Saturday, December 2, 2023

Reactivating silenced fetal hemoglobin genes could counter sickle cell–related diseases

Credit: Cell Stem Cell (2023). DOI: 10.1016/j.stem.2023.10.007

Researchers from multiple institutions in China have found a way to use gene editing to reactivate dormant fetal oxygen-transporting proteins in adult blood cells to potentially reverse a wide range of blood disorders.

In a paper, “Base editing of the HBG promoter induces potent expression with no detectable off-target mutations in human HSCs,” published in Cell Stem Cell, the team compares gene editing techniques while formulating a method that could have important clinical applications.

Fetal gamma (γ) globin is normally replaced by adult (β) hemoglobin during development. In an odd quirk of evolution, only humans and a few types of monkeys are known to switch from γ to β gene expression.

The producing the fetal hemoglobin become silenced and dormant after the by repressors such as BCL11A and ZBTB7A, whose binding motifs have been identified as targets for reactivation.

β-hemoglobinopathies, including β-thalassemia and , result from mutations in the HBB gene, leading to impaired β-globin production and resulting in anemia, impaired oxygen delivery to tissues and possible multi-organ tissue damage.

The researchers experimentally discovered that reactivating γ-globin expression could be developed into a universal therapeutic strategy for these conditions.

Six regulatory motifs (BCL11A enhancer and HBG1/2 promoter regions) were targeted using a recently developed cytosine base editor—transformer base editor (tBE). The team compared tBE with other base editors and Cas9 nuclease for efficiency and off-target effects.

In the study, tBE exhibited comparable or higher editing efficiency than other editors across the targeted motifs. Comprehensive analysis revealed no detectable off-target mutations in tBE-edited cells, indicating the potential of tBE as a safer and more potent treatment strategy for β-hemoglobinopathies.

Experiments conducted with patient-derived highlighted that disrupting the BCL11A binding sites within the HBG1/2 promoters led to the highest levels of γ-globin expression. Xenotransplantation in mice showed persistent editing in HSCs and their progenies, maintaining engraftment potential and differentiation ability.

The increased γ-globin expression observed due to tBE-mediated editing signifies a promising therapeutic avenue for β-hemoglobinopathies.

While editing methods and not direct were the focus of the study, the substantial enhancement in γ-globin expression levels strongly suggests potential clinical benefits, including symptom alleviation and improved disease management for individuals affected by β-hemoglobinopathies.

More information:
Wenyan Han et al, Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs, Cell Stem Cell (2023). DOI: 10.1016/j.stem.2023.10.007

© 2023 Science X Network

Reactivating silenced fetal hemoglobin genes could counter sickle cell–related diseases (2023, November 24)
retrieved 25 November 2023

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