CRISPR-based gene therapy for the induction of fetal hemoglobin in sickle cell disease.

Introduction: Sickle cell disease is ameliorated and perhaps can be 'cured' if enough fetal hemoglobin is present in most erythrocytes. Hydroxyurea, which increases fetal hemoglobin levels, is widely available and effective, especially in children. Nevertheless, only cell-based gene therapy can achieve a 'curative' fetal hemoglobin threshold.

Areas Covered: We cover the path to modulating fetal hemoglobin gene expression and the use of CRISPR/Cas9 gene editing as a viable clinical modality for treating severe sickle cell disease relying on references obtained from PubMed. Mobilized autologous hematopoietic stem and progenitor cells are engineered with vectors that derepress genes that regulate fetal hemoglobin gene expression. Following myeloablative conditioning, gene-edited cells are reinfused, engrafted, and make large amounts of fetal hemoglobin. Within months, fetal hemoglobin forms more than 40% of the total hemoglobin and hemoglobin levels normalize; symptoms of sickle cell disease disappear.

Expert Opinion: Optimistically, these patients are 'cured,' but long term follow-up is needed. Although approved by regulatory agencies and highly efficacious, because of its technical imperatives and cost, this first gene editing therapeutic will be unavailable to most people with severe sickle cell disease. It is highly likely that improved methods of genomic editing will simplify gene therapy, reduce its costs, and lead to its wider applicability.