Targeting BCL11A in haemoglobinopathies

Strategies that modulate BCL11A promise a real revolution in the treatment of beta-thalassaemia and sickle cell disease.

The global context of haemoglobin disorders

In recent years, molecular haematology has made a conceptual and therapeutic leap forward thanks to the study of the so-called foetal-to-adult haemoglobin switch, the transition from foetal haemoglobin (HbF) to adult haemoglobin (HbA). The possibility of modulating this transition, in particular through the targeted inhibition of the transcriptional repressor BCL11A, has opened up new treatment prospects for the two most common haemoglobinopathies worldwide: beta-thalassaemia and sickle cell disease.

According to the Global Burden of Disease Study, more than 500,000 children are born with sickle cell disease each year, with infant mortality in sub-Saharan Africa exceeding 50% within 5 years. Beta-thalassaemia, which is particularly prevalent in areas of the Mediterranean, the Middle East and South Asia, is another haemoglobinopathy with a high clinical impact: every year, nearly 60,000 newborns worldwide are born with this disease. Despite advances in supportive care (regular transfusions, iron chelation, hydroxyurea therapy) access to treatment remains uneven and the global burden of the disease remains high.

The protective role of HbF has been known for decades. Clinical observation that newborns with sickle cell disease do not show symptoms as long as HbF levels remain high has led to the persistence of foetal haemoglobin being considered the most powerful genetic modifier of phenotype. Family and genetic studies have confirmed that high levels of HbF are associated with a significant attenuation of symptoms and a reduction in mortality. In patients with beta-thalassaemia, the presence of HbF partially compensates for the absence of the β chain, reducing erythropoietic inefficiency.

Over the years, efforts to reactivate HbF in adulthood have focused on pharmacological approaches such as hydroxyurea, whose mechanism remains unclear but is thought to act by stimulating “stress erythropoiesis” pathways. However, the efficacy of hydroxyurea is variable, and not all patients respond adequately.

BCL11A: the master switch

A paradigm shift occurred with the identification of BCL11A, a transcription factor selectively expressed in adult erythroid precursors, as a key repressor of γ-globin genes. This result was obtained thanks to GWAS studies that linked polymorphisms in the BCL11A locus with HbF levels. Subsequent functional experiments confirmed that BCL11A acts by recruiting the NuRD complex, rendering γ-globin promoters inaccessible. Its inactivation in mouse models led to widespread reactivation of HbF and normalisation of haematological parameters in sickle cell disease models.

A further step forward came with the discovery of a specific erythroid enhancer within the second intron of BCL11A. This regulatory element contains a binding site for GATA1, which is crucial for gene expression in erythroid cells. Inactivating this enhancer, while leaving BCL11A expression intact in B lymphocytes and haematopoietic stem cells, allows for selective and safer intervention.

Approved gene therapies: targeted editing of the erythroid enhancer

This strategy was the basis for the development of exa-cel (exagamglogene autotemcel, Casgevy), the first approved gene therapy based on CRISPR-Cas9 editing. The treatment involves the mobilisation and collection of CD34+ cells, ex vivo modification using CRISPR targeting the enhancer, and reinsertion after myeloablative conditioning. The clinical results have been extremely promising: most patients with beta-thalassaemia achieved transfusion independence, while those with sickle cell disease no longer experienced vaso-occlusive crises. The average level of HbF per modified erythrocyte exceeded 35%, which is sufficient to prevent HbS polymerisation.

Alongside this, other gene strategies have reached the clinical stage, such as the lentiviral therapies lov-cel (Lyfgenia) and beti-cel (Zynteglo), which introduce a copy of healthy β-globin into haematopoietic precursors. In these cases too, clinical responses have been excellent, but concerns remain about the random insertion of the transgene and the large-scale production of vectors.

New perspectives: in vivo editing and small molecules

Despite these advances, ex vivo gene therapy has several obstacles: extremely high costs (up to $3 million per treatment), the need for myeloablative conditioning, highly specialised infrastructure, and long procedure times. In many resource-limited countries, where the incidence of sickle cell disease is highest, this option is not realistically accessible.

For this reason, research is now moving towards more accessible and scalable approaches. In vivo editing, base editing, and small molecule therapies represent the next frontiers. Some epigenetic compounds — such as DNMT1 or LSD1 inhibitors — have shown some preclinical efficacy, but their potency is often limited by the persistence of BCL11A activity. More recently, strategies based on PROTACs and “molecular glues” capable of selectively degrading BCL11A or altering its tetrameric structure are being explored.

In conclusion, understanding the molecular mechanisms underlying the transition from HbF to HbA has opened up a whole new chapter in the treatment of haemoglobinopathies. Today's approved therapies represent a breakthrough, but the biggest challenge will be to democratise access to them and develop simpler, cheaper and more sustainable treatments. The path to HbF reactivation has been mapped out, and BCL11A is the key.

Translating these advances into routine care will require multidisciplinary strategies, patient selection frameworks, and global policies aimed at equity of access.

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