Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Therapeutic strategies for sickle cell disease: towards a multi-agent approach

Abstract

For over 100 years, clinicians and scientists have been unravelling the consequences of the A to T substitution in the β-globin gene that produces haemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso-occlusion, anaemia, haemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of haemoglobin S polymerization and its effects on red blood cells, only two therapies for SCD — hydroxyurea and l-glutamine — are approved by the US Food and Drug Administration. Moreover, these treatment options do not fully address the manifestations of SCD, which arise from a complex network of interdependent pathophysiological processes. In this article, we review efforts to develop new drugs targeting these processes, including agents that reactivate fetal haemoglobin, anti-sickling agents, anti-adhesion agents, modulators of ischaemia–reperfusion and oxidative stress, agents that counteract free haemoglobin and haem, anti-inflammatory agents, anti-thrombotic agents and anti-platelet agents. We also discuss gene therapy, which holds promise of a cure, although its widespread application is currently limited by technical challenges and the expense of treatment. We thus propose that developing systems-oriented multi-agent strategies on the basis of SCD pathophysiology is needed to improve the quality of life and survival of people with SCD.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Pathophysiology of sickle cell disease.
Fig. 2: Sickle cell disease pathophysiological pathways and opportunities for targeted therapy.
Fig. 3: The pipeline of sickle cell disease therapies.

References

  1. 1.

    Bunn, H. F. Pathogenesis and treatment of sickle cell disease. N. Engl. J. Med. 337, 762–769 (1997).

    CAS  Google Scholar 

  2. 2.

    Rees, D. C., Williams, T. N. & Gladwin, M. T. Sickle-cell disease. Lancet 376, 2018–2031 (2010).

    CAS  Google Scholar 

  3. 3.

    Platt, O. S. et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N. Engl. J. Med. 330, 1639–1644 (1994).

    CAS  Google Scholar 

  4. 4.

    Kauf, T. L., Coates, T. D., Huazhi, L., Mody-Patel, N. & Hartzema, A. G. The cost of health care for children and adults with sickle cell disease. Am. J. Hematol. 84, 323–327 (2009).

    Google Scholar 

  5. 5.

    Elmariah, H. et al. Factors associated with survival in a contemporary adult sickle cell disease cohort. Am. J. Hematol. 89, 530–535 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Arnold, S. D., Bhatia, M., Horan, J. & Krishnamurti, L. Haematopoietic stem cell transplantation for sickle cell disease — current practice and new approaches. Br. J. Haematol. 174, 515–525 (2016).

    Google Scholar 

  7. 7.

    Fitzhugh, C. D., Abraham, A. A., Tisdale, J. F. & Hsieh, M. M. Hematopoietic stem cell transplantation for patients with sickle cell disease: progress and future directions. Hematol. Oncol. Clin. North Amer. 28, 1171–1185 (2014).

    Google Scholar 

  8. 8.

    Hulbert, M. L. & Shenoy, S. Hematopoietic stem cell transplantation for sickle cell disease: progress and challenges. Pediatr. Blood Cancer 65, e27263 (2018).

    Google Scholar 

  9. 9.

    Kassim, A. A. & Sharma, D. Hematopoietic stem cell transplantation for sickle cell disease: the changing landscape. Hematol. Oncol. Stem Cell Ther. 10, 259–266 (2017).

    Google Scholar 

  10. 10.

    Oringanje, C., Nemecek, E. & Oniyangi, O. Hematopoietic stem cell transplantation for people with sickle cell disease. Cochrane Database Syst. Rev. 19, CD007001 (2016).

    Google Scholar 

  11. 11.

    Walters, M. C. Update of hematopoietic cell transplantation for sickle cell disease. Curr. Opin. Hematol. 22, 227–233 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Eaton, W. A. & Bunn, H. F. Treating sickle cell disease by targeting HbS polymerization. Blood 129, 2719–2726 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Hebbel, R. P. Ischemia-reperfusion injury in sickle cell anemia: relationship to acute chest syndrome, endothelial dysfunction, arterial vasculopathy, and inflammatory pain. Hematol. Oncol. Clin. North Amer. 28, 181–198 (2014).

    Google Scholar 

  14. 14.

    Hebbel, R. P., Vercellotti, G. & Nath, K. A. A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis. Cardiovascular Hematol. Disord. Drug Targets 9, 271–292 (2009).

    CAS  Google Scholar 

  15. 15.

    Hebbel, R. P. Reconstructing sickle cell disease: a data-based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence-based medicine. Am. J. Hematol. 86, 123–154 (2011).

    CAS  Google Scholar 

  16. 16.

    Hebbel, R. P., Osarogiagbon, R. & Kaul, D. The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy. Microcirculation 11, 129–151 (2004).

    CAS  Google Scholar 

  17. 17.

    Zennadi, R. et al. Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-αvβ3 interactions. Blood 104, 3774–3781 (2004).

    CAS  Google Scholar 

  18. 18.

    Zennadi, R. et al. Erythrocyte plasma membrane-bound ERK1/2 activation promotes ICAM-4-mediated sickle red cell adhesion to endothelium. Blood 119, 1217–1227 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    George, A. et al. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood 121, 2099–2107 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Wun, T. et al. Platelet-erythrocyte adhesion in sickle cell disease. J. Investig. Med. 47, 121–127 (1999).

    CAS  Google Scholar 

  21. 21.

    Wun, T. et al. Platelet activation and platelet-erythrocyte aggregates in patients with sickle cell anemia. J. Lab. Clin. Med. 129, 507–516 (1997).

    CAS  Google Scholar 

  22. 22.

    Frenette, P. S. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr. Opin. Hematol. 9, 101–106 (2002).

    Google Scholar 

  23. 23.

    Frenette, P. S. Sickle cell vasoocclusion: heterotypic, multicellular aggregations driven by leukocyte adhesion. Microcirculation 11, 167–177 (2004).

    CAS  Google Scholar 

  24. 24.

    Turhan, A., Weiss, L. A., Mohandas, N., Coller, B. S. & Frenette, P. S. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proc. Natl Acad. Sci. USA 99, 3047–3051 (2002).

    CAS  Google Scholar 

  25. 25.

    Brittain, J. E., Knoll, C. M., Ataga, K. I., Orringer, E. P. & Parise, L. V. Fibronectin bridges monocytes and reticulocytes via integrin α4β1. Br. J. Haematol. 141, 872–881 (2008).

    CAS  Google Scholar 

  26. 26.

