Sickle cell disease (SCD), the first monogenic disease to be characterized at a molecular level, results from a homozygous missense mutation in the β-globin gene. This mutation permits the polymerization of hemoglobin S in the deoxygenated state resulting in the deformation of the red blood cell into the canonical sickle cell shape. Clinically, sickling red cells cause vaso-occlusion causing tissue damage and pain as well as profound hemolytic anemia. While allogeneic hematopoietic stem cell (HSC) transplantation has shown curative potential in this disease, the devastating complications of graft rejection and graft vs host disease have severely limited its application. The ability to manipulate a patient’s own HSCs ex vivo and return the autologous gene-modified HSCs to the patient offers the potential to realize the benefits of stem cell transplantation while avoiding the challenges inherent to the use of allogeneic donor cells. Here we review our work with LentiGlobin gene therapy (bb1111) in severe SCD. Our data in SCD patients to date highlights both the disease-specific hurdles which must be overcome to obtain optimal clinical outcomes as well as the potential for gene therapy to impact this disease.

Lentiviral vector gene therapy for sickle cell disease

ACS Fall 2021

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