Reactivation of inhibited fetal hemoglobin genes could counter sickle cell diseases

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

In a paper titled “HBG promoter base editing induces potent fetal hemoglobin expression without detectable off-target mutations in human HSCs,” published in Stem cellthe team compares gene editing techniques while formulating a method that could have important clinical applications.

Fetal gammaglobin (γ) is normally replaced by adult hemoglobin (β) during development. In a strange quirk of evolution, only humans and a few types of monkeys are known to switch from expressing γ to β genes.

Genes producing fetal hemoglobin become silent and dormant after genetic change by repressors such as BCL11A and ZBTB7A, whose binding motifs have been identified as targets for reactivation.

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

Researchers have experimentally discovered that reactivating γ-globin expression could become a universal therapeutic strategy for these conditions.

Six regulatory motifs (BCL11A enhancers and HBG1/2 promoter regions) were targeted using a recently developed cytosine base editor: transformer base editor (tBE). The team compared tBE to other base editors and the Cas9 nuclease to check its effectiveness and off-target effects.

In the study, tBE showed comparable or better editing efficiency than other editors for the targeted patterns. 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 with patient-derived cells demonstrated that disruption of BCL11A binding sites within HBG1/2 promoters led to the highest levels of γ-globin expression. Xenotransplantation in mice showed persistent editing of HSCs and their progeny, thereby maintaining engraftment potential and differentiation capacity.

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

Although the study focused on editing methods and not direct clinical results, the substantial improvement in γ-globin expression levels strongly suggests potential clinical benefits, including alleviation of symptoms and better disease management for people affected by β-hemoglobinopathies.

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