Initial results of a an in-human pilot study using genetic targeting of the fetal to adult globin switch shows proof of principle for this novel approach in patients with sickle cell disease (SCD).
Currently, the only established cure for SCD is a transplant of healthy stem cells from a matched sibling donor. However, many patients with SCD do not have a suitable sibling donor and sometimes stem cell transplants may fail. Gene therapy is an alternative approach that uses the patient’s own stem cells and does not rely on the availability of a compatible donor.
This novel technique for gene therapy for SCD is inspired by changes observed in hemoglobin before and after birth. Fetuses in the womb need to extract oxygen from their mother’s circulation. For this purpose, they have fetal hemoglobin that accepts and releases oxygen at lower blood and tissue oxygen levels compared with adult hemoglobin. Soon after birth, a switch is turned off and fetal hemoglobin begins to be replaced by adult hemoglobin – or, in infants with SCD, with sickle hemoglobin.
Researchers have long recognized that fetal hemoglobin inhibits the development of sickle hemoglobin polymers from forming. More recently, preclinical research from Boston Children’s Hospital has shown that suppressing the action of BCL11A can reverse SCD by reactivating fetal hemoglobin production. In the current study, the action of BCL11A in red blood cells was blocked by microRNA-adapted shRNA targeting BCL11A.
To date, 4 adult patients have been enrolled in the trial, with one having received this gene therapy. This patient, who, prior to transplant, required monthly blood transfusions to alleviate SCD symptoms, has required only a single transfusion in the six months following treatment, with no transfusions required following engraftment. Blood tests show high levels of fetal hemoglobin in this patient. Two other patients are awaiting transplant, with the fourth patient set for stem cell collection by year-end.
Esrick EB et al.: Flipping the switch: initial results of genetic targeting of the fetal to adult globin switch in sickle cell patients. ASH Annual Meeting 2018, abstract #1023