    Hidalgo, A. et al. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nat. Med. 15, 384–391 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Shiu, Y. T., Udden, M. M. & McIntire, L. V. Perfusion with sickle erythrocytes up-regulates ICAM-1 and VCAM-1 gene expression in cultured human endothelial cells. Blood 95, 3232–3241 (2000).

    CAS  Google Scholar 

  28. 28.

    Li, H. & Lykotrafitis, G. Erythrocyte membrane model with explicit description of the lipid bilayer and the spectrin network. Biophys. J. 107, 642–653 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    de Jong, K., Larkin, S. K., Styles, L. A., Bookchin, R. M. & Kuypers, F. A. Characterization of the phosphatidylserine-exposing subpopulation of sickle cells. Blood 98, (860–867 (2001).

    Google Scholar 

  30. 30.

    Joiner, C. H., Jiang, M. & Franco, R. S. Deoxygenation-induced cation fluxes in sickle cells. IV. Modulation by external calcium. Am. J. Physiol. 269, C403–409 (1995).

    CAS  Google Scholar 

  31. 31.

    Mankelow, T. J. et al. Autophagic vesicles on mature human reticulocytes explain phosphatidylserine-positive red cells in sickle cell disease. Blood 126, 1831–1834 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kuypers, F. A. & de Jong, K. The role of phosphatidylserine in recognition and removal of erythrocytes. Cell. Mol. Biol. 50, 147–158 (2004).

    CAS  Google Scholar 

  33. 33.

    Villagra, J. et al. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 110, 2166–2172 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Brittain, H. A., Eckman, J. R., Swerlick, R. A., Howard, R. J. & Wick, T. M. Thrombospondin from activated platelets promotes sickle erythrocyte adherence to human microvascular endothelium under physiologic flow: a potential role for platelet activation in sickle cell vaso-occlusion. Blood 81, 2137–2143 (1993).

    CAS  Google Scholar 

  35. 35.

    Setty, B. N., Kulkarni, S., Rao, A. K. & Stuart, M. J. Fetal hemoglobin in sickle cell disease: relationship to erythrocyte phosphatidylserine exposure and coagulation activation. Blood 96, 1119–1124 (2000).

    CAS  Google Scholar 

  36. 36.

    Arumugam, P. I. et al. Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice. Blood 126, 1844–1855 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Lee, S. P., Ataga, K. I., Orringer, E. P., Phillips, D. R. & Parise, L. V. Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation. Arterioscler. Thromb. Vasc. Biol. 26, 1626–1631 (2006).

    CAS  Google Scholar 

  38. 38.

    Lee, S. P. et al. Phase I study of eptifibatide in patients with sickle cell anaemia. Br. J. Haematol. 139, 612–620 (2007).

    CAS  Google Scholar 

  39. 39.

    Polanowska-Grabowska, R. et al. P-Selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease. Arterioscler. Thromb. Vasc. Biol. 30, 2392–2399 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Bennewitz, M. F. et al. Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli. JCI Insight 2, e89761 (2017).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Dominical, V. M. et al. Prominent role of platelets in the formation of circulating neutrophil-red cell heterocellular aggregates in sickle cell anemia. Haematologica 99, e214–217 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zennadi, R., Chien, A., Xu, K., Batchvarova, M. & Telen, M. J. Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium. Blood 112, 3474–3483 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Belcher, J. D. et al. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J. Clin. Invest. 116, 808–816 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Ghosh, S. et al. Extracellular hemin crisis triggers acute chest syndrome in sickle mice. J. Clin. Invest. 123, 4809–4820 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Belcher, J. D. et al. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123, 377–390 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Bean, C. J. et al. Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease. Blood 120, 3822–3828 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Belcher, J. D., Nath, K. A. & Vercellotti, G. M. Vasculotoxic and proinflammatory effects of plasma heme: cell signaling and cytoprotective responses. ISRN Oxidative Med. 2013, 831596 (2013).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Nagel, R. L. et al. Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S. Proc. Natl Acad. Sci. USA 76, 670–672 (1979).

    CAS  Google Scholar 

  49. 49.

    Akinsheye, I. et al. Fetal hemoglobin in sickle cell anemia. Blood 118, 19–27 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Estepp, J. H. et al. A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy. Am. J. Hematol. 92, 1333–1339 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Powars, D. R., Weiss, J. N., Chan, L. S. & Schroeder, W. A. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 63, 921–926 (1984).

    CAS  PubMed  Google Scholar 

  52. 52.

    Charache, S. et al. Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the γ-δ-β-globin gene complex. Proc. Natl Acad. Sci. USA 80, 4842–4846 (1983).

    CAS  Google Scholar 

  53. 53.

    DeSimone, J., Heller, P., Hall, L. & Zwiers, D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc. Natl Acad. Sci. USA 79, 4428–4431 (1982).

    CAS  Google Scholar 

  54. 54.

    Ley, T. J. et al. 5-Azacytidine selectively increases γ-globin synthesis in a patient with β+ thalassemia. N. Engl. J. Med. 307, 1469–1475 (1982).

    CAS  Google Scholar 

  55. 55.

    McGann, P. T. & Ware, R. E. Hydroxyurea therapy for sickle cell anemia. Expert Opin. Drug Saf. 14, 1749–1758 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Molokie, R. et al. Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: a randomized phase 1 study. PLOS Med. 14, e1002382 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Atweh, G. F. et al. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood 93, 1790–1797 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Kutlar, A. et al. A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am. J. Hematol. 88, E255–E260 (2013).

    CAS  Google Scholar 

  59. 59.

    Reid, M. E. et al. A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am. J. Hematol. 89, 709–713 (2014).

    CAS  Google Scholar 

  60. 60.

    Bradner, J. E. et al. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc. Natl Acad. Sci. USA 107, 12617–12622 (2010).

    CAS  Google Scholar 

  61. 61.

    Shi, L., Cui, S., Engel, J. D. & Tanabe, O. Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat. Med. 19, 291–294 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Rivers, A. et al. RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases γ-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model. Exp. Hematol. 43, 546–553 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Cui, S. et al. The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice. Blood 126, 386–396 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Dai, Y., Chen, T., Ijaz, H., Cho, E. H. & Steinberg, M. H. SIRT1 activates the expression of fetal hemoglobin genes. Am. J. Hematol. 92, 1177–1186 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Lanaro, C. et al. A thalidomide-hydroxyurea hybrid increases HbF production in sickle cell mice and reduces the release of proinflammatory cytokines in cultured monocytes. Exp. Hematol. 58, 35–38 (2018).

