Curative approaches for sickle cell disease: A review of allogeneic and autologous strategies
Introduction
All curative therapies depend upon engraftment of hematopoietic cells. In this review we use “cure” to mean durable modification of hematopoietic stem cells in a manner to prevent clinical manifestations of SCD. Cure could be achieved by transplant of HSCs from a healthy donor, addition of an anti-sickling globin gene to patient HSCs, repair of the sickle cell mutation itself, or induction of fetal hemoglobin (HbF) to levels that prevent sickling. We discuss each of these approaches in detail below (Fig. 1). Various intensities of pre-transplantation conditioning therapies may be given to promote hematopoietic cell engraftment accompanied by an array of regimens to limit the risk of graft-versus-host disease (GvHD) that is mediated by allogeneic immune cells. With myeloablative protocols, total body irradiation (TBI) and/or chemotherapy is given at doses which would not allow autologous hematopoietic recovery. Nonmyeloablative regimens rely on intensive immunosuppressive conditioning along with high numbers of donor CD34 + cells and donor T lymphocytes to enable engraftment. Reduced intensity regimens deliver an intermediate level of conditioning. Investigational targeted therapies suggest the future potential to “make space” in the bone marrow for HSC engraftment without the risks of conventional chemotherapy or radiotherapy [1], [2], [3].
Section snippets
HLA-matched sibling donors
The first successful report of HSCT in SCD was in 1984, a patient transplanted for AML [4]. Since then, myeloablative conditioning, including busulfan and cyclophosphamide, have become established as the standard approach for pediatric patients with severe disease [5]. The French group reported a decrease in graft rejection rate from 22.6% to 2.9% with the addition of anti-thymocyte globulin (ATG) and an impressive event-free survival (EFS) of 95% [6]. ATG use is now commonplace. Published data
Hematopoietic stem cell based gene therapy
Since the first successful gene therapy was reported more than a decade ago, the field has rapidly evolved [44]. During the first decade of the millennium, hematopoietic cell based gene therapies for several life threatening immunodeficiencies using γ-retroviral vectors led to mixed results (for X-linked severe combined immunodeficiency, adenosine deaminase-deficient severe combined immunodeficiency, Wiskott-Aldrich syndrome, and X-linked chronic granulomatous disease) [44], [45], [46], [47].
Gene editing
Genome editing technology enables the production of specified changes to DNA sequences within cells. Diseases with a genetic etiology like SCD could be fundamentally addressed by genome editing. In this section we consider the current landscape of genome editing technologies and review therapeutic approaches relevant to SCD, including key parameters for success, areas of challenge, and anticipated future directions for the field.
Since the discovery of the molecular basis of SCD as a single
Conclusion
As curative therapies for SCD advance, a moral imperative will be to extend these gains to as many patients as possible, including those in Africa, where the worldwide burden of SCD is greatest. Major areas of future research will be how to simplify the procedures for allogeneic HSCT, viral gene therapy, and genome editing. Advances in HSC procurement, ex vivo manipulation of pluripotent and hematopoietic stem cells, and conditioning therapy could help extend curative therapies. Alternatively,
Acknowledgements
D.E.B. was supported by NIDDK (K08DK093705, R03DK109232), NHLBI (DP2OD022716), Burroughs Wellcome Fund (1014696), American Society of Hematology, Harvard Stem Cell Institute, and the Doris Duke Charitable Foundation (2015134), Charles H. Hood Foundation, and Cooley's Anemia Foundation. C.B. was supported by NIH grant HL117720-03. C.D.F. was supported by the intramural program of the National Heart, Lung, and Blood Institute, NIH.
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