Sickle Cell Diseases Could Be Alleviated by Reactivating Fetal Hemoglobin Genes

In their publication titled “Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs,” featured in Cell Stem Cell, the research team explores various gene editing techniques and proposes a method with potential significant clinical applications.

During normal development, fetal gamma (γ) globin is typically replaced by adult (β) hemoglobin. Interestingly, in a peculiar evolutionary twist, only humans and certain types of monkeys are known to undergo a switch from γ to β gene expression.

After this genetic switch, the genes responsible for producing fetal hemoglobin are silenced and rendered dormant by repressors such as BCL11A and ZBTB7A. The binding motifs of these repressors have been identified as targets for reactivation.

Conditions like β-thalassemia and sickle cell disease, collectively termed β-hemoglobinopathies, stem from mutations in the HBB gene. These mutations lead to impaired β-globin production, resulting in anemia, compromised oxygen delivery to tissues, and the potential for multi-organ tissue damage.

The researchers empirically uncovered that rejuvenating γ-globin expression holds promise as a universal therapeutic strategy for addressing these conditions.

To target six regulatory motifs, including the BCL11A enhancer and HBG1/2 promoter regions, the team employed a recently developed cytosine base editor known as the transformer base editor (tBE). They systematically compared the efficiency and off-target effects of tBE with other base editors and the Cas9 nuclease.

In the investigation, the transformer base editor (tBE) demonstrated editing efficiency equal to or surpassing other editors across the targeted motifs. Thorough analysis revealed an absence of detectable off-target mutations in cells edited with tBE, underscoring its potential as a safer and more potent therapeutic approach for β-hemoglobinopathies.

Experiments using patient-derived cells emphasized that disrupting BCL11A binding sites within the HBG1/2 promoters resulted in the highest levels of γ-globin expression. Through xenotransplantation in mice, sustained editing in hematopoietic stem cells (HSCs) and their progenies was observed, maintaining engraftment potential and differentiation capability.

The substantial increase in γ-globin expression achieved through tBE-mediated editing presents a promising therapeutic avenue for addressing β-hemoglobinopathies.

While the study focused on editing methodologies rather than direct clinical outcomes, the notable enhancement in γ-globin expression strongly suggests potential clinical benefits, including symptom alleviation and improved disease management for individuals affected by β-hemoglobinopathies.

Resources

1. ^{ONLINE NEWS} Jackson, J. & Medical Xpress. (2023, November 24). Reactivating silenced fetal hemoglobin genes could counter sickle cell–related diseases. Medical Xpress. [Medical Xpress]
2. ^JOURNAL Han, W., Qiu, H., Sun, S., Fu, Z., Wang, G., Qian, X., Wang, L., Zhai, X., Wang, J., Wang, Y., Guo, Y., Cao, G., Ji, R., Zhang, Y., Ma, H., Wang, H., Zhao, M., Wu, J., Bi, L., . . . Zhang, Y. (2023). Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs. Cell Stem Cell. [Cell Stem Cell]