Sickle cell disease (SCD) is characterized by hemolytic anemia, pain, and progressive organ damage. These manifestations are ameliorated by sufficiently fetal hemoglobin (HbF) because a high level of HbF mitigates sickle hemoglobin polymerization and sickling. BCL11A is a repressor of gamma globin expression and HbF production in adult erythrocytes. Its downregulation is a promising therapeutic strategy for induction of HbF. We enrolled patients with SCD in a single-center, open-label, pilot trial. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes an shRNA targeting BCL11A mRNA embedded in a microRNA (shmiR) allowing erythroid lineage-specific knockdown. Ten patients have been enrolled and 9 have been infused with gene modified cells with followup in half of these patients now over 2 years after receiving BCH-BB694 gene therapy. All patients engrafted. Seven fully evaluable patients achieved robust and stable HbF induction (%HbF 21.6-40.0% at latest follow-up) with broadly distributed HbF in red cells 58.9-93.6%) and HbF per F cell of 9.0-18.6 pg/cell. Clinical manifestations of SCD were reduced or absent during the followup period. We find HbF content in single-RBC measurements was higher in gene therapy subjects as compared to 14 hydroxyurea-treated patients. Engraftment kinetics were faster in patients infused with cell products transduced with one enhancer as compared to two enhancers. This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk/benefit profile in SCD. A multi-institutional, phase 2 study is underway.