BCL11A: A New Gene Therapy Target in Sickle Cell Disease?

A BCL11A-targeting gene therapy in patients with sickle cell disease (SCD) led to higher levels of fetal hemoglobin (HbF) and reductions in the severity of disease, according to findings from a small pilot study. The results of this ongoing study were presented by Erica Esrick, MD, from Boston Children’s Hospital, as a late-breaking abstract at the 2019 ASH Annual Meeting.

“Fetal hemoglobin prevents the polymerization of sickle hemoglobin [and] pancellular distribution of fetal hemoglobin is a therapeutic goal because it protects a large proportion of cells from sickling,” Dr. Esrick explained. “The transcription factor BCL11A is a strong repressor of gamma-globin, making it an appealing target for fetal hemoglobin induction.”

In this pilot study, investigators evaluated the approach of knocking down BCL11A using RNA interference to induce gamma-globin expression with BCH-BB694. BCH-BB694 is an investigational gene therapy product manufactured by embedding a BCL11A-targeting structure in patients’ autologous CD34-positive cells using a shmiR lentiviral vector. This new lentiviral vector “allows for delivery of a more ‘physiologic’ genetic payload and for regulated erythroid expression, avoiding the toxicity that would occur if we knocked down BCL11A in hematopoietic stem cells or B cells,” Dr. Esrick noted.

Per study protocol, participants underwent stem cell mobilization with plerixafor and CD34-positive cells were collected for ex vivo transduction; during transduction, patients received myeloablative conditioning with busulfan. The modified cells were then infused into patients.

As of data presentation, 8 patients were enrolled in the trial. Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. Cell products were manufactured for 6 patients, Dr. Esrick reported, with cell doses of 3.3 to 8.3 million CD34-positive cells/kg and high vector copy numbers, “indicating successful manufacturing and a highly efficient vector.”

Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. The only grade ≥3 AEs observed were related to central venous line (including thrombosis, pneumothorax, and infection). In addition, there were no AEs related to the medicinal product.

Following infusion of modified cells, the vector copy number was found to be stable at 6 months, indicating effective knockdown of BCL11A at the protein level. Gene therapy treatment also appeared to be associated with “consistent and substantial induction” of HbF.

At the latest follow-up (which ranged from 1 to 18 months post–gene therapy), total HbF levels had increased to between 23.8% and 42.8%, and remained stable, Dr. Esrick said. Patients also appeared to be producing high average amounts of HbF per F cell (erythrocytes that produce HbF), with percentages of HbF per F cell ranging from 37.4% to 62.1%.

The increase in HbF translated to improvement in severity of SCD, she noted. After gene therapy, the treated patients have not experienced any instances of vaso-occlusive crises, respiratory events, or neurologic events. Also, no patient required transfusions, except in one patient with severe underlying neurovascular disease who was planned to continue transfusions after gene therapy.

Among 4 patients who had been followed for at least 3 months after gene therapy infusion, Hb returned to “near-normal” levels (range = 10.9-11.8 g/dL) and had substantially increased compared with baseline Hb levels. For the patient who required transfusion, gene therapy allowed clinicians to extend his transfusion interval from 1 to 2 months, while still maintaining a pre-transfusion sickle Hb level no higher than the level prior to infusion, Dr. Esrick added.

These results suggest that BCL11A is an effective molecular target for patients with SCD and that targeting the factor with the shmiR vector leads to effective HbF induction, the authors concluded. However, results from this small, single-arm pilot study will need to be validated in larger, longer-term studies.

The authors report relationships with bluebird bio, which provided support for this trial.


Esrick EB, Achebe M, Armant M, et al. Validation of BCL11A as therapeutic target in sickle cell disease: results from the adult cohort of a pilot/feasibility gene therapy trial inducing sustained expression of fetal hemoglobin using post-transcriptional gene silencing. Abstract #LBA-5. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL.