Found the "Switch Protein" for Intractable Anemia...Will It Open a New Path for Gene Therapy[Reading Science]

Korea University team identifies LDB1 as a key regulator of hemoglobin switching

The key protein that acts as a "switch" to convert fetal hemoglobin to the adult form has been identified for the first time. Experts say this presents a new molecular target that could broaden therapeutic strategies for intractable hereditary anemias.

On the 23rd, the National Research Foundation of Korea announced that the research team led by Professor Jeon Taehoon at Korea University College of Medicine has identified the role of the key protein LDB1, which regulates "hemoglobin switching" - the process by which the type of hemoglobin changes as red blood cells mature.

Schematic showing the conversion of fetal hemoglobin (HbF, alpha2gamma2) to adult hemoglobin (HbA, alpha2beta2) after birth during erythroid differentiation in mammals. In the adult stage, BCL11A, CBFA2T3, SOX6, and others repress gamma-globin expression to induce the switch. Figure provided and described by Jeon Taehoon, Professor at Korea University.

Hemoglobin switching is the phenomenon in which the type of hemoglobin changes as an individual grows from the fetal stage to adulthood. If this process does not proceed properly, production of adult hemoglobin is reduced, leading to hereditary anemias such as beta-thalassemia. However, until now, the "upstream factor" that integratively regulates this process had not been clearly identified.

The research team generated a mouse model in which LDB1 is selectively deficient in erythroid progenitor cells and confirmed that LDB1 is a transcriptional activator that directly promotes the expression of genes that repress fetal hemoglobin.

In the experiment, cells deficient in LDB1 showed a marked reduction in the expression of fetal hemoglobin repressor genes such as BCL11A, CBFA2T3, and SOX6, while fetal hemoglobin itself increased more than 50-fold. At the same time, reactive oxygen species (ROS) levels rose by about 10-fold, inducing apoptosis of erythroid progenitor cells and preventing normal erythroid differentiation.

In fact, LDB1-deficient mice had less than 10% of the normal number of red blood cells and all died within seven days after birth. This recapitulates pathophysiology similar to the hematopoietic defects observed in patients with beta-thalassemia.

Comparison of the differentiation processes of normal and LDB1-deficient erythroid progenitor cells. When LDB1 is deficient, expression of repressor genes such as Bcl11a is reduced, leading to excessive maintenance of fetal hemoglobin; increased reactive oxygen species and apoptosis halt erythrocyte maturation. Figure provided and explained by Professor Jeon Taehoon, Korea University.

The crux of this study is that it demonstrated LDB1 is not a mere accessory protein but an "upstream regulator" that simultaneously controls multiple key genes such as BCL11A. While existing therapeutic strategies have focused on single-gene targets, this research is significant in that it proposes a pathway capable of integratively controlling hemoglobin switching.

Professor Jeon Taehoon said, "We have confirmed that LDB1 is a key regulatory factor that drives the switch from fetal to adult hemoglobin," adding, "This could be expanded into a next-generation therapeutic strategy that simultaneously regulates multiple switching-related genes, including BCL11A, the main target gene of the gene-editing therapy Casgevy currently used to treat beta-thalassemia."

Casgevy is the world’s first gene-editing therapy developed using CRISPR-Cas9-based gene-editing technology, and it received approval in 2023 from both the U.S. Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). It is regarded as a breakthrough therapy that can replace lifelong transfusions with a single treatment, but it also has the limitation of being centered on a single-gene target.

This research was conducted with support from the Mid-career Researcher Program promoted by the Ministry of Science and ICT and the National Research Foundation of Korea, and the results were published online on the 4th in Redox Biology, an international journal in the field of biochemistry and molecular biology.

The research team expects that the LDB1-deficient mouse model can be used as a preclinical model for studying oxidative-stress-related blood disorders such as beta-thalassemia and sideroblastic anemia, as well as for evaluating the efficacy of therapeutics.

This study is drawing attention in academia because it suggests the possibility of expanding therapeutic strategies for intractable hereditary anemias from "single-gene editing" to "modulation of upstream transcriptional regulatory pathways."