A study published in the New England Journal of Medicine investigated BCL11A gene silencing for treating sickle cell disease.
Each year, approximately 400,000 children are born with sickle cell disease. The inherited disorder is characterized by the presence of a mutated form of hemoglobin (HbS). As a result, the red blood cells become sickle shaped. These misshapen cells then block vessels, impairing oxygen and blood flow. Thus, resulting in pain, hemolytic anemia, necrosis, organ damage, and infections. Although hydroxyurea help reduce sickling of cells and painful episodes, it is not effective in all patients. On the other hand, stem-cell transplant with a matched sibling donor is curative in more than 90% of cases. However, finding a matched donor is not always possible and the procedure carries a high risk of complications in older patients. As a result, researchers have begun exploring gene therapy for sickle cell disease.
In a study published in the New England Journal of Medicine, researchers investigated BCL11A gene inhibition through posttranscriptional gene silencing. Previous studies have linked the gene to repressing fetal hemoglobin (HbF) production in adult red blood cells. Typically, elevated levels of HbF help prevent sickling of red blood cells. However, levels of HbF start to decline after the first 6 months of life. Thus, leading to development of symptoms in affected individuals. Through silencing of the BCL11A gene, researchers hoped to induce HbF.
The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA.– study authors
Treatment Increases HbF Concentration
The pilot study enrolled patients with severe sickle cell disease, six of which underwent a follow up of at least 6 months. Results revealed stable HbF induction in the patients, with strong distribution in red blood cells. According to the study, during follow-up, researchers noticed a reduction or complete absence of sickle disease symptoms. Moreover, none of the six patients experienced any cases of vaso-occlusive crisis, acute chest syndrome, or stroke after treatment.
Based on the observed HbF levels and percentage in red blood cells, the study authors predict that the treatment can likely treat both acute and chronic complications of sickle cell disease. They plan to conduct additional follow up for analysis of long-term effects of the treatment.
Esrick, Erica B., et al. “Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.” New England Journal of Medicine, vol. 384, no. 3, 2021, pp. 205–215., doi:10.1056/nejmoa2029392.