Science1 publisher2 min readPublished
Boston Children's and Broad find a fetal-hemoglobin switch independent of Casgevy's target
Vijay Sankaran's team pooled genetic data from more than 28,000 people and found a BACH2-NRF2 axis that switches on fetal hemoglobin without going through BCL11A. Blocking it in cells raised fetal hemoglobin, pointing drug programs at a target beyond Casgevy's gene edit.
The Scientist · Science desk
What happened
- The genome-wide scan pulled together 91 genetic associations across 12 regions of the genome tied to fetal-hemoglobin levels.
- The team traced the new lead to a single variant, rs1010474-C, that lowers BACH2 in the erythroid progenitor cells where hemoglobin is made.
- BACH2 was already known as a transcription regulator, though its role in fetal-hemoglobin control had gone unrecognised until now.
- Casgevy, the gene-editing cell therapy from Vertex and CRISPR Therapeutics, won approval in December 2023 as clinical proof that hitting BCL11A works.
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Why it matters
- capability Because a small molecule already raises fetal hemoglobin in cells, the axis points toward a drug, a different route to patients than a one-time gene edit.
- constraint Every effect here is in cultured red-cell progenitors, so the study does not show a dose, an animal result, or how much fetal hemoglobin a patient would gain.
- precedent Because hitting BACH2 and BCL11A together raised gamma-globin more than either alone, combination therapies move onto the table alongside single-target ones.
Fetal hemoglobin normally falls away in the first 6 to 12 months of life, replaced by the adult form [15]. For decades, raising it again has been the therapeutic idea behind treatments for sickle cell disease and thalassemia [19]. In the Nature paper, Sankaran's group traces a way to do that to a BACH2-NRF2 axis that works without BCL11A [1][2]. Blocking BACH2 three ways, by short hairpin RNA knockdown, a base edit, and a small-molecule inhibitor, raised gamma-globin transcription and the fraction of red cells carrying fetal hemoglobin, with no disruption to normal red-cell production [8]. The paper calls the rise marked and robust. It does not put a number on it, and every result is in cultured erythroid progenitor cells [8].
BACH2 sits at the gamma-globin promoter and locus control region as a repressor that keeps the activator NRF2 off the chromatin [9]. Remove BACH2 and NRF2 spreads across the region, forming nuclear foci at active sites of gamma-globin transcription [9]. The two proteins also bind each other directly, and that contact mutes NRF2 [10]. Single-base edits in the promoter raised fetal hemoglobin by loosening BACH2 and tightening NRF2 [17].
In that promoter the BACH2 and NRF2 motifs overlap, and the site sits between two BCL11A binding sites [18]. Even so, the team found no physical contact between BCL11A and either protein, and the axis works independently of BCL11A, the target Casgevy edits [11].
The genetic signal that pointed here was among the strongest in the scan, though weaker than the BCL11A signal that teams led by Swee-Lay Thein and by Sankaran and Stuart Orkin found almost 20 years ago [5][14]. The authors write that the findings "establish the BACH2-NRF2 axis as a tractable and potentially therapeutically targetable regulatory node involved in HbF activation" [16].
What to watch
- Whether a BACH2 small-molecule inhibitor moves from cultured cells into animal studies and holds up on safety.
- Whether anyone tests the additive BACH2-plus-BCL11A combination beyond cell culture.
- Whether the cell-level HbF gains reach the levels that ease sickle cell or thalassemia in patients.