Hemoglobin research comes of age to revolutionize β-thalassemia treatment

β-thalassemia (beta-thalassemia) is often discussed in the same breath as sickle cell disease — and for good reason. Both are inherited diseases that affect the oxygen-carrying molecule hemoglobin found in red blood cells, specifically, a subunit of hemoglobin called β-globin. Patients with these diseases are also both benefiting from the same wave of therapeutic innovation. 

Sickle cell disease is typically caused by a single mutation in the β-globin gene, HBB, that alters β-globin’s function. In contrast, β-thalassemia is caused by a wide range of HBB mutations that impair or abolish β-globin production altogether. While approximately 20 HBB mutations account for most cases of b-thalassemia, more than 350 disease-causing variants have been identified, reflecting the considerable genetic complexity of the disorder. Different mutations can reduce expression of β-globin at different levels, resulting in a disease impact spectrum ranging from mild to severe. 

Incredible ULK removes toxic α-globin to keep symptoms in check 

While the absence of β-globin sparks β-thalassemia, the buildup of its binding partner, α-globin (alpha-globin), fuels it. Understanding this phenomenon has been a particular interest of Mitchell Weiss, MD, PhD, Department of Hematology chair. 

“In β-thalassemia, poisonous α-globin builds up in red blood cell precursors, which die before they can mature into red blood cells,” Weiss explained. “The body senses it’s not getting enough red blood cells, so it signals to the bone marrow to make more. It’s like having a car assembly line stop at one point, and all the unfinished cars start piling up.”

There are two ways around this: either remove the excess α-globin to prevent the pile-up or replace the lost β-globin to complete hemoglobin assembly. St. Jude researchers are addressing both pathways.

In a 2019 study in Science Translational Medicine, Weiss, co-corresponding author Mondira Kundu, MD, PhD, Department of Cell & Molecular Biology, and their colleagues identified ULK1 as a key protein that cells use to remove α-globin. ULK1 regulates a recycling process for misfolded and waste proteins called autophagy. Prior studies showed that ULK1 activity is balanced by the cell growth-promoting protein complex mTORC1. By inhibiting mTORC1, the researchers boosted ULK1 function, reduced α-globin build-up, and lessened the severity of β-thalassemia in a mouse model. 

A 2023 follow-up in Blood showed that mTORC1 was excessively activated in the disease. By disrupting a particular microRNA that helps control how much mTORC1 a cell makes, β-thalassemia symptoms were alleviated. 

“ULK1 activity is regulated by multiple cellular pathways related to metabolism and metabolic stress. Targeting these pathways represents a potential therapeutic strategy for treating b-thalassemia, especially cases of intermediate severity where some b-globin is produced,” Weiss said.

BCL11A discovery sets the stage for gene therapy

Targeting ULK1 regulatory pathways may alleviate free α-globin buildup, but a replacement for missing β-globin is already in the wings. Specifically, the related protein γ-globin (gamma-globin) can pair with a-globin and substitute for the functions of b-globin. In early life, γ-globin binds with α-globin to form fetal hemoglobin. After birth, expression of γ-globin gradually switches to that of b-globin over the first 6 months. This switch helps explain why symptoms of b-thalassemia and sickle cell disease typically do not manifest until the first several months of life, when protective fetal hemoglobin levels decline. Reactivating γ-globin after birth therefore presents a promising option to replace the damaged β-globin in β-thalassemia and sickle cell disease. 

Jian Xu, PhD, Department of Pathology, has contributed significantly to understanding the γ-to-β–globin gene switch and how to control it. “Patients with higher fetal hemoglobin levels have less severe symptoms in both sickle cell disease and β-thalassemia,” Xu explained. “This means that inducing fetal hemoglobin could be therapeutically beneficial, but previously none of the regulators identified were sufficiently important to do so.”

The landmark discovery of BCL11A in 2007 in Nature Genetics, and subsequent unraveling of the mechanism behind its function in 2008 in Science, helped solve this problem. BCL11A was found to be a dominant “off switch” for γ-globin. Researchers, including co-author Xu, showed that reducing BCL11A levels was sufficient to reactivate γ-globin and reduce disease symptoms in humanized mouse models. Published in 2011 in Science, these results established proof of concept for targeting BCL11A. 

“Fortunately, tissue-specific regulatory elements, called enhancers, were further identified to control the expression of BCL11A,” Xu said. “This work, combined with recent advances in genetic engineering, has enabled the translation of those discoveries into successful gene therapies.”

