Genetic Regulators of fetal hemoglobin
Background
During human development, the major hemoglobin in red blood cells changes from fetal hemoglobin (HbF, α₂γ₂) to adult hemoglobin (HbA, α₂β₂) shortly after birth. This change, known as the fetal-to-adult hemoglobin switch, involves a transcriptional shift from the γ-globin gene to the β-globin gene.
Hemoglobinopathies refer to a group of genetic anemias characterized by reduced production or increased destruction of red blood cells. These disorders are often due to the insufficient or absent production of normal β-globin. For instance, β-thalassemia results from a partial or complete defect in β-globin gene expression, leading to reduced or absent HbA, while sickle cell anemia arises from a point mutation in the β-globin gene, producing an abnormal hemoglobin. Clinically, in sickle cell disease and β-thalassemia, sustained HbF production beyond infancy can alleviate symptoms and extend their life spans. Therefore, understanding the mechanisms regulating HbF is crucial for identifying potential therapeutic targets to treat sickle cell disease and β-thalassemia.
Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation.
Technology Overview
This research identifies BACH2 as a novel therapeutic target for HbF induction and introduces innovative gene-editing methods, presenting promising approaches to enhance treatment for sickle cell disease and β-thalassemia.
The proof of concept for this invention can be summarized as:
- In this research, the largest multi-ancestry Genome-wide association studies (GWAS) to date is conducted and rare variation in a population stratified across extremes of HbF is accessed to define the architecture of human genetic variation impacting HbF.
- BACH2 is a new genetically-nominated regulator of hemoglobin switching. BACH2 has a dosage-dependent repression on HbF level, and loss of BACH2 leads to increase of HBG1/2, which encodes the beta unit of HbF and decreased of HBB, which encodes beta unit of HbA.
- In this study, multiple variants impact known regulators, such as BCL11A. Polygenic variation interacts with rare large-effect alterations to modify HbF levels. Combination approaches might be used to achieve optimal therapeutic in the future.
Conditions of CRISPR-Cas9 gene editing of BACH2 have been optimized in patient-derived HSCs with reactions lacking detectable genotoxicity or deleterious impact on stem cell function.
Applications
- Treatment of sickle cell disease and β-thalassemia.
Advantages
- BACH2 is a promising therapeutic target for HbF induction in the treatment of sickle cell disease and β-thalassemia
- Existing therapeutic approaches could be substantially improved by mimicking the multiplexed approach that naturally occurs in the switching between fetal to adult hemoglobin.
Publications
- Cato, L. D., Li, R., Lu, H. Y., Yu, F., Wissman, M., Mkumbe, B. S., Ekwattanakit, S., Deelen, P., Mwita, L., Sangeda, R., Suksangpleng, T., Riolueang, S., Bronson, P. G., Paul, D. S., Kawabata, E., Astle, W. J., Aguet, F., Ardlie, K., de Lapuente Portilla, A. L., Kang, G., … Sankaran, V. G. (2023). Genetic regulation of fetal hemoglobin across global populations. medRxiv : the preprint server for health sciences, 2023.03.24.23287659. https://doi.org/10.1101/2023.03.24.23287659