    CAS  Google Scholar 

  66. 66.

    Theodorou, A. et al. The investigation of resveratrol and analogs as potential inducers of fetal hemoglobin. Blood Cells Mol. Dis. 58, 6–12 (2016).

    CAS  Google Scholar 

  67. 67.

    Krishnamoorthy, S. et al. Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease. JCI Insight 2, 96409 (2017).

    Google Scholar 

  68. 68.

    Gomperts, E. et al. The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises. Am. J. Hematol. 92, 569–582 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Belcher, J. D. et al. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood 122, 2757–2764 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Howard, J. et al. Safety and tolerability of MP4CO: A dose escalation study In stable patients with sickle cell disease. Blood 122, 2205 (2013).

    Google Scholar 

  71. 71.

    Misra, H., Lickliter, J., Kazo, F. & Abuchowski, A. PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial. Artif. Organs 38, 702–707 (2014).

    CAS  Google Scholar 

  72. 72.

    Abuchowski, A. PEGylated bovine carboxyhemoglobin (SANGUINATE): results of clinical safety testing and use in patients. Adv. Exp. Med. Biol. 876, 461–467 (2016).

    CAS  Google Scholar 

  73. 73.

    Swift, R. et al. SCD-101: a new anti-sickling drug reduces pain and fatigue and improves red blood cell shape in peripheral blood of patients with sickle cell disease. Blood 128, 121–121 (2016).

    Google Scholar 

  74. 74.

    Iyamu, E. W., Turner, E. A. & Asakura, T. In vitro effects of NIPRISAN (Nix-0699): a naturally occurring, potent antisickling agent. Br. J. Haematol. 118, 337–343 (2002).

    CAS  Google Scholar 

  75. 75.

    Wambebe, C. et al. Double-blind, placebo-controlled, randomised cross-over clinical trial of NIPRISAN in patients with sickle cell disorder. Phytomedicine 8, 252–261 (2001).

    CAS  Google Scholar 

  76. 76.

    Lehrer-Graiwer, J. et al. Long-term dosing in sickle cell disease subjects with GBT440, a novel HbS polymerization inhibitor. Blood 128, 2488 (2016).

    Google Scholar 

  77. 77.

    Hebbel, R. P. & Hedlund, B. E. Sickle hemoglobin oxygen affinity-shifting strategies have unequal cerebrovascular risks. Am. J. Hematol. 93, 321–325 (2018).

    Google Scholar 

  78. 78.

    Morris, C. R. et al. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 111, 402–410 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Whillier, S., Garcia, B., Chapman, B. E., Kuchel, P. W. & Raftos, J. E. Glutamine and α-ketoglutarate as glutamate sources for glutathione synthesis in human erythrocytes. FEBS J. 278, 3152–3163 (2011).

    CAS  PubMed  Google Scholar 

  80. 80.

    Niihara, Y. et al. L-Glutamine therapy reduces endothelial adhesion of sickle red blood cells to human umbilical vein endothelial cells. BMC Blood Disord. 5, 4 (2005).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Niihara, Y. et al. A Phase 3 study of L-glutamine therapy for sickle cell anemia and sickle ß-thalassemia. Blood 124, 86–86 (2014).

    Google Scholar 

  82. 82.

    Wilmore, D. W. Food and Drug Administration approval of glutamine for sickle cell disease: success and precautions in glutamine research. JPEN J. Parenter Enteral Nutr. 41, 912–917 (2017).

    Google Scholar 

  83. 83.

    Wood, K. C., Hebbel, R. P. & Granger, D. N. Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice. FASEB J. 19, 989–991 (2005).

    CAS  Google Scholar 

  84. 84.

    Kaul, D. K. et al. Anti-inflammatory therapy ameliorates leukocyte adhesion and microvascular flow abnormalities in transgenic sickle mice. American journal of physiology. Heart Circulatory Physiol. 287, H293–301 (2004).

    CAS  Google Scholar 

  85. 85.

    Nur, E. et al. N-Acetylcysteine reduces oxidative stress in sickle cell patients. Ann. Hematol. 91, 1097–1105 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Ozpolat, H. T. et al. A pilot study of high-dose N-acetylcysteine infusion in patients with sickle cell disease. Blood 128, 1299–1299 (2016).

    Google Scholar 

  87. 87.

    Sins, J. W. R. et al. N-acetylcysteine in patients with sickle cell disease: a randomized controlled trial. Blood 128, 123–123 (2016).

    Google Scholar 

  88. 88.

    Wallace, K. L. & Linden, J. Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease. Blood 116, 5010–5020 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Reilly, E. C., Wands, J. R. & Brossay, L. Cytokine dependent and independent iNKT cell activation. Cytokine 51, 227–231 (2010).

    CAS  Google Scholar 

  90. 90.

    Field, J. J. et al. Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood 121, 3329–3334 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Field, J. J. et al. Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease. Blood Adv. 1, 1645–1649 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Solovey, A. et al. A monocyte-TNF-endothelial activation axis in sickle transgenic mice: therapeutic benefit from TNF blockade. Am. J. Hemat. 12292, 1119–1130 (2017).

    Google Scholar 

  93. 93.

    Adelowo, O. & Edunjobi, A. S. Juvenile idiopathic arthritis coexisting with sickle cell disease: two case reports. BMJ Case Rep. 2011, bcr1020114889 (2011).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Gorsuch, W. B., Chrysanthou, E., Schwaeble, W. J. & Stahl, G. L. The complement system in ischemia-reperfusion injuries. Immunobiology 217, 1026–1033 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Wang, R. H., Phillips, G. Jr., Medof, M. E. & Mold, C. Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients. J. Clin. Invest. 92, 1326–1335 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Zwaal, R. F. & Schroit, A. J. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 89, 1121–1132 (1997).

    CAS  Google Scholar 

  97. 97.

    Krisinger, M. J. et al. Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood 120, 1717–1725 (2012).

    CAS  Google Scholar 

  98. 98.

    Schaid, T. R. et al. Complement activation in a murine model of sickle cell disease: inhibition of vaso-occlusion by blocking C5 activation. Blood 128, 158 (2016).

    Google Scholar 

  99. 99.

