Pilot Study Tests Novel Approach to Gene Therapy for Sickle Cell Disease

Get Permission

Initial findings from a first-in-human trial have provided proof of principle for a groundbreaking approach to gene therapy for sickle cell disease, according to data presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1

Erica B. Esrick, MD

Erica B. Esrick, MD

Early results of genetic targeting of the fetal-to-adult globin switch showed effective collection, gene modification, and clinical grade manufacturing of a BCL11A-targeted stem cell product in three patients with sickle cell disease. Although only one patient has completed treatment thus far, lead study author Erica B. Esrick, MD, called the results “very encouraging” and said they support the promising preclinical data that were the basis for the trial.

“This is the first gene therapy trial in any disease—not just sickle cell disease—to use this novel engineering strategy,” said Dr. Esrick, a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “Early data on engraftment in one patient demonstrate the first use of this ‘shMIR’ [short-hairpin RNA sequences engineered into microRNA backbones] construct vector with a good short-term safety profile, validation of BCL11A as an effective target for fetal hemoglobin induction in humans as evidenced by high levels of fetal hemoglobin per F cell, high numbers of F cells in circulation, and early mitigation of some of the cellular phenotypes of sickle cell disease.”

Origins of the Disease

As Dr. Esrick explained, during fetal life, high levels of gamma globin are expressed, and when combined with alpha globin, they form fetal hemoglobin, which is a healthy, nonsickling type of hemoglobin. After birth, however, a natural switch occurs, shifting expression from gamma globin to beta globin. This is where problems begin for patients with sickle cell disease, said Dr. Esrick, because the mutation that causes the disorder is located in the beta globin gene. Instead of making normal adult beta globin, these patients make hemoglobin S or sickle hemoglobin, which causes all of the downstream complications in sickle cell disease.

Our therapeutic goal is to use gene therapy to provide a set of genetic instructions to the red blood cell precursors to ‘flip the switch’ back to producing high levels of fetal hemoglobin and low levels of sickle hemoglobin.
— Erica B. Esrick, MD

Tweet this quote

At present, the only established cure for sickle cell disease is a transplant of healthy stem cells from a donor, preferably a completely matched sibling donor. However, many patients with sickle cell disease lack a suitable sibling donor, and stem cell transplants from other donors are complicated by higher risks of graft-vs-host disease (GVHD) and graft rejection. Gene therapy is an alternative approach that uses the patient’s own stem cells and thus does not rely on the availability of a compatible donor and eliminates any risk of GVHD.

“Our therapeutic goal is to use gene therapy to provide a set of genetic instructions to the red blood cell precursors to ‘flip the switch’ back to producing high levels of fetal hemoglobin and lower levels of sickle hemoglobin,” said Dr. Esrick.

Study Methodology

In the current study, David A. Williams, MD, Chief Scientific Officer at Boston Children’s Hospital, and colleagues devised a technique to genetically engineer an inactivated virus to deliver a gene that blocks the action of BCL11A in red blood cells using the cell’s own microRNA machinery. The key feature of the new approach is targeting BCL11A with a structure they have named a shMIR.

David A. Williams, MD

David A. Williams, MD

The first step for patients is to have hematopoietic stem cells collected via peripheral stem cell mobilization. The cells are then transferred to a cell-processing facility, where blood stem cells are selected, transduced with the BCL11A vector, and cryopreserved. Once the product successfully meets all release criteria, the patient is admitted to the -transplant unit to receive myeloablative conditioning with busulfan before infusion of the gene-modified cells. During the study’s 2-year follow-up, patients are monitored closely for safety and lab outcomes, including BCL11A levels, fetal hemoglobin levels, and any sign of sickle cell symptoms.

For this single-center pilot and feasibility study, the investigators plan to enroll a total of seven patients in three staggered age cohorts, starting with adults before moving on to younger patients. There are currently four subjects enrolled, and all four subjects have undergone peripheral stem cell mobilization and apheresis, with manufacturing completed in three of the four patients. At the time of the ASH meeting, one patient had been treated with an infusion of gene-modified cells and had undergone follow-up of over 6 months.

Reversal of Sickle Cell Phenotype

As Dr. Esrick reported, the autologous transplant course for this patient was uncomplicated. Adverse events were all consistent with myeloablative conditioning, she said, and no adverse events were associated with the medicinal product. The level of fetal hemoglobin rose substantially after gene therapy and has remained in the 25% to 28% range since month 3 after gene therapy, while levels of normal adult hemoglobin, which were initially measurable because of the prior transfused blood, decreased to 0% by 4 months after gene transfer.

“Just as important as the total amount of fetal hemoglobin is how that fetal hemoglobin is distributed, and this can be assessed by looking at the number of fetal hemoglobin–containing cells, call F cells,” said Dr. Esrick. “Our patient is producing and maintaining a very high level of F cells, which suggests that his fetal hemoglobin is distributed broadly, protecting a large proportion of cells against sickling.”


  • A pilot study testing a novel approach to gene therapy for sickle cell disease has demonstrated effective collection, gene modification, and clinical grade manufacturing of a microRNA-adapted shMIR stem cell product targeting BCL11A in three patients.
  • The one patient to complete treatment thus far has experienced reversal of the sickle cell phenotype.

Finally, Dr. Esrick reported that the subject had so far experienced reversal of the sickle cell phenotype. There had been no pain, respiratory events, or neurologic events, said Dr. Esrick, and the patient was not anemic, with a normal total hemoglobin of 11 g/dL at 6 months. Laboratory outcomes at 6 months after gene therapy also show evidence of significantly decreased hemolysis with a low reticulocyte count and lactate dehydrogenase.

“There have been no transfusions required since engraftment, and 6 months after gene therapy, there are no visible sickled cells on the peripheral blood smear,” said Dr. Esrick. Two other patients were awaiting transplant, she added, and the fourth patient had just completed stem cell collection.

“Durability is one of the most important things that we’re assessing in this study,” said Dr. Esrick, when questioned about the permanence of the approach. “Of course, we’re hopeful and optimistic that the effect will be durable, and it’s encouraging that there has been a plateau in the levels at this point.”

At a press briefing held during the ASH meeting, Dr. Esrick was asked whether it would be possible to develop RNA interference approaches that might not be curative but would be less expensive and have a broader reach. She replied: “People are looking into the possibility of developing a small molecule to target BCL11A instead of requiring gene therapy, but there is nothing yet ready for translation. In addition, a team in Boston led by Dr. Williams is working with the Gates Foundation to determine whether the approach validated in these early results can be developed for ‘in vivo’ gene delivery using a simplified treatment approach that would allow use in developing countries. This work is just beginning.” 

DISCLOSURE: This study was funded by the National Institutes of Health. Dr. Esrick has received honoraria for advisory board activity with Bluebird Bio. Dr. Williams has received research funding from Bluebird Bio, which also provided reagents important for this study. Dr. Williams is a cofounder of and scientific advisory board member for Orchard Therapeutics and cofounder of Alerion Biosciences.


1. Esrick EB, Brendel C, Manis JP, et al: Flipping the switch: Initial results of genetic targeting of the fetal to adult globin switch in sickle cell patients. 2018 ASH Annual Meeting & Exposition. Abstract 1023. Presented December 3, 2018.