Curative treatment for severe sickle cell disease: allogeneic hematopoietic cell transplant or gene therapy.

Abstract

Sickle cell disease (SCD) is characterized by chronic hemolysis, ischemia-reperfusion injury, and progressive end organ damage. Although survival for children with SCD in the United States (US) is excellent the life expectancy for adults is approximately two decades shorter compared to those without SCD. Consequently, those with severe SCD, estimated to be about 20% of individuals with SCD in the US deserve to be offered treatment choices with the potential for cure. Two treatment options with curative intent are available. The first, hematopoietic cell transplantation is limited by donor availability and complicated by graft failure, graft versus host disease and prolonged immune suppression. The second, gene therapy and gene editing offered in clinical trials and in 2023, the US Food and Drug Administration approved two of these therapies. Gene therapy and gene editing obviate the need for a donor, and have shown efficacy, yet challenges include difficulty in obtaining sufficient numbers of autologous hematopoietic stem cell progenitors for genetic manipulation and loss of cells during the manufacturing process. Long term follow up is only available for recipients of matched sibling transplantation as all other potentially curative treatment modalities are relatively recent. We recommend transplantation be reserved for those with neurologic injury as gene therapy/editing trials have not systematically studied their effect to stabilize cerebral hemodynamic stress. When the indication for curative treatment is frequent pain or recurrent acute chest syndrome for those aged 12 years and older and a matched sibling is not available, we recommend a treatment algorithm that prioritize gene therapy or gene editing therapies over alternative donor transplantation.