Plate Nº 55 · recorded September 30, 2026
Health & Medicine ResearchReported finding
New BACH2 Pathway Could Expand Hemoglobin Disorder Treatments
A Harvard-led team has found that the BACH2 gene acts as a brake on fetal hemoglobin, revealing a potential new route to treat sickle cell disease and beta thalassemia.
By Priya Raman3 min read694 words
In brief
- Researchers identified a BACH2–NRF2 pathway that regulates fetal hemoglobin independently of BCL11A, the target of two FDA-approved gene therapies.
- The study analyzed fetal hemoglobin levels and genes in more than 28,000 people of European, African and Asian ancestries.
- In lab experiments, inhibiting BACH2 raised fetal hemoglobin in human blood stem cells, while overexpressing it reduced levels.
Researchers at Harvard Medical School, working at Boston Children's Hospital and Dana-Farber Cancer Institute, have identified a previously unknown biological pathway that controls the production of fetal hemoglobin — a form of the oxygen-carrying protein that the body normally stops making shortly after birth.
The discovery, published Sept. 30 in Nature, centers on a gene called BACH2. It opens a potential second route to treating sickle cell disease and beta thalassemia, two inherited blood disorders caused by mutations in adult hemoglobin. These conditions can cause severe pain, organ damage and premature death.
Why fetal hemoglobin matters
Hemoglobin is the protein in red blood cells that carries oxygen. Before birth, fetuses use a form called fetal hemoglobin; soon after birth, the body switches to adult hemoglobin. In people with sickle cell disease or beta thalassemia, the adult version is defective.
Two gene therapies already approved by the U.S. Food and Drug Administration treat these diseases by switching fetal hemoglobin production back on. Both work by silencing a gene called BCL11A, one of the few genes known to control the fetal-to-adult switch. The newly discovered pathway acts independently of BCL11A — meaning it could offer an alternative target, or a way to boost the effect of existing therapies.
"Nearly 20 years ago, human genetics pointed us to BCL11A and ultimately helped open a path to gene therapies," said senior author Vijay Sankaran, the HMS Jan Ellen Paradise, MD Professor of Pediatrics at Boston Children's and a physician-scientist at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "The same approach is still revealing entirely new ways to turn fetal hemoglobin back on."
Sankaran, along with mentor Stuart Orkin (the HMS David G. Nathan Distinguished Professor of Pediatrics), colleague Daniel Bauer (the HMS Donald S. Fredrickson, MD Associate Professor of Pediatrics) and others, helped reveal BCL11A's role in sickle cell disease and contributed discoveries that enabled the development of the current gene therapies.
A genome-wide search
For the new study, an international research team conducted a genome-wide association study — a method that scans the DNA of large groups to link genetic variations with specific traits. They analyzed fetal hemoglobin levels and related genes in more than 28,000 people of European, African and Asian ancestries.
The analysis pointed to BACH2, a gene previously associated with autoimmune and allergic diseases but never before linked to hemoglobin production. The researchers found that BACH2 acts as a brake on fetal hemoglobin. When BACH2's activity drops, a protein called NRF2 — a transcription factor, which turns genes on — can activate fetal hemoglobin genes.
In laboratory experiments with blood stem cells isolated from bone marrow, the team confirmed the relationship works both ways: inhibiting BACH2 raised fetal hemoglobin levels, while overexpressing BACH2 reduced them.
"We show proof-of-principle that pharmacologic inhibition of BACH2 can increase fetal hemoglobin in human blood cells," said Sankaran, who is also an associate member of the Broad Institute of MIT and Harvard and an investigator at the Howard Hughes Medical Institute. "Because this pathway works independently of BCL11A, it provides another potential route for therapeutic development."
What comes next
Because the BACH2–NRF2 pathway and BCL11A operate independently of each other, targeting both at once might produce more fetal hemoglobin than either approach alone and give patients additional benefit, the authors suggest.
That possibility remains preliminary, and the researchers stress that much work lies ahead. The first step is to determine whether BACH2 can be targeted safely and effectively in people — the current results come from population genetics and lab-grown cells, not clinical trials. BACH2 also plays roles in the immune system, so a drug aimed at it would need careful safety testing.
The team also hopes the genetic insights from this study will help map other regulators of the fetal-to-adult hemoglobin switch, potentially uncovering further therapeutic targets for sickle cell disease, beta thalassemia and related disorders.
"There is much more biology to learn," Sankaran said.
Publication: Chun-Jie Guo et al., "Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation," Nature (2026). DOI: 10.1038/s41586-026-11113-2
via Medical Xpress (Source)
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Senior reporter covering industry trends and analytics at SciBeat.
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