Rare Disease Report

Novel Gene Therapy Promising for Sickle Cell Disease

DECEMBER 03, 2018
Rachel Lutz
A promising new gene therapy for sickle cell disease aims to promote the patient’s own ability to produce fetal hemoglobin, according to research presented at the 60th ASH Annual Meeting & Exposition in San Diego, California, this past weekend.

Investigators from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center delivered a case report of a 21-year-old male patient who previously required monthly blood transfusions to manage his sickle cell disease. The investigators attempted to enable patients to create their own fetal form of hemoglobin, which does not form sickle cells. Prior studies have demonstrated that people who make their own fetal hemoglobin have milder sickle cell disease severity.

In most cases, people stop creating fetal hemoglobin shortly after birth due to the BCL11A gene. Healthy adults will transition to creating adult hemoglobin; however, patients with sickle cell disease make mutated, or sickled, hemoglobin.

The gene therapy is designed to inhibit the expression of the BLC11A gene to promote the production of fetal hemoglobin. The investigators collected the patient’s blood stem cells and then treated for BCL11A suppression. Then, the patient underwent chemotherapy in order to condition the body into accepting his genetically modified cells, which were introduced through an intravenous infusion.

“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 leader David A. Williams, MD said in a press release. “Other gene therapy trials for sickle cell disease are adding genes that encode fetal hemoglobin or corrected, non-sickling 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.”

The 21-year-old male patient in the case report is symptom-free and the investigators added that he has significantly increased levels of fetal hemoglobin. He has no demonstrable sickled cells in his blood, they reported.

“We have collected cells from several additional patients and will be ready for them to undergo infusions soon,” co-principal investigator Erica Esrick, MD added in the statement. “It’s a very exciting time for patients, physicians, and researchers in the sickle cell disease community, with curative approaches such as gene therapy and gene editing showing great promise.”

The study authors said their ongoing clinical trial, funded by the National Institutes of Health, will include this gene therapy treatment for patients between 3 and 40 years of age.

Studies backing up this gene therapy date back to 2008, when Dana-Farber teams learned that BCL11A expressions can affect fetal hemoglobin levels. Then, a team reversed sickle cell disease in a mouse in 2011.

“This is a successful example of collaborative bench-to-bedside research,” Dr. Esrick added.

The team reported adverse events observed throughout their study were consistent with those in myeloablative conditioning, and that there were no product-related adverse events. In addition, they said, there were no sickle cell disease-related complications throughout the course of the intervention.

Their study is proof of feasibility, the study authors said, as well as support for the possibility of near-full suppression of sickle cell disease.

The abstract, “Flipping the Switch: Initial Results of Genetic Targeting of the Fetal to Adult Globin Switch in Sickle Cell Patients,” was published online.

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