Gene-editing breaks up BCL11A insulation

CRISPR-Cas9 gene therapy was approved in 2024 for the treatment of β-thalassemia in patients aged 12 and older, with eligibility expanded in 2026 to children as young as 2 years of age. The therapy, exagamglogene autotemcel (exa-cel), involves removing blood cell precursors from the patient and using CRISPR-Cas9 to introduce a DNA double-strand break within an enhancer region of the BCL11A gene. The edited cells are then reinfused into the patient, reducing BCL11A expression and restoring fetal hemoglobin production. Researchers in the Departments of Hematology and Bone Marrow Transplantation & Cellular Therapy at St. Jude recently opened a clinical trial for sickle cell disease called SAGES1, which uses CRISPR-Cas9 genome editing to reactivate fetal hemoglobin by disrupting a key BCL11A-binding sequence in the γ-globin promoter.

Xu and colleagues wanted to better understand how the exa-cel therapy worked, and in a 2025 study in Blood, they revealed that the DNA region of the BCL11A gene targeted by the therapy forms a complex three-dimensional “rosette” structure, which insulates the gene to ensure high expression levels are maintained in postnatal red blood cell precursors. The CRISPR-Cas9 therapy disrupts this structure to silence the gene.  

The team also found that a noncoding RNA transcribed from the BCL11A enhancer is essential for rosette formation. Targeting this RNA with an antisense oligonucleotide had the same effect as exa-cel, indicating a potential therapeutic opportunity. “This could be a more cost-effective, accessible, and scalable alternative to current gene therapy,” senior corresponding author Xu explained. “It’s important not only to keep improving existing approaches but to also consider new ones that could potentially offer a long-term cure.”

In line with identifying alternative approaches to Cas9-based therapy, a 2023 Nature Genetics publication led by co-corresponding authors Weiss and Jonathan Yen, PhD, Department of Hematology, discovered that base editing at the γ-globin promoter achieved 2- to 4-fold greater fetal hemoglobin levels than Cas9 editing. “The γ-globin gene is a good target for base editing,” Weiss said. “There are very precise mutations that can reactivate its expression, which may provide a powerful ‘one-size-fits-all’ treatment for all mutations that cause sickle cell disease and β-thalassemia.” This strategy forms the basis for a planned clinical trial.

Sickle cell and β-thalassemia gene therapy see early success

As Weiss and Xu dig into mechanisms and alternative strategies to reintroduce γ-globin, the overlapping benefits of this approach mean β-thalassemia is once again intertwined with sickle cell disease. Fortunately, this means Akshay Sharma, MBBS, MSc, Department of Bone Marrow Transplantation & Cellular Therapy, can leverage his expertise in bone marrow transplantation to advise on clinical trials for both. This includes CLIMB THAL-141 and CLIMB SCD-151, ongoing international Phase 3 studies evaluating exa-cel in children aged 5 to 11 years. 

Published in 2026 in the New England Journal of Medicine, the study participants who received exa-cel reported no further need for red blood cell transfusions. “All of these patients were receiving regular blood transfusions before gene therapy, often every month or sometimes more frequently,” Sharma said. “After gene therapy, most patients no longer require blood transfusions. Some patients still need transfusions, but far less often, perhaps only a few times a year.” Sharma is also the principal investigator of the St. Jude–based SAGES1 clinical trial.

A cure years in the making, a future yet to come

Clinical success stories are already starting to come through for β-thalassemia gene therapy; however, it’s important to note the ongoing challenges. For example, the therapy’s complexity limits availability to only the best-equipped facilities. “Altogether, the treatment requires extensive medical logistics, complex manufacturing and specialized care and is currently not accessible to the vast majority of patients, especially those in resource-limited regions where many affected individuals live,” said Xu.

Further, in a 2025 publication in Blood Advances, co-corresponding authors Weiss and Yen highlighted deleterious effects of silencing BCL11A, identifying it as a regulator of at least 25 genes, some of which contribute to red blood cell development. “We need to improve gene therapy to make it more broadly accessible, and we need better therapeutics to induce fetal hemoglobin production. St. Jude is actively supporting work in that area,” said Weiss.

For the long journey ahead, Sharma needs only to reflect on the progress already made to feel optimistic about the future. “Until recently, we lacked reliable tools to remove cells from the body, modify them, return them and ensure that they still function normally. Fifteen years ago, CRISPR-Cas9 had not even been discovered; today we are using it to treat human diseases,” he said. “Our understanding of the genetics behind β-thalassemia has improved dramatically and so has our ability to manipulate related biological pathways to eliminate the disease effectively. All of this was made possible by advances across multiple scientific disciplines that ultimately converged into therapeutic approaches that are changing patients’ lives.”