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Results of a proof-of-principle study demonstrated the feasibility of using a microRNA-adapted shRNA (shRNAmiR) lentiviral vector to target a repressor of gamma globin expression (BCL11A) for autologous gene therapy in patients with sickle cell disease. Presented at the 60th ASH Annual Meeting and Exposition, the study reported on enrollment, cell procurement and GMP manufacturing in four adults with sickle cell disease, and successful rapid induction of fetal hemoglobin (HbF) in the first patient infused.
“This is the first gene therapy trial in any disease – not just sickle cell disease – to use this novel engineering strategy,” Erica B. Esrick, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, said in a prepared statement. “Although only one patient has so far completed treatment, the results we’re seeing are very encouraging and support the promising preclinical data that were the basis for this trial.”
According to the study, the only cure for sickle cell disease is stem cell transplant from an HLA-matched sibling donor. However, many patients with sickle cell disease do not have a suitable donor available. The researchers wanted to use a novel technique for gene therapy inspired by changes observed in hemoglobin before and after birth. Fetuses have a special type of hemoglobin known as fetal hemoglobin that accepts and releases oxygen at lower blood and tissue oxygen levels compared with adult hemoglobin. After birth, a “switch” is turned off and fetal hemoglobin begins to be replaced by adult hemoglobin, or in infants with sickle cell disease, with sickle hemoglobin.
Recent research has shown that suppressing the action of the BCL11A protein can reverse sickle cell disease by reactivating fetal hemoglobin production. According to Esrick and colleagues, the use of erythroid-specific inactivation of BCL11A has the advantage of simultaneously inducing fetal hemoglobin and decreasing sickle hemoglobin. Effective BCL11A repression should prevent the sickling phenotype within red cells.
Esrick and colleagues using shRNAmiR lentiviral vector to target BCL11A in four patients with sickle cell disease. Transduction of hematopoietic cells with the lentiviral vector expressing the shRNAmiR for BCL11A in an erythroid-specific fashion had no toxicity during engraftment and genotoxicity assays. There were efficient transduction rates of between 80% to 95% of CD34-positive-derived colony forming cells from healthy donors and sickle cell disease patients, and more than 95% of transduced erythroid colonies demonstrating fetal hemoglobin levels of 50% to 95% of total hemoglobin.
One of the four patients underwent this gene therapy. Prior to transplant, this patient required monthly blood transfusions to alleviate sickle cell disease symptoms. Now, this patient has required only a single transfusion in the six months after treatment, with no transfusions required following engraftment. Blood tests show high levels of fetal hemoglobin in this patients.  Two other patients are awaiting transplant.
Esrick EB, et al. Flipping the switch: Initial results of genetic targeting of the fetal to adult globin switch in sickle cell patients. . Presented at 60th Annual ASH Meeting and Exposition; December 1-4, 2018; San Diego. Abstract #1023.

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Results of a proof-of-principle study demonstrated the feasibility of using a microRNA-adapted shRNA (shRNAmiR) lentiviral vector to target a repressor of gamma globin ...

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