Among patients with sickle cell disease (SCD), inhibition of BCL11A via gene knockdown is an effect target to induce fetal hemoglobin (HbF), and appears to be a promising avenue of treatment, according to research published in The New England Journal of Medicine.

While allogeneic hematopoietic stem cell transplantation remains the standard curative treatment for patients with SCD, it is associated with a high risk of adverse events (AEs) in elderly patients, including graft-vs-host disease.

There is evidence that high levels of erythrocyte HbF may help to reduce the frequency of sickle hemoglobin polymerization and erythrocyte sickling. BCL11A, a gene known to be involved with repressing HbF production in adults, is a promising therapeutic target in this patient population.

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For this open-label pilot trial ( Identifier, NCT03282656), researchers enrolled patients with SCD to receive gene therapy, which involved infusion of CD34+ cells transduced with a lentiviral vector BCH-BB694, which has shown promise in preclinical study.

A total of 6 patients (aged 7-25 years) were enrolled in the study, and received BCH-BB694 gene. All patients presented with severe SCD symptoms, including stroke, priapism, or a vaso-occlusive event. The percentage of CD34+ cells transduced ranged from 62% to 100%, and the median patient follow-up after infusion was 18 months (range, 7-29).

In all evaluable patients, the HbF fraction of total hemoglobin increased and remained stable. At the most recent follow-up, the fraction of HbF increased from 20.4% to 41.5%, and HbF was broadly distributed in red blood cells. In addition, clinical manifestations of SCD were either less frequent or absent altogether.

Grade 3 nausea, priapism, and febrile neutropenia were among the AEs noted in a supplementary table; many of these were, furthermore, considered study-related.

“On the basis of current HbF levels, percentage of F-cells [reported as a percentage of untransfused red cells], and HbF per F-cell, we predict that the patients in this study will have protection from sickling to prevent or significantly ameliorate both acute and chronic complications of sickle cell disease. Additional follow-up will clarify the long-term effects,” the authors concluded.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. Published online December 5, 2020. doi:10.1056/NEJMoa2029392