Current and future treatments for sickle cell disease - from hematopoietic stem cell transplantation to in vivo gene therapy.

Abstract

Sickle cell disease (SCD) is a single-gene disorder caused by a point mutation of the β-globin gene, resulting in hemolytic anemia, acute pain, multiorgan damage, and early mortality. Hydroxyurea is a first-line drug therapy that switches sickle-globin to non-pathogenic γ-globin; however, it requires lifelong oral administration. Allogeneic hematopoietic stem cell (HSC) transplantation allows for a one-time cure for SCD, albeit with histocompatibility limitations. Therefore, autologous HSC gene therapy was developed to cure SCD in a single treatment, without HSC donors. Current HSC gene therapy is based on the ex vivo culture of patients' HSCs with lentiviral gene addition and gene editing, followed by autologous transplantation back to the patient. However, the complexity of the treatment process and high costs hinder the universal application of ex vivo gene therapy. Therefore, the development of in vivo HSC gene therapy, where gene therapy tools are directly administered to patients, is desirable to provide a more accessible, cost-effective solution that can cure SCD worldwide. In this review, we discuss current treatments including drug therapies, HSC transplantation, and ex vivo gene therapy, the development of gene therapy tools, and progress toward curative in vivo gene therapy in SCD.