    Hoppe, C. et al. A pilot study of the short-term use of simvastatin in sickle cell disease: effects on markers of vascular dysfunction. Br. J. Haematol. 153, 655–663 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Hoppe, C. et al. Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial. Br. J. Haematol. 177, 620–629 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Rybicki, A. C. & Benjamin, L. J. Increased levels of endothelin-1 in plasma of sickle cell anemia patients. Blood 92, 2594–2596 (1998).

    CAS  Google Scholar 

  102. 102.

    Sabaa, N. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. J. Clin. Invest. 118, 1924–1933 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Prado, G. N., Romero, J. R. & Rivera, A. Endothelin-1 receptor antagonists regulate cell surface-associated protein disulfide isomerase in sickle cell disease. FASEB J. 27, 4619–4629 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Koehl, B. et al. The endothelin B receptor plays a crucial role for the adhesion of neutrophils to the endothelium in sickle cell disease. Haematologica 1028, 1161–1172 (2017).

    Google Scholar 

  105. 105.

    Elisa, T. et al. Endothelin receptors expressed by immune cells are involved in modulation of inflammation and in fibrosis: relevance to the pathogenesis of systemic sclerosis. J. Immunol. Res. 2015, 147616 (2015).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Chang, J., Shi, P. A., Chiang, E. Y. & Frenette, P. S. Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion. Blood 111, 915–923 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Jang, J. E., Hidalgo, A. & Frenette, P. S. Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1. Circul. Res. 110, 1057–1066 (2012).

    CAS  Google Scholar 

  108. 108.

    Manwani, D. et al. Single-dose intravenous γ-globulin can stabilize neutrophil Mac-1 activation in sickle cell pain crisis. Am. J. Hematol. 90, 381–385 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Almeida, C. B. et al. Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood 120, 2879–2888 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Barbosa, M. C. et al. The effect of a selective inhibitor of phosphodiesterase-9 on oxidative stress, inflammation and cytotoxicity in neutrophils from patients with sickle cell anaemia. Bas. Clin. Pharmacol. Toxicol. 118, 271–278 (2016).

    CAS  Google Scholar 

  111. 111.

    McArthur, J. C. et al. Novel highly potent and selective PDE9 inhibitor for the treament of sickle cell disease. Blood 128, 268 (2016).

    Google Scholar 

  112. 112.

    Morris, C. R. Alterations of the arginine metabolome in sickle cell disease: a growing rationale for arginine therapy. Hematol. Oncol. Clin. North Am. 28, 301–321 (2014).

    Google Scholar 

  113. 113.

    Morris, C. R. et al. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 98, 1375–1382 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Almeida, C. B. et al. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. Blood 126, 711–720 (2015).

    CAS  Google Scholar 

  115. 115.

    King, S. B. Nitric oxide production from hydroxyurea. Free Radic. Biol. Med. 37, 737–744 (2004).

    CAS  Google Scholar 

  116. 116.

    Belcher, J. D. et al. Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: role of heme oxygenase-1 induction. PLOS ONE 13, e0196455 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Vercellotti, G. M. et al. Hepatic overexpression of hemopexin inhibits inflammation and vascular stasis in murine models of sickle cell disease. Mol. Med. 22, 437–451 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Belcher, J. D. et al. Haptoglobin and hemopexin infusion efficiently activates the Nrf2/HO-1 axis and inhibits inflammation and vaso-occlusion in murine sickle cell disease. Blood 128, 2477–2477 (2016).

    Google Scholar 

  119. 119.

    Sparkenbaugh, E. & Pawlinski, R. Interplay between coagulation and vascular inflammation in sickle cell disease. Br. J. Haematol. 162, 3–14 (2013).

    CAS  Google Scholar 

  120. 120.

    Zhang, D., Xu, C., Manwani, D. & Frenette, P. S. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 127, 801–809 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Setty, B. N. & Stuart, M. J. Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease. Blood 88, 2311–2320 (1996).

    CAS  Google Scholar 

  122. 122.

    Lim, M. Y., Ataga, K. I. & Key, N. S. Hemostatic abnormalities in sickle cell disease. Curr. Opin. Hematol. 20, 472–477 (2013).

    CAS  Google Scholar 

  123. 123.

    Noubouossie, D., Key, N. S. & Ataga, K. I. Coagulation abnormalities of sickle cell disease: relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev. 30, 245–256 (2016).

    CAS  Google Scholar 

  124. 124.

    Whelihan, M. F. et al. Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. J. Thromb. Haemost. 14, 1941–1952 (2016).

    CAS  Google Scholar 

  125. 125.

    Gordon, E. M. et al. Reduction of contact factors in sickle cell disease. J. Pediatr. 106, 427–430 (1985).

    CAS  Google Scholar 

  126. 126.

    LourenCo, D., Sampaio, M. U., Kerbauy, J. & Sampaio, C. A. Estimation of plasma kallikrein in sickle-cell anemia, and its relation to the coagulation and fibrinolytic systems. Adv. Exp. Med. Biol. 247B, 553–557 (1989).

    CAS  Google Scholar 

  127. 127.

    Miller, R. L., Verma, P. S. & Adams, R. G. Studies of the kallikrein-kinin system in patients with sickle cell anemia. J. Natl Med. Associ. 75, 551–556 (1983).

    CAS  Google Scholar 

  128. 128.

    Solovey, A., Gui, L., Key, N. S. & Hebbel, R. P. Tissue factor expression by endothelial cells in sickle cell anemia. J. Clin. Invest. 101, 1899–1904 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Solovey, A. et al. Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin. Blood 104, 840–846 (2004).

    CAS  Google Scholar 

  130. 130.

    Salvaggio, J. E., Arnold, C. A. & Banov, C. H. Long-term anti-coagulation in sickle-cell disease. A clinical study. N. Engl. J. Med. 269, 182–186 (1963).

    CAS  Google Scholar 

  131. 131.

    Adelson, H. T. Long-term dicumarol administration as a therapeutic trial in sicklemia; report of a case. N. Engl. J. Med. 256, 353–354 (1957).

    CAS  Google Scholar 

  132. 132.

    Chaplin, H. Jr. et al. Preliminary trial of minidose heparin prophylaxis for painful sickle cell crises. East Afr. Med. J. 66, 574–584 (1989).

    Google Scholar 

  133. 133.

    Qari, M. H. et al. Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Thromb. Haemostasis 98, 392–396 (2007).

    CAS  Google Scholar 

  134. 134.

    Wun, T. et al. Platelet activation in patients with sickle cell disease. Br. J. Haematol. 100, 741–749 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Kataoka, H. et al. Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells. Blood 102, 3224–3231 (2003).

