto, Daniele, et al. « Selection of Human Hematopoietic Stem Cells Bearing the Intended Functional Edit by Transient AND-Gate Reporters ». Nature Biotechnology, juin 2026, p. 1‑14. www.nature.com, https://doi.org/10.1038/s41587-026-03142-z.
