Gene therapy for blood disorders such as sickle cell disease and beta thalassemia switch on fetal hemoglobin and replace faulty adult hemoglobin by regulating levels of BCL11A, which was identified by Dana-Farber research two decades ago. In this new research, Dana-Farber investigators – including Vijay Sankaran, MD, PhD, who was involved in the discovery of the role BCL11A in blood disorders – have identified a new pathway that regulates fetal hemoglobin.
That pathway involves BACH2 and NRF2 and was discovered using a large genome-wide association study that enabled an analysis of genes related to fetal hemoglobin from a wide range of ancestries, including European, African, and Asian ancestries. According to the study, BACH2 normally acts as a brake on fetal hemoglobin production. Reducing BACH2 enables NRF2 to activate fetal hemoglobin genes. The study also found that pharmacological inhibition of BACH2 increases fetal hemoglobin in human red blood cell precursors.
Significance
The BACH2-NRF2 pathway may provide a foundation for future gene-editing or drug-based treatments for blood disorders such as sickle cell disease and beta thalassemia. The additional genetic insights gained through this study could also deepen understanding of the regulators involved in this process, helping to identify new therapeutic opportunities. The team plans further research to determine whether this pathway can be targeted safely and effectively. In addition, because BACH2-NRF2 and BCL11A act through independent pathways, the researchers aim to investigate whether targeting both simultaneously could offer added benefit to patients. The study also highlights the value of large international collaborations, bringing together researchers from countries including Tanzania, Thailand, Sweden, the United Kingdom, the Netherlands, Brazil, and Italy.
Nearly 20 years ago, human genetics pointed us to BCL11A and ultimately helped open a path to gene therapies such as Casgevy, What is exciting about this study is that the same approach is still revealing entirely new ways to turn fetal hemoglobin back on.”
Vijay Sankaran, MD, PhD, Physician-Scientist, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Dana-Farber Cancer Institute
Funding
Howard Hughes Medical Institute, New York Stem Cell Foundation, National Institutes of Health, Gates Foundation, Edward P. Evans Foundation, Alex’s Lemonade Stand Foundation, Blood Cancer United, and the Leona and Harry Helmsley Charitable Trust.
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