Regulated GATA1 expression as a gene therapy cure for DBA

Despite the genetic heterogeneity of DBA, erythroid progenitors in all DBA patients undergo maturation arrest due to ribosomal dysfunction, which converges on impaired translation of the erythroid master regulator GATA1. This observation provides a potential avenue for a unified gene therapy approach that would be applicable to all DBA patients, irrespective of the underlying genotype. Previous work revealed a rescue of erythroid differentiation arrest in DBA patient samples by constitutive overexpression of GATA1, but unregulated expression of GATA1 in hematopoietic stem cells (HSC) leads to forced erythroid differentiation at the expense of HSC maintenance. To overcome this limitation, we dissected the endogenous regulatory elements governing GATA1 expression in erythroid cells to engineer the human GATA1 enhancer (hG1E) element which leads to developmentally faithful, erythroid-lineage restricted expression of transgenes. We synthesized a clinical-grade lentiviral hG1E-GATA1 vector that augments erythroid output in primary DBA patient samples of varied genotypes without impacting HSC function (Voit et al, manuscript submitted, 2024). We are currently pursuing regulatory approval to initiate the first-in-human universal gene therapy trial for DBA.

Selected Publications

Regulated GATA1 expression as a gene therapy for Diamond-Blackfan anemia
Voit RA., Liao X, Caulier A, Cohen B, Armant M, Antoszewski M, Lu HY, Fleming TJ, Kamal E, Wahlster L, Roche AM, Everett JK, Petrichenko A, Huang M, Clarke W, Myers KC, Forester C, Perez-Atayde A, Bushman FD, Pellin D, Shimamura A, William DA, Sankaran VG. (2024) Cell Stem Cell DOI: 10.1016/j.stem.2024.10.012. [DOI]

Gene therapy for congenital marrow failure syndromes – no longer grasping at straws?
Voit RA., Corey SJ. (2023) Haematologica [DOI]