Allogeneic cellular and autologous stem cell therapy for sickle cell disease: ‘whom, when and how’

Abstract

Sickle cell disease (SCD) is an autosomal recessive inherited hematological disorder characterized by chronic hemolysis and vaso-occlusion, resulting in multiorgan dysfunction and premature death. The only known curative therapy for patients with severe SCD is myeloablative conditioning and allo-SCT from HLA-matched sibling donors. In this state of the art review, we discuss current and future considerations including patient selection/eligibility, intensity of conditioning regimens, allogeneic graft sources, graft manipulation, mixed donor chimerism, organ function and stability and autologous gene correction stem cell strategies. Recent novel approaches to promote mixed donor chimerism have included the use of matched unrelated adult donors, umbilical cord blood donors, haploidentical familial donors and the utilization of nonmyeloablative, such as reduced intensity and reduced toxicity conditioning regimens. Future strategies will include gene therapy and autologous gene correction stem cell designs. Prospects are bright for novel stem and cellular approaches for patients with severe SCD, and we are currently at the end of the beginning for utilizing cellular therapeutics for the curative treatment of this chronic and debilitating condition.

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease

“…Perhaps the time has arrived where allo-SCT is offered to children with HLA-matched sibling donors with or without early SCD complications. 36,37 Limitations to this trial include the small number of patients with limited follow-up. In addition, the authors are aware that alemtuzumab is not readily available to all centers performing allo-SCT for SCD.…”

Smoothing the crescent curve: sickle cell disease

“…35,36 Most recently, the technology to develop iPSCs from mature somatic cells has allowed advanced gene editing approaches using site directed endonucleases, such as zinc finger nucleases, transcription activator-like effector nucleases, and clustered regulatory interspaced short palindromic repeat endonucleases, to induce double-stranded DNA breaks and after nonhomologous end joining or homology-directed repair/homologous reconstitution gene correction strategies ( Figure 4A-D). 21,37,38 Future studies are required to determine the long-term efficacy and safety of these recent iPSC gene-editing strategies.…”

“…21 For patients with thalassemia, Lucarelli et al originally designed a conditioning regimen consisting of hydroxyurea and azathioprine between days Ϫ45 and Ϫ11 before Flu 20 mg/m 2 /d ϫ 6 days, Bu 14 mg/kg/total dose and Cy 60 mg/kg/total dose in 33 poor-risk class 3 thalassemia patients before allo-HSCT. Graft rejection was reduced to only 8% compared with the previous 30% reported from the same group without the hydroxyurea, azathioprine, and Flu.…”

“…21 We have adopted the conditioning regimen that Lucarelli piloted in the FHI TCD allo-HSCT study in a high-risk thalassemia population ( Figure 1A). We have included the addition of total lymphoid irradiation to potentially reduce the rejection rate in this SCD population.…”

“…21 To circumvent this limitation, gene therapy using autologous stem cells offers an alternative therapeutic strategy to overcome lack of HLA-matched allogeneic donors and allo-HSCT-related morbidity and mortality. 25 Alternatively, recent investigations of developing induced pluripotent stem cells (iPSCs) and new gene-editing approaches to deliver site-specific double-stranded DNA breaks allows for both nonhomologous end joining and homology-directed repair/homologous reconstitution facilitating gene correction strategies in SCD.…”