Gene therapy strategies against Diamond-Blackfan anaemia (DBA) have been hampered by the multiple and heterogeneous causative mutations. A study now shows that modulating GATA1 expression is sufficient to tackle the erythroid maturation arrest in DBA models and patient-derived samples.

Voit et al. first identified endogenous regulatory elements (hG1E-GATA1) guiding erythroid-restricted expression of GATA1 in human haematopoietic cells and then showed that hG1E-GATA1 treatment supports erythropoiesis without affecting haematopoietic stem cell function. Subsequently, they demonstrated that hG1E-GATA1 treatment can improve erythroid output in DBA models, as well as in samples from individuals with DBA, including in vivo, as suggested by xenotransplantation assays. Using single-cell transcriptomics, Voit et al. found that hG1E-GATA1 treatment reverses the DBA-characteristic erythroid transcriptional dysregulation. Finally, integration site analysis revealed that the genomic integration profile of hG1E-GATA1 lentiviral vector is comparable to that of other lentiviral gene therapy products, thus supporting the presented approach as a good candidate to test in the clinic.