Investigational Gene Therapy May Induce Fetal Hemoglobin Production, Eliminate Clinical Manifestations of SCD

January 25, 2021

An investigational gene therapy reduced or eliminated clinical manifestations of sickle cell disease (SCD) and led to robust and stable fetal hemoglobin induction in six patients after at least six months of follow-up, according to findings published recently in the New England Journal of Medicine

The investigational gene therapy targets the BCL11A gene, which is a repressor of gamma-globin expression and fetal hemoglobin production in adult erythrocytes. All six patients in the trial received an 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 (shmiR) and allows for erythroid lineage–specific knockdown. Investigators assessed patients for primary end points of engraftment and safety and for hematologic and clinical responses to treatment.  

After at least six months of follow-up, all six patients had engraftment and achieved “robust and stable” fetal hemoglobin induction. In addition, all patients who could be fully evaluated showed fetal hemoglobin broadly distributed in red cells. Adverse events were consistent with effects of the preparative chemotherapy. Patients experienced reduction or elimination of clinical SCD manifestations during the follow-up period. 

According to investigators, the initial results of this trial provide validation that BCL11A can be targeted to lead to successful fetal hemoglobin induction. Furthermore, they predict that that the patients in this study will have protection from sickling to prevent or significantly ameliorate both acute and chronic SCD complications, although additional follow-up will clarify the long-term effects.

The authors also noted that use of a short hairpin RNA embedded within an endogenous microRNA scaffold (termed a shmiR vector) to alter genetic expression (rather than reliance on the addition of a protein coding sequence) may have potential implications for other diseases.