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Novel Approach to Gene Therapy for SCD Shows Promise in Pilot Trial #ASH18

One adult patient with SCD is doing well after receiving an infusion of his own stem cells in which a genetic “switch” was flipped on to induce the cells to both start producing healthy hemoglobin and stop producing unhealthy (sticky or harmful) “sickle” hemoglobin, according to a new study. This first-in-human pilot study provides a proof of principle for this novel approach to gene therapy for SCD, said lead study author Erica B. Esrick, MD, hematologist at Dana-Farber /Boston Children’s Cancer and Blood Disorders Center.

“This is the first gene therapy trial in any disease –– not just in SCD –– to use this novel engineering strategy,” Dr. Esrick said. “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.”

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 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. 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, the basis of sickled cells, from forming. More recently, preclinical research from Boston Children’s Hospital has shown that suppressing the action of a protein known as BCL11A can reverse SCD by reactivating fetal hemoglobin production.

In the current study, David 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 machinery called a microRNA. The key feature of the new approach is targeting BCL11A with a structure they named a shMIR.

“We are in effect providing the cells with instructions to stop producing sickle hemoglobin and start producing fetal hemoglobin instead,” Dr. Esrick said.

To date, four 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.

“He has had no pain or other symptoms that could be attributed to SCD,” Dr. Esrick said. “He’s back to his normal life.”

Two other patients are awaiting transplant, with the fourth patient set for stem cell collection by year-end.

This study was funded by the National Institutes of Health.

Erica B. Esrick, MD, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, will present this study during an oral presentation session on Monday, December 3, at 6:15 p.m. PST, Room 6B, San Diego Convention Center.

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