    CAS  Google Scholar 

  136. 136.

    Coughlin, S. R. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800–1814 (2005).

    CAS  Google Scholar 

  137. 137.

    Loscalzo, J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ. Res. 88, 756–762 (2001).

    CAS  Google Scholar 

  138. 138.

    Kim, K. et al. Neutrophil Akt2 plays a critical role in heterotypic neutrophil-platelet interactions during vascular inflammation. Blood 122, 321–321 (2013).

    Google Scholar 

  139. 139.

    Li, J. et al. Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation. J. Clin. Invest. 124, 1483–1496 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Barazia, A., Li, J., Kim, K., Shabrani, N. & Cho, J. Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice. Blood 126, 2511–2517 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Hoppe, C. C. et al. Design of the DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) trial: a global Phase 3 double-blind, randomized, placebo-controlled, multicenter study of the efficacy and safety of prasugrel in pediatric patients with sickle cell anemia utilizing a dose titration strategy. Pediatr. Blood Cancer 63, 299–305 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Heeney, M. M. et al. A multinational trial of prasugrel for sickle cell vaso-occlusive events. N. Engl. J. Med. 374, 625–635 (2016).

    CAS  Google Scholar 

  143. 143.

    Styles, L. et al. Prasugrel in children with sickle cell disease: pharmacokinetic and pharmacodynamic data from an open-label, adaptive-design, dose-ranging study. J. Pediatr. Hematol. Oncol. 37, 1–9 (2015).

    CAS  Google Scholar 

  144. 144.

    Jakubowski, J. A. et al. A phase 1 study of prasugrel in patients with sickle cell disease: effects on biomarkers of platelet activation and coagulation. Thromb. Res. 133, 190–195 (2014).

    CAS  Google Scholar 

  145. 145.

    Wun, T. et al. A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease. J. Hematol. Oncol. 6, 17 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Chang, J. et al. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 116, 1779–1786 (2010).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Telen, M. J. et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 125, 2656–2664 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Ataga, K. I. et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N. Engl. J. Med. 376, 429–439 (2017).

    CAS  Google Scholar 

  149. 149.

    Telen, M. J. et al. Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion. Br. J. Haematol. 175, 935–948 (2016).

    CAS  Google Scholar 

  150. 150.

    Leitgeb, A. M. et al. Low anticoagulant heparin disrupts Plasmodium falciparum rosettes in fresh clinical isolates. Am. J. Trop. Med. Hyg. 84, 390–396 (2011).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Alshaiban, A., Muralidharan-Chari, V., Nepo, A. & Mousa, S. A. Modulation of sickle red blood cell adhesion and its associated changes in biomarkers by sulfated nonanticoagulant heparin derivative. Clin. Appl. Thromb. Hemost. 22, 230–238 (2015).

    Google Scholar 

  152. 152.

    Kaul, D. K. et al. Monoclonal antibodies to αVβ3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood 95, 368–374 (2000).

    CAS  Google Scholar 

  153. 153.

    Zennadi, R. et al. Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo. Blood 110, 2708–2717 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Zennadi, R. et al. Role and regulation of sickle red cell interactions with other cells: ICAM-4 and other adhesion receptors. Transfus. Clin. Biol. 15, 23–28 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    De Castro, L. M., Zennadi, R., Jonassaint, J. C., Batchvarova, M. & Telen, M. J. Effect of propranolol as antiadhesive therapy in sickle cell disease. Clin. Transl Sci. 5, 437–444 (2012).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    De Castro, L. M. Propranolol: anti-adhesive scd treatment. (a phase II study of propranolol as anti-adhesive therapy for sickle cell disease). J. Sick. Cell Dis. Hemoglobinopathies 15, 00039 (2015).

    Google Scholar 

  157. 157.

    Soderblom, E. J. et al. Proteomic analysis of ERK1/2-mediated human sickle red blood cell membrane protein phosphorylation. Clin. Proteomics 10, 1 (2013).

    Google Scholar 

  158. 158.

    Zennadi, R. MEK inhibitors, novel anti-adhesive molecules, reduce sickle red blood cell adhesion in vitro and in vivo, and vasoocclusion in vivo. PLOS ONE 9, e110306 (2014).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Allareddy, V. et al. Outcomes of acute chest syndrome in adult patients with sickle cell disease: predictors of mortality. PLOS ONE 9, e94387 (2014).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Ataga, K. I. et al. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br. J. Haematol. 134, 109–115 (2006).

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Gladwin, M. T. et al. Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLOS ONE 9, e99489 (2014).

    PubMed  PubMed Central  Google Scholar 

  162. 162.

    Lima, A. R., Ribeiro, V. S. & Nicolau, D. I. Trends in mortality and hospital admissions of sickle cell disease patients before and after the newborn screening program in Maranhao. Brazil. Revista Brasileira Hematol. Hemoterapia 37, 12–16 (2015).

    Google Scholar 

  163. 163.

    Sabarense, A. P., Lima, G. O., Silva, L. M. & Viana, M. B. Characterization of mortality in children with sickle cell disease diagnosed through the Newborn Screening Program. J. Pediatr. 91, 242–247 (2014).

    Google Scholar 

  164. 164.

    Wang, Y. et al. Mortality of New York children with sickle cell disease identified through newborn screening. Genet. Med. 174, 452–459 (2014).

    Google Scholar 

  165. 165.

    Stuart, M. J. & Setty, B. N. Sickle cell acute chest syndrome: pathogenesis and rationale for treatment. Blood 94, 1555–1560 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    US Food and Frug Administration. FDA approved L-glutamine powder for the treatment of sickle cell disease. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm566097.htm (FDA, 2017).

  167. 167.

    Styles, L. et al. Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE). Br. J. Haematol. 157, 627–636 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Maitre, B. et al. Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study. Intensive Care Med. 41, 2121–2129 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Barr, F. E. et al. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J. Thorac. Cardiovasc. Surg. 134, 319–326 (2007).

    CAS  Google Scholar 

  170. 170.

    Quinn, C. T. et al. Tapered oral dexamethasone for the acute chest syndrome of sickle cell disease. Br. J. Haematol. 155, 263–267 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Kumar, R., Qureshi, S., Mohanty, P., Rao, S. P. & Miller, S. T. A short course of prednisone in the management of acute chest syndrome of sickle cell disease. J. Pediatr. Hematol. Oncol. 32, e91–94 (2010).

