Researchers identified a biological pathway that could help produce healthy red blood cells in patients with inherited blood disorders like sickle cell disease.
RT’s Three Key Takeaways:
- New Biological Pathway: Researchers identified a genetic pathway involving BACH2 and NRF2 that controls the activation of fetal hemoglobin in red blood cells.
- Dual-Target Strategy: Because this pathway operates independently from BCL11A, targeting both mechanisms simultaneously could provide added clinical benefits for patients with blood disorders.
- Potential Drug Foundation: Laboratory inhibition of the BACH2 protein increased fetal hemoglobin in human cell precursors, establishing a potential basis for future gene-editing or medication-based therapies.
Investigators at Dana-Farber Cancer Institute have identified a biological pathway that regulates fetal hemoglobin, revealing a possible new target for the treatment of sickle cell disease and beta thalassemia, according to a study published in Nature.
The mechanism involves two proteins, BACH2 and NRF2, which were discovered using a large genome-wide association study that evaluated genes linked to fetal hemoglobin across diverse ancestries, including European, African, and Asian populations, the researchers reported. Under normal conditions, BACH2 functions as a brake on fetal hemoglobin production, but reducing BACH2 allows NRF2 to activate fetal hemoglobin genes, according to study findings.
Potential for Drug Development and Gene Editing
In experimental models, pharmacological inhibition of BACH2 led to an increase in fetal hemoglobin levels within human red blood cell precursors, according to the study. The authors noted that this mechanism may offer a foundation for future gene-editing strategies or drug-based therapies designed to replace faulty adult hemoglobin with functional fetal hemoglobin.
“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,” said Vijay Sankaran, MD, PhD, a physician-scientist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, in a news release.
Independent Pathways and Global Collaboration
Current gene therapies for sickle cell disease and beta thalassemia work by switching on fetal hemoglobin through the regulation of BCL11A, a target discovered by Dana-Farber investigators two decades ago. Because the BACH2-NRF2 axis acts via a separate biological pathway from BCL11A, the researchers stated that they plan to evaluate whether targeting both pathways at the same time could provide additional therapeutic benefit to patients.
The research team indicated plans to conduct further studies to determine whether the pathway can be targeted safely and effectively, according to the announcement. The study was supported by an international collaboration involving researchers from Brazil, Italy, the Netherlands, Sweden, Tanzania, Thailand, and the United Kingdom.
