Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia
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.
Authors
- Vijay G. Sankaran (ORCID: https://orcid.org/0000-0003-0044-443X)
- Henry Y. Lu (ORCID: https://orcid.org/0000-0002-1645-7748)
- Kasiani C. Myers (ORCID: https://orcid.org/0000-0002-5528-4405)
- Lara Wahlster (ORCID: https://orcid.org/0000-0001-8409-7580)
- J.K. Everett (ORCID: https://orcid.org/0000-0002-9200-9322)
- Myriam Armant (ORCID: https://orcid.org/0000-0002-5205-3003)
- Frederic D. Bushman (ORCID: https://orcid.org/0000-0003-4740-4056)
- Craig M. Forester (ORCID: https://orcid.org/0000-0002-1868-5760)
- Meimei Huang (ORCID: https://orcid.org/0000-0002-0570-9989)
- William T. Clarke (ORCID: https://orcid.org/0000-0001-7159-7025)
- David A. Williams (ORCID: https://orcid.org/0000-0002-5052-4895)
- Xiaotian Liao (ORCID: https://orcid.org/0000-0002-9715-270X)
- Mateusz Antoszewski (ORCID: https://orcid.org/0000-0002-7651-0547)
- Blake Cohen
- Akiko Shimamura
- Aoife M. Roche
- Elena Kamal
- Travis Fleming (ORCID: https://orcid.org/0000-0003-0993-4152)
- Danilo Pellin (ORCID: https://orcid.org/0000-0002-2647-0508)
- Richard A. Voit (ORCID: https://orcid.org/0000-0002-6790-8641)
- Alexis Caulier (ORCID: https://orcid.org/0009-0003-1505-7085)
- Antonio R. Pérez‐Atayde (ORCID: https://orcid.org/0000-0001-8036-6288)
- Angelina Petrichenko (ORCID: https://orcid.org/0000-0003-0600-0709)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Children's Hospital Colorado (US)
- Dana-Farber Cancer Institute (US)
- Harvard Stem Cell Institute (US)
- University of Pennsylvania (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1016/j.stem.2024.10.012
- Citations
- 16
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.74
Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Diamond Blackfan Anemia Foundation
- Boettcher Foundation
- Edward P. Evans Foundation
- National Institutes of Health