BIOBRIEF
A 28,000 person Nature study maps a second, independent route for reactivating fetal hemoglobin, the oxygen carrying protein babies make in the womb, beyond Casgevy's gene editing approach.
Sickle cell disease and beta-thalassemia are inherited blood disorders caused by problems with adult hemoglobin. One leading strategy is to reactivate fetal hemoglobin (HbF), the oxygen-carrying protein that babies make in the womb and normally stop producing after infancy. A Nature meta-analysis of 28,279 people across 11 cohorts now points to a second, independent genetic switch for that reactivation, separate from the route used by Casgevy, the first approved gene-editing therapy for both diseases.
Casgevy works by dialing down BCL11A, a gene that represses HbF. The new paper identifies BACH2 as a separate brake on the same program: BACH2 restrains NRF2, a transcription factor that would otherwise turn γ-globin genes back on. Disrupting BACH2 in cells raised γ-globin transcription and HbF-containing cells, and combining it with BCL11A depletion produced additive increases, evidence that the two switches act in parallel.
The study reports 91 conditionally independent association signals across 12 genomic windows in European, African and Thai participants and describes the BACH2-NRF2 axis as "potentially therapeutically targetable," not a validated drug target. The cohort is numerically dominated by European participants, and the authors note that strong enrichment for high HbF in the Thai group can bias heritability estimates. Vijayakrishna Sankaran of Boston Children's and the Broad Institute told GEN that molecules now in development might be redirected at BACH2, but the path from a statistical signal to a working small-molecule drug typically takes years and often fails. The BACH2 signal is also weaker than the BCL11A hit that anchored the field two decades ago, so even a confirmed target would compete with an editing approach already in the clinic.