ASH Annual Meeting and Exposition

ASH Annual Meeting and Exposition

Perspective from Ifeyinwa Osunkwo, MD, MPH
December 02, 2018
4 min read

Autologous gene therapy shows promise for sickle cell disease

Perspective from Ifeyinwa Osunkwo, MD, MPH
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Erica B. Esrick, MD
Erica B. Esrick

SAN DIEGO — An adult with sickle cell disease responded positively to autologous gene therapy, providing the first proof that this approach could be effective for sickle cell disease, according to results of a pilot study presented at ASH Annual Meeting and Exposition.

The patient received an infusion of their own stem cells in which researchers had flipped a genetic “switch” of fetal to adult globin by knocking down BCL11A to induce the cells to start producing healthy hemoglobin and stop producing sickle hemoglobin.

“Obviously, you can’t draw large conclusions from [one patient], but in a small study where this is the first demonstration of the proof of principle, it is very encouraging to see the expected result based on our preclinical work of increasing fetal hemoglobin,” Erica B. Esrick, MD, hematologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, told HemOnc Today. “Of course, we’ll need more data from more patients to draw larger conclusions.”

The only current cure for sickle cell disease is a hematopoietic stem cell transplantation from a healthy matching donor. However, many patients lack a matching donor or their transplants fail.

Fetal hemoglobin has been previously found to stop the development of sickle hemoglobin polymers.

The BCL11A protein is a validated repressor of fetal hemoglobin. Recent preclinical research has shown that suppressing the action of BCL11A can reverse sickle cell disease by reactivating fetal hemoglobin production.

Thus, researchers hypothesized that knocking down BCL11A with RNA interference would induce gamma-globulin expression. They genetically engineered a virus to deliver a gene that blocks the BCL11A protein in red blood cells using microRNA to simultaneous increase fetal hemoglobin and decrease sickle hemoglobin.

Murine models showed erythroid-specific expression of microRNA-adapted short hairpin RNAs (shRNAmiR) targeting BCL11A effectively induced fetal hemoglobin in human erythroid cells derived from transduced hematopoietic stem cells, mitigating the hematologic effects of sickle cell disease while avoiding negative effects in the stem cells and B lymphocytes.

“Our gene therapy approach is unique in that it leverages the physiology of the hemoglobin switch to simultaneously increase fetal hemoglobin, which does not sickle, and directly reduce sickling hemoglobin,” study author David A. Williams, MD, president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, chief scientific officer and senior vice president of Boston Children's Hospital, and professor at Harvard Medical School, said in a press release. “Other gene therapy trials for sickle cell disease are adding genes that encode fetal hemoglobin or corrected, nonsickling adult hemoglobin, without directly targeting the fetal switch of the sickle hemoglobin gene. We predict this strategy is a very effective way to reduce or even eliminate the sickling of cells.”


In the current study, researchers sought to evaluate a shRNAmiR lentiviral vector that targets BCL11A as autologous gene therapy in four patients with sickle cell disease.

After 3 months of blood transfusions, researchers collected autologous CD34-positive cells from the patients using plerixafor mobilization and apheresis. Patients were then transduced with a BCH_BB-LCRshRNAmiR vector.

At the time of the presentation, three of the patients underwent 3 (n = 2) or 4 (n = 1) days of mobilization. Mean single-day apheresis yields were 3.2 (range 1.5 - 6.8) x 106 CD34-positive cells/kg.

Researchers observed no grade 3 or grade 4 adverse events associated with mobilization and collection, although one patient developed an incidentally discovered line-associated atrial clot and pulmonary embolism.

Transduced cell products for these three patients have cell doses of 3.3 to 6.7 x 106 CD34-positive cells/kg, vector copy numbers of 3.3 to 5.1 copies per cell, and greater than 95% vector-positive CD34-positive-derived colonies.

To date, one patient has received an infusion of gene-modified cells.

Postinfusion follow-up was 78 days.

This patient, a 21-year-old male who previously required monthly blood transfusions for 17 years, now only requires transfusions every 6 months. New blood tests show this patient now has high levels of fetal hemoglobin and no demonstrable sickled cells.

At day 76, the number of F cells had risen to 59.7%, with 12 pg fetal hemoglobin/F cell. Further, BCL11A protein was reduced by approximately 90%.

He also no longer has pain or other symptoms related to sickle cell disease, Esrick said.

Two of the other patients in this trial are awaiting transplant, and the fourth will soon undergo stem cell collection.

“Targeting BCL11A appears using gene therapy looks to be a promising approach to increase fetal hemoglobin and reverse the findings of sickle cell,” Esrick told HemOnc Today. “Historically, transplanting sickle cell disease has been only a treatment for young patients, but that’s changing.” – by John DeRosier


Esrick E, et al. Abstract 1023. Presented at: ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego.

Disclosures : NIH funded this study. Esrick reports honoraria from Bluebird Bio. Please see the abstract for all authors’ disclosures.