Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia

Richard A Voit; Xiaotian Liao; Alexis Caulier; Mateusz Antoszewski; Blake Cohen; Myriam Armant; Henry Y Lu; Travis J Fleming; Elena Kamal; Lara Wahlster; Aoife M Roche; John K Everett; Angelina Petrichenko; Mei-Mei Huang; William Clarke; Kasiani C Myers; Craig Forester; Antonio Perez-Atayde; Frederic D Bushman; Danilo Pellin; Akiko Shimamura; David A Williams; Vijay G Sankaran

doi:10.1016/j.stem.2024.10.012

Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia

Cell Stem Cell. 2024 Nov 8:S1934-5909(24)00374-6. doi: 10.1016/j.stem.2024.10.012. Online ahead of print.

Authors

Richard A Voit¹, Xiaotian Liao², Alexis Caulier², Mateusz Antoszewski², Blake Cohen², Myriam Armant³, Henry Y Lu², Travis J Fleming², Elena Kamal², Lara Wahlster², Aoife M Roche⁴, John K Everett⁴, Angelina Petrichenko⁴, Mei-Mei Huang³, William Clarke³, Kasiani C Myers⁵, Craig Forester⁶, Antonio Perez-Atayde³, Frederic D Bushman⁴, Danilo Pellin⁷, Akiko Shimamura⁷, David A Williams⁷, Vijay G Sankaran⁸

Affiliations

¹ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].
² Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁵ Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁶ Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁸ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].

PMID: 39532107
DOI: 10.1016/j.stem.2024.10.012

Abstract

Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1. We show that this vector is capable of augmenting erythropoiesis in DBA models and diverse patient samples without impacting hematopoietic stem cell function or demonstrating any signs of premalignant clonal expansion. These preclinical safety and efficacy data provide strong support for the first-in-human universal gene therapy trial for DBA through regulated GATA1 expression.

Keywords: Diamond-Blackfan anemia; GATA1; bone marrow failure; enhancer; erythropoiesis; gene therapy; hematopoiesis; hematopoietic stem cell; hypoplastic anemia; lentivirus.