Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

Abstract

Summary Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft‐versus‐host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.

Base editing of haematopoietic stem cells rescues sickle cell disease in mice

“…Several approaches for autologous therapies to treat SCD are being tested in clinical trials 7,8,[10][11][12] . It is not yet known which strategy is safest or most effective.…”

“…Ex vivo modification of autologous HSCs to circumvent the deleterious effects of the SCD mutation underlies several experimental therapies [7][8][9] (Supplementary References). Approaches that have shown early clinical promise include ectopic expression of an anti-sickling β-like globin gene by lentiviral vectors 10 and induction of fetal haemoglobin (HbF) by suppression 11 or Cas9-mediated disruption 12 of BCL11A.…”

Recent Advances in the Treatment of Sickle Cell Disease

“…For the majority of patients without a MSD, haploidentical HSCT with recent promising data of improved overall survival presents an alternative for curative therapy. Multiple gene therapy strategies utilizing patient's own stem cells, are also being pursued, but this has the disadvantage of myeloablative conditioning (Leonard et al, 2020).…”

Hematopoietic Stem Cells and Mesenchymal Stromal Cells in Acute Radiation Syndrome

“…Accumulated gene mutation or instabilities may lead to malignant diseases several years later. Stem cell therapy has been proven effective in genetic diseases, like sickle cell disease, thalassemia, and immunodeficiency diseases [ 39 – 41 ]. Oxidative stress caused by free radicals generated from radiation plays a major role in radiation-induced injury.…”