Long-term stability of posttranscriptional genetic silencing of BCL11A using a shmiR vector in sickle cell disease.

Sickle cell disease (SCD) is characterized by chronic hemolysis, and painful vaso-occlusive episodes (VOE). High levels of fetal hemoglobin (HbF) attenuate the disease phenotype. We used a lentivirus vector (LVV) expressing a short hairpin RNA embedded in a microRNA (shmiR) that targets BCL11A in erythrocytes to induce HbF in a first-in-human study in SCD. The purpose of the study was to assess hematopoietic stem/progenitor cells collection, transduction parameters, safety, HbF induction, and durability. Eleven eligible patients with SCD underwent hematopoietic stem cell (HSC) collection. Plerixafor-mobilized peripheral blood HSCs required for manufacturing were obtained in 1 mobilization cycle for 10 of 11 participants, and 11 of 11 patient products were successfully manufactured with a median time to release of product of 39 days. Ten patients were infused with HSCs transduced with the shmiR vector. Engraftment occurred in all 10 patients. At a median follow-up of 58 months (range, 35-82) after infusion, there were no adverse events attributed to the vector. The transduction efficiency was 93.1%. One patient demonstrated low engraftment of the transduced cells and had suboptimal HbF induction. In the remaining 9 patients, at 2 years after treatment, the peripheral blood demonstrated 71% F cells with 11.9 pg HbF per F cells, and both parameters remained stable in 9 patients with ≥48 months follow-up. All patients who had VOEs before gene therapy demonstrated sustained mitigation of pain events. These data demonstrate excellent manufacturing efficiency, efficacy and safety of targeting BCL11A using a shmiR LVV, and long-term durability of the shmiR vector, leading to a pivotal, multisite, phase 2 trial that is currently underway (NCT05353647). This trial was registered at www.clinicaltrials.gov as NCT03282656.