    CAS  Google Scholar 

  172. 172.

    Strouse, J. J., Takemoto, C. M., Keefer, J. R., Kato, G. J. & Casella, J. F. Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatr. Blood Cancer 50, 1006–1012 (2008).

    PubMed  PubMed Central  Google Scholar 

  173. 173.

    Sabaa, N. et al. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. J. Clin. Invest. 118, 1924–1933 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Minniti, C. P. et al. Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease. Br. J. Haematol. 147, 737–743 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Barst, R. J. et al. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br. J. Haematol. 149, 426–435 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Ashley-Koch, A. E. et al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br. J. Haematol. 155, 386–394 (2011).

    CAS  Google Scholar 

  177. 177.

    De Castro, L. M., Jonassaint, J. C., Graham, F. L., Ashley-Koch, A. & Telen, M. J. Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am. J. Hematol. 83, 19–25 (2008).

    Google Scholar 

  178. 178.

    Falk, R. J. et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N. Engl. J. Med. 326, 910–915 (1992).

    CAS  Google Scholar 

  179. 179.

    Sasongko, T. H., Nagalla, S. & Ballas, S. K. Angiotensin-converting enzyme (ACE) inhibitors for proteinuria and microalbuminuria in people with sickle cell disease. Cochrane Database Syst. Rev. 6, CD009191 (2015).

    Google Scholar 

  180. 180.

    Ataga, K. I., Derebail, V. K. & Archer, D. R. The glomerulopathy of sickle cell disease. Am. J. Hematol. 89, 907–914 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Quinn, C. T. et al. Losartan for the nephropathy of sickle cell anemia: a phase-2, multi-center trial. Am. J. Hematol. 92, E520–E528 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Walters, M. C. et al. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol. Blood Marrow Transplant. 7, 665–673 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Perumbeti, A. et al. A novel human γ-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood 114, 1174–1185 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Naldini, L. Lentiviruses as gene transfer agents for delivery to non-dividing cells. Curr. Opin. Biotechnol. 9, 457–463 (1998).

    CAS  Google Scholar 

  185. 185.

    Case, S. S. et al. Stable transduction of quiescent CD34+CD38 human hematopoietic cells by HIV-1-based lentiviral vectors. Proc. Natl Acad. Sci. USA 96, 2988–2993 (1999).

    CAS  Google Scholar 

  186. 186.

    Sessa, M. et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 388, 476–487 (2016).

    CAS  Google Scholar 

  187. 187.

    Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341, 1233151 (2013).

    PubMed  PubMed Central  Google Scholar 

  188. 188.

    Eichler, F. et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N. Engl. J. Med. 377, 1630–1638 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823 (2009).

    CAS  Google Scholar 

  190. 190.

    Ribeil, J. A. et al. Gene therapy in a patient with sickle cell disease. N. Engl. J. Med. 376, 848–855 (2017).

    CAS  Google Scholar 

  191. 191.

    Cavazzana-Calvo, M. et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 467, 318–322 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Thompson, A. A. et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 378, 1479–1493 (2018).

    CAS  Google Scholar 

  193. 193.

    Pawliuk, R. et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 294, 2368–2371 (2001).

    CAS  PubMed  Google Scholar 

  194. 194.

    Hoban, M. D. et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood 125, 2597–2604 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    Levasseur, D. N., Ryan, T. M., Pawlik, K. M. & Townes, T. M. Correction of a mouse model of sickle cell disease: lentiviral/antisickling β-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood 102, 4312–4319 (2003).

    CAS  PubMed  Google Scholar 

  196. 196.

    Levasseur, D. N. et al. A recombinant human hemoglobin with anti-sickling properties greater than fetal hemoglobin. J. Biol. Chem. 279, 27518–27524 (2004).

    CAS  Google Scholar 

  197. 197.

    Dever, D. P. et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    De Ravin, S. S. et al. CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease. Sci. Transl Med. 9, eaah3480 (2017).

    Google Scholar 

  199. 199.

    Cornu, T. I., Mussolino, C. & Cathomen, T. Refining strategies to translate genome editing to the clinic. Nat. Med. 23, (415–423 (2017).

    Google Scholar 

  200. 200.

    Bak, R. O. & Porteus, M. H. CRISPR-mediated integration of large gene cassettes using AAV donor vectors. Cell Rep. 20, 750–756 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Wang, J. et al. Homology-driven genome editing in hematopoietic stem and progenitor cells using ZFN mRNA and AAV6 donors. Nat. Biotechnol. 33, 1256–1263 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Lin, S., Staahl, B. T., Alla, R. K. & Doudna, J. A. Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. eLife 3, e04766 (2014).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Charpentier, M. et al. CtIP fusion to Cas9 enhances transgene integration by homology-dependent repair. Nat. Commun. 9, 1133 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Canny, M. D. et al. Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nat. Biotechnol. 36, 95–102 (2018).

    CAS  Google Scholar 

  205. 205.

    Kuscu, C., Arslan, S., Singh, R., Thorpe, J. & Adli, M. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease. Nat. Biotechnol. 32, 677–683 (2014).

    CAS  Google Scholar 

  206. 206.

    Fu, Y. et al. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat. Biotechnol. 31, 822–826 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Basak, A. et al. BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations. J. Clin. Invest. 125, 2363–2368 (2015).

    PubMed  PubMed Central  Google Scholar 

  208. 208.

    Brendel, C. et al. Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J. Clin. Invest. 126, 3868–3878 (2016).

    PubMed  PubMed Central  Google Scholar 

  209. 209.

    Traxler, E. A. et al. A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22, 987–990 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210.

    Hoban, M. D. et al. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol. Ther. 24, 1561–1569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    DeWitt, M. A. et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci. Transl Med. 8, 360ra134 (2016).

    PubMed  PubMed Central  Google Scholar 

  212. 212.

    Boulad, F. et al. Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results. Haematologica 103, 770–777 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213.

    Hsieh, M. M. & Tisdale, J. F. Hematopoietic stem cell mobilization with plerixafor in sickle cell disease. Haematologica 103, 749–750 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214.

    Lagresle-Peyrou, C. et al. Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. Haematologica 103, 778–786 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215.

    Hoppe, C. C. et al. Initial results from a cohort in a phase 2a study (GBT440-007) evaluating adolescents with sickle cell disease treated with multiple doses of GBT440, a HbS polymerization inhibitor. Blood 689, 689 (2017).

