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Clinical manifestations of sickle cell disease, such as hemolytic anemia, pain, and progressive organ damage, can be alleviated by high levels of erythrocyte fetal hemoglobin (HbF). The BCL11A gene represses γ-globin expression and adult erythrocyte fetal hemoglobin production. This study, published in the New England Journal of Medicine, focuses on the genetic silencing of BCL11A, resulting in the induction of HbF.

This study was a single-center, open-label pilot study on patients with sickle cell disease. The intervention involved infusing autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA targeting BCL11A mRNA embedded in a microRNA, allowing erythroid lineage-specific knockdown. The researchers assessed their primary endpoints of engraftment and participant safety, as well as participant hematologic and clinical responses to treatment.

Six patients were followed for at least 6 months after receiving this gene therapy, with a median follow-up of 18 months. All patients had engraftment, and adverse events were consistent with the effects of the preparative chemotherapy. All fully evaluated patients achieved stable and robust HbF induction (percentage HbF/(F+S) at most recent follow-up: 20.4 to 41.3%). Clinical signs of sickle cell disease were reduced or absent during the follow-up period.

The researchers concluded that BCL11A inhibition is an effective way to induce HbF. Although the evidence is preliminary, this study suggests that microRNA-based gene knockdown may provide a favorable risk-benefit profile for the treatment of sickle cell disease [1].


[1] Esrick, E. B., Lehmann, L. E., Biffi, A., Achebe, M., Brendel, C., Ciuculescu, M. F., Daley, H., MacKinnon, B., Morris, E., Federico, A., Abriss, D., Boardman, K., Khelladi, R., Shaw, K., Negre, H., Negre, O., Nikiforow, S., Ritz, J., Pai, S. Y., . . . Williams, D. A. (2021). Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. New England Journal of Medicine, 384(3), 205–215. https://doi.org/10.1056/nejmoa2029392

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