Blocking key protein opens potential new path for SCD treatment
Study says findings could build on established approach
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Blocking the activity of a protein called BACH2 may be a valuable strategy for treating sickle cell disease (SCD) and related blood disorders, a study shows.
Researchers found that suppressing BACH2 could increase the production of fetal hemoglobin (HbF). Increasing HbF levels is an established approach for SCD treatment, and this discovery opens new molecular avenues to achieve that effect.
The study, “Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation,” was published in Nature. The work was funded by the National Institutes of Health alongside a range of academic and charitable groups, including Alex’s Lemonade Stand Foundation and Blood Cancer United.
Multiple approved SCD treatments work by increasing HbF levels
SCD is a genetic disorder caused by mutations that lead to the production of an abnormal version of hemoglobin, the protein that red blood cells use to ferry oxygen through the bloodstream. The abnormal hemoglobin clumps up in blood cells, which deforms the cells so they’re prone to being destroyed or getting stuck in blood vessels. This ultimately drives SCD symptoms.
The disease specifically affects the adult version of hemoglobin. HbF is an alternative form of the molecule that is normally produced only during development in the womb. In most people, the body switches from HbF to adult hemoglobin shortly after birth — this helps infants adjust to taking oxygen in through their lungs, rather than absorbing it from their mother’s bloodstream.
It’s well-established that boosting HbF levels can help to mitigate the disease-driving effects of mutant hemoglobin. In fact, multiple approved SCD treatments work by increasing HbF levels.
Treatments to boost HbF production are also approved for beta-thalassemia, another blood disorder marked by problems with hemoglobin. Available HbF-modulating treatments specifically work by targeting a gene called BCL11A, which is known to help regulate when HbF production is switched on or off.
“Nearly 20 years ago, human genetics pointed us to BCL11A and ultimately helped open a path to gene therapies,” Vijay Sankaran, MD, PhD, the study’s senior author at Harvard Medical School, said in a university news story. “The same approach is still revealing entirely new ways to turn fetal hemoglobin back on.”
Suppressing BACH2 production increased fetal hemoglobin levels
In this study, Sankaran and colleagues wanted to more fully understand the molecular mechanisms that control HbF activation. To do that, they analyzed genetic data from more than 28,000 people of various ethnic backgrounds. Essentially, the researchers were looking for genetic variations that were associated with significant differences in HbF activation.
Previous studies have used similar approaches, but generally with smaller numbers of participants and less diverse backgrounds. Including more patients and more diversity increases the statistical power of this type of analysis to identify meaningful associations, the researchers noted.
“Our study provides an example of how increasingly larger [genetic studies] can enable further insights into even seemingly well-understood and therapeutically important human [traits] like HbF,” the scientists wrote.
Results indicated that HbF levels are altered in people who carry certain mutations in the gene that encodes the BACH2 protein. Further tests in lab-grown human cells showed that increasing BACH2 levels reduced HbF production — and, conversely, suppressing BACH2 production increased HbF levels.
Our study provides an example of how increasingly larger [genetic studies] can enable further insights into even seemingly well-understood and therapeutically important human [traits] like HbF.
Additional experiments showed that BACH2 suppresses the activity of NRF2, a transcription factor, or a protein that helps to turn genes on or off. NRF2 is able to stick to cells’ DNA and switch on the genes that are used to make HbF, and reducing BACH2 allows more NRF2 to stick to DNA, ultimately leading to more HbF production.
“By providing cross-ancestry genetic evidence and a clear mechanistic framework for BACH2-mediated HbF regulation, our study provides a fundamental basis for further investigation of this pathway and its potential therapeutic relevance,” the researchers wrote.
Notably, this BACH2-NRF2 molecular signaling axis acts independently from BCL11A, the gene that was already known to regulate HbF production. As such, this finding may open up avenues for novel approaches to increase HbF levels in people with SCD and related blood disorders.
“We show proof-of-principle that pharmacologic [suppression] of BACH2 can increase fetal hemoglobin in human blood cells,” Sankaran said. “Because this pathway works independently of BCL11A, it provides another potential route for therapeutic development.”
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