    Google Scholar 

  216. 216.

    Paszty, C. et al. Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease. Science 278, 876–878 (1997).

    CAS  Google Scholar 

  217. 217.

    Ryan, T. M. et al. Human sickle hemoglobin in transgenic mice. Science 247, 566–568 (1990).

    CAS  Google Scholar 

  218. 218.

    Heeney, M. M., Hoppe, C. C. & Rees, D. C. Prasugrel for sickle cell vaso-occlusive events. N. Engl. J. Med. 375, 185–186 (2016).

    Google Scholar 

  219. 219.

    Charache, S. et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The multicenter study of hydroxyurea in sickle cell anemia. Medicine 75, 300–326 (1996).

    CAS  Google Scholar 

  220. 220.

    Alayash, A. I. Oxidative pathways in the sickle cell and beyond. Blood Cells Mol. Dis. 70, 78–86 (2017).

    Google Scholar 

  221. 221.

    Sangokoya, C., Telen, M. J. & Chi, J. T. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood 116, 4338–4348 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Jagadeeswaran, R. et al. Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease. Exp. Hematol. 50, 46–52 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    Kato, G. J., Steinberg, M. H. & Gladwin, M. T. Intravascular hemolysis and the pathophysiology of sickle cell disease. J. Clin. Invest. 127, 750–760 (2017).

    PubMed  PubMed Central  Google Scholar 

  224. 224.

    Schaer, D. J., Buehler, P. W., Alayash, A. I., Belcher, J. D. & Vercellotti, G. M. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 121, 1276–1284 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225.

    Manwani, D. & Frenette, P. S. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood 122, 3892–3898 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226.

    Dulmovits, B. M. et al. Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors. Blood 127, 1481–1492 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. 227.

    Abdulmalik, O. et al. 5-Hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells. Br. J. Haematol. 128, 552–561 (2005).

    CAS  Google Scholar 

  228. 228.

    Iyamu, E. W., Turner, E. A. & Asakura, T. Niprisan (Nix-0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions. Br. J. Haematol. 122, 1001–1008 (2003).

    CAS  Google Scholar 

  229. 229.

    Abdulmalik, O. et al. Crystallographic analysis of human hemoglobin elucidates the structural basis of the potent and dual antisickling activity of pyridyl derivatives of vanillin. Acta Crystallogr. D Biol. Crystallogr. 67, 920–928 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Abraham, D. J. et al. Vanillin, a potential agent for the treatment of sickle cell anemia. Blood 77, 1334–1341 (1991).

    CAS  Google Scholar 

  231. 231.

    Ouattara, B. et al. Antisickling properties of divanilloylquinic acids isolated from Fagara zanthoxyloides Lam. (Rutaceae). Phytomedicine 16, 125–129 (2009).

    CAS  Google Scholar 

  232. 232.

    Safo, M. K. et al. Vzhe-039, a novel structurally-enhanced allosteric hemoglobin effector inhibits sickling of SS erythrocytes in vitro, and exhibits improved pharmacologic properties in vivo. Blood 128, 3645–3645 (2016).

    Google Scholar 

  233. 233.

    Nakagawa, A. et al. Identification of a small molecule that increases hemoglobin oxygen affinity and reduces SS erythrocyte sickling. ACS Chem. Biol. 9, 2318–2325 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234.

    Zhang, Y. et al. Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression. J. Clin. Invest. 124, 2750–2761 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235.

    De Franceschi, L., Brugnara, C., Rouyer-Fessard, P., Jouault, H. & Beuzard, Y. Formation of dense erythrocytes in SAD mice exposed to chronic hypoxia: evaluation of different therapeutic regimens and of a combination of oral clotrimazole and magnesium therapies. Blood 94, 4307–4313 (1999).

    Google Scholar 

  236. 236.

    Brugnara, C. et al. Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease. J. Clin. Invest. 97, 1227–1234 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237.

    Ataga, K. I. et al. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br. J. Haematol. 153, 92–104 (2011).

    CAS  Google Scholar 

  238. 238.

    Hebbel, R. P. et al. The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice. Blood 115, 2483–2490 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239.

    Kaul, D. K. et al. Robust vascular protective effect of hydroxamic acid derivatives in a sickle mouse model of inflammation. Microcirculation 13, 489–497 (2006).

    CAS  Google Scholar 

  240. 240.

    Zhao, Y., Schwartz, E. A., Palmer, G. M. & Zennadi, R. MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. FASEB J. 30, 1171–1186 (2016).

    CAS  Google Scholar 

  241. 241.

    Mahaseth, H. et al. Polynitroxyl albumin inhibits inflammation and vasoocclusion in transgenic sickle mice. J. Lab. Clin. Med. 145, 204–211 (2005).

    CAS  Google Scholar 

  242. 242.

    Martins, V. D., Manfredini, V., Peralba, M. C. & Benfato, M. S. α-lipoic acid modifies oxidative stress parameters in sickle cell trait subjects and sickle cell patients. Clin. Nutr. 28, 192–197 (2009).

    CAS  Google Scholar 

  243. 243.

    El-Beshlawy, A. et al. Diastolic dysfunction and pulmonary hypertension in sickle cell anemia: is there a role for L-carnitine treatment? Acta Haematol. 115, 91–96 (2006).

    CAS  Google Scholar 

  244. 244.

    Serjeant, B. E., Harris, J., Thomas, P. & Serjeant, G. R. Propionyl-L-carnitine in chronic leg ulcers of homozygous sickle cell disease: a pilot study. J. Am. Acad. Dermatol. 37, 491–493 (1997).

    CAS  Google Scholar 

  245. 245.

    Musicki, B., Liu, T., Sezen, S. F. & Burnett, A. L. Targeting NADPH oxidase decreases oxidative stress in the transgenic sickle cell mouse penis. J. Sex. Med. 9, 1980–1987 (2012).

    CAS  Google Scholar 

  246. 246.

    Field, J. J. et al. A phase I single ascending dose study of NKTT120 in stable adult sickle cell patients. Blood 122, 977 (2013).

    Google Scholar 

  247. 247.

    Kalish, B. T. et al. Dietary omega-3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease. Haematologica 100, 870–880 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. 248.

    Daak, A. A. et al. Effect of omega-3 (n-3) fatty acid supplementation in patients with sickle cell anemia: randomized, double-blind, placebo-controlled trial. Am. J. Clin. Nutr. 97, 37–44 (2013).

