Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia

We designed this study to elevate fetal hemoglobin for the treatment of β-thalassemia and sickle cell disease (SCD). It has long been known that some individuals who are compound heterozygotes of β-thalassemia or SCD with deletional hereditary persistence of fetal hemoglobin (HPFH) have minimal hematological abnormalities and mild clinical manifestation compared with the homozygous patients. We used CRISPR-Cas9 to modify normal bone marrow hematopoietic stem and progenitor cells (HSPCs) to the deletional HPFH genotype. The erythroid cells derived from such modified HSPCs showed significantly higher γ-globin expression compared with the nondeletion-modified cells. This study provides proof of concept for developing a potential new approach to autologous transplantation therapy for the treatment of homozygous β-thalassemia and SCD.