Paper of the field n°9
Click here to learn more about safety and efficacy of gene therapy approaches for sickle cell disease!
Abstract for General public
Allogeneic bone marrow (BM) transplantation represents the definitive cure for sickle cell disease (SCD), but limitations in finding suitable donors lead researchers to develop gene therapy (GT) approaches by correcting the genetic defect in the patient’s own cells. In a new study, researchers compared three promising GT approaches, using a humanized mouse model that supports the circulation of human blood cells upon transplantation in mice, to understand which might work best and be safest. Two of these approaches are already US Food and Drug Administration (FDA) approved for use in patients: lovo-cel (Lyfgenia), which adds a healthy haemoglobin gene using lentiviral (LV) based therapy (BB305-LV) and exa-cel (Casgevy), a gene editing therapy exploiting CRISPR-Cas9 technology to reactivate endogenous fetal haemoglobin (HbF) expression. The third approach is a preclinical base editing (BE) strategy converting sickle β-globin to a naturally occurring variant without sickling properties (Makassar β-globin). Here, the research helps clarify which approaches best balance effectiveness and safety. All three approaches showed comparable effectiveness, preserving normal blood stem and progenitor cell characteristics and correcting the sickle cell phenotype. However, CRISPR-Cas9 approach exhibited higher toxicity than those treated with the other methods. Moreover, when transplanted in vivo in humanized mouse model, manipulated cells with all the approaches showed a good engraftment of human blood cells in mouse BM at 16 weeks. Notably, BE and BB305-LV approaches resulted in a higher proportion of myeloid cells compared to CRISPR-Cas9 editing, suggesting a potential lineage bias or preferential expansion. Interestingly, when the different GT-treated cells had to compete with each other to rebuild the blood system when transplanted in the same mouse, BE and LV-based approaches performed better than the CRISPR-Cas9 method, also reducing red blood cell sickling more effectively. Overall, the results show that while all three GT strategies have the potential to treat SCD, BE and LV-based GT may provide better results than CRISPR-Cas9 gene editing in this experimental setting. These findings may help guide future choices for safer and more effective treatments for people with SCD.
Abstract written by Giulia Chianelli from Ospedale San Raffaele (Italy)
Butt H, Sathish S, London E, Le A, Li Q, Gudmundsdottir B, Lee DY, Burke EV, Yates BP, Liu DR, Hsieh M, Leonard A, Eaton WA, Uchida N, Pierciey FJ Jr, Newby GA, Tisdale JF, Demirci S. Comparative analysis of CRISPR-Cas9, lentiviral transduction, and base editing for sickle cell disease in a murine model. Blood Adv. 2026 Jan 27;10(2):289-300. doi: 10.1182/bloodadvances.2025017321. PMID: 41150843.