    CAS  Google Scholar 

  249. 249.

    Beckman, J. D. et al. Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease. Am. J. Physiol. Heart Circ. Physiol. 297, H1243–1253 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250.

    Misra, H. et al. A Phase Ib open label, randomized, safety study of SANGUINATE in patients with sickle cell anemia. Rev. Bras. Hematol. Hemoter 39, 20–27 (2017).

    Google Scholar 

  251. 251.

    Haynes, J. et al. Zileuton induces hemoglobin F synthesis in erythroid progenitors: role of the L-arginine-nitric oxide signaling pathway. Blood 103, 3945–3950 (2004).

    CAS  Google Scholar 

  252. 252.

    Eiymo Mwa Mpollo, M. S. et al. Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13. J. Clin. Invest. 126, 571–584 (2016).

    Google Scholar 

  253. 253.

    Opene, M., Kurantsin-Mills, J., Husain, S. & Ibe, B. O. Sickle erythrocytes and platelets augment lung leukotriene synthesis with downregulation of anti-inflammatory proteins: relevance in the pathology of the acute chest syndrome. Pulmonary Circul. 4, 482–495 (2014).

    Google Scholar 

  254. 254.

    Belcher, J. D. et al. The fucosylation inhibitor, 2-fluorofucose, inhibits vaso-occlusion, leukocyte-endothelium interactions and NF-κB activation in transgenic sickle mice. PLOS ONE 10, e0117772 (2015).

    PubMed  PubMed Central  Google Scholar 

  255. 255.

    Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256.

    Valverde, Y., Benson, B., Gupta, M. & Gupta, K. Spinal glial activation and oxidative stress are alleviated by treatment with curcumin or coenzyme Q in sickle mice. Haematologica 101, e44–e47 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. 257.

    Semple, M. J., Al-Hasani, S. F., Kioy, P. & Savidge, G. F. A double-blind trial of ticlopidine in sickle cell disease. Thromb. Haemostasis 51, 303–306 (1984).

    CAS  Google Scholar 

  258. 258.

    Cabannes, R. et al. Clinical and biological double-blind-study of ticlopidine in preventive treatment of sickle-cell disease crises. Agents and actions. Supplements 15, 199–212 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259.

    Eke, F. U., Obamyonyi, A., Eke, N. N. & Oyewo, E. A. An open comparative study of dispersible piroxicam versus soluble acetylsalicylic acid for the treatment of osteoarticular painful attack during sickle cell crisis. Trop. Med. Int. Health 5, 81–84 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. 260.

    Desai, P. C. et al. A pilot study of eptifibatide for treatment of acute pain episodes in sickle cell disease. Thromb. Res. 132, 341–345 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261.

    Schnog, J. B. et al. Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study. Am. J. Hematol. 68, 179–183 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. 262.

    van Zuuren, E. J. & Fedorowicz, Z. Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. Cochrane Database Syst. Rev. 12, CD010155 (2015).

    Google Scholar 

  263. 263.

    Gladwin, M. T. et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 305, 893–902 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 264.

    Silva, F. H. et al. Beneficial effect of the nitric oxide donor compound 3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate on dysregulated phosphodiesterase 5, NADPH oxidase, and nitrosative stress in the sickle cell mouse penis: implication for priapism treatment. J. Pharmacol. Exp. Ther. 359, 230–237 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. 265.

    Katusic, Z. S., d’Uscio, L. V. & Nath, K. A. Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects. Trends Pharmacol. Sci. 30, 48–54 (2009).

    CAS  Google Scholar 

  266. 266.

    Machado, R. F. et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood 118, 855–864 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  267. 267.

    Minniti, C. P. et al. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. Lancet Haematol. 1, e95–e103 (2014).

    PubMed  PubMed Central  Google Scholar 

  268. 268.

    Belcher, J. D. N. et al. Dimethyl fumarate induces cytoprotection and inhibits vaso-occlusion in transgenic sickle mice. Blood 124, 219 (2014).

    Google Scholar 

  269. 269.

    Keleku-Lukwete, N. et al. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. Proc. Natl Acad. Sci. USA 112, 12169–12174 (2015).

    CAS  Google Scholar 

  270. 270.

    Ghosh, S. et al. Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice. JCI Insight 1, e81090 (2016).

    PubMed  PubMed Central  Google Scholar 

  271. 271.

    Belcher, J. D. et al. Heme oxygenase-1 gene delivery by Sleeping Beauty inhibits vascular stasis in a murine model of sickle cell disease. J. Mol. Med. 88, 665–675 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. 272.

    Shi, P. A. et al. Sustained treatment of sickle cell mice with haptoglobin increases HO-1 and H-ferritin expression and decreases iron deposition in the kidney without improvement in kidney function. Br. J. Haematol. 175, 714–723 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  273. 273.

    Vinchi, F. et al. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood 127, 473–486 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. 274.

    Burnette, A. D. et al. RNA aptamer therapy for vaso-occlusion in sickle cell disease. Nucleic Acid. Ther. 21, 275–283 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. 275.

    Gutsaeva, D. R. et al. Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood 117, 727–735 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. 276.

    De Franceschi, L. et al. Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice. FASEB J. 22, 1849–1860 (2008).

    PubMed  PubMed Central  Google Scholar 

  277. 277.

    Aoki, R. Y. & Saad, S. T. Enalapril reduces the albuminuria of patients with sickle cell disease. Am. J. Med. 98, 432–435 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. 278.

    Foucan, L. et al. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am. J. Med. 104, 339–342 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was partially supported by the following grant awards from the US National Institutes of Health: R21DK106509 (National Institute of Diabetes and Digestive and Kidney Diseases; to M.J.T.), U01-HL117709 and RO1-HL112603 (National Heart, Lung and Blood Institute (NHLBI); to P.M.) and R01HL114567 (NHLBI; to G.M.V.). M.J.T. and P.M. also received support from the Doris Duke Charitable Foundation.

Author information

Affiliations

Authors

Contributions

All authors contributed equally to the conception, writing and editing of this manuscript.

Corresponding author

Correspondence to Marilyn J. Telen.

Ethics declarations

Competing interests

M.J.T., P.M. and G.M.V. have been involved in clinical and/or basic research involving multiple compounds and therapeutic strategies discussed in this article.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Telen, M.J., Malik, P. & Vercellotti, G.M. Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Nat Rev Drug Discov 18, 139–158 (2019). https://doi.org/10.1038/s41573-018-0003-2

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing