UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Investigational therapies for sickle cell disease

Author
Griffin P Rodgers, MD
Section Editors
Stanley L Schrier, MD
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

The major causes of morbidity and mortality in sickle cell disease (SCD) are the acute and long-term consequences of vasoocclusion, many of which involve irreversible tissue injury or infarction, coupled with the effects of chronic hemolytic anemia.

The major interventions to reduce vasoocclusive episodes include long-term hydroxyurea administration or regular blood transfusions (or exchange transfusions). However, hydroxyurea is not completely effective in preventing vasoocclusive episodes, and chronic transfusions place a high burden on the patient, and it often is not feasible to administer transfusions indefinitely.

This topic reviews potential therapies for SCD that are under development or clinical investigation, including their rationale, preclinical data, and information from early clinical trials of their use.

Separate topic reviews discuss existing management options including comprehensive care, administration of hydroxyurea, red blood cell (RBC) transfusion, and hematopoietic cell transplantation (HCT) in SCD:

Management overview – (See "Overview of the management and prognosis of sickle cell disease".)

                         

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Apr 2017. | This topic last updated: May 18, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Mansilla-Soto J, Rivière I, Sadelain M. Genetic strategies for the treatment of sickle cell anaemia. Br J Haematol 2011; 154:715.
  2. Nienhuis AW. Development of gene therapy for blood disorders. Blood 2008; 111:4431.
  3. Pawliuk R, Westerman KA, Fabry ME, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 2001; 294:2368.
  4. Wu LC, Sun CW, Ryan TM, et al. Correction of sickle cell disease by homologous recombination in embryonic stem cells. Blood 2006; 108:1183.
  5. Perumbeti A, Higashimoto T, Urbinati F, et al. A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood 2009; 114:1174.
  6. Zou J, Mali P, Huang X, et al. Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood 2011; 118:4599.
  7. Takekoshi KJ, Oh YH, Westerman KW, et al. Retroviral transfer of a human beta-globin/delta-globin hybrid gene linked to beta locus control region hypersensitive site 2 aimed at the gene therapy of sickle cell disease. Proc Natl Acad Sci U S A 1995; 92:3014.
  8. Townes TM. Gene replacement therapy for sickle cell disease and other blood disorders. Hematology Am Soc Hematol Educ Program 2008; :193.
  9. Hoban MD, Cost GJ, Mendel MC, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood 2015; 125:2597.
  10. Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med 2017; 376:848.
  11. Blouin MJ, Beauchemin H, Wright A, et al. Genetic correction of sickle cell disease: insights using transgenic mouse models. Nat Med 2000; 6:177.
  12. Campbell AD, Cui S, Shi L, et al. Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes. Proc Natl Acad Sci U S A 2011; 108:18808.
  13. Wilber A, Hargrove PW, Kim YS, et al. Therapeutic levels of fetal hemoglobin in erythroid progeny of β-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer. Blood 2011; 117:2817.
  14. Xu J, Peng C, Sankaran VG, et al. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science 2011; 334:993.
  15. Steinberg MH, Rodgers GP. HbA2 : biology, clinical relevance and a possible target for ameliorating sickle cell disease. Br J Haematol 2015; 170:781.
  16. Lan N, Howrey RP, Lee SW, et al. Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors. Science 1998; 280:1593.
  17. Alami R, Gilman JG, Feng YQ, et al. Anti-beta s-ribozyme reduces beta s mRNA levels in transgenic mice: potential application to the gene therapy of sickle cell anemia. Blood Cells Mol Dis 1999; 25:110.
  18. Weatherall DJ. Gene therapy: repairing haemoglobin disorders with ribozymes. Curr Biol 1998; 8:R696.
  19. Mabaera R, Greene MR, Richardson CA, et al. Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin. Blood 2008; 111:411.
  20. DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci U S A 1982; 79:4428.
  21. Koshy M, Dorn L, Bressler L, et al. 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood 2000; 96:2379.
  22. DeSimone J, Koshy M, Dorn L, et al. Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 2002; 99:3905.
  23. Saunthararajah Y, Hillery CA, Lavelle D, et al. Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 2003; 102:3865.
  24. Saunthararajah Y, Molokie R, Saraf S, et al. Clinical effectiveness of decitabine in severe sickle cell disease. Br J Haematol 2008; 141:126.
  25. Meiler SE, Wade M, Kutlar F, et al. Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. Blood 2011; 118:1109.
  26. Fard AD, Hosseini SA, Shahjahani M, et al. Evaluation of Novel Fetal Hemoglobin Inducer Drugs in Treatment of β-Hemoglobinopathy Disorders. Int J Hematol Oncol Stem Cell Res 2013; 7:47.
  27. Dulmovits BM, Appiah-Kubi AO, Papoin J, et al. Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors. Blood 2016; 127:1481.
  28. Lowrey CH. Down the repressors! Up the fetal hemoglobin! Blood 2016; 127:1384.
  29. Wiech NL, Fisher JF, Helquist P, Wiest O. Inhibition of histone deacetylases: a pharmacological approach to the treatment of non-cancer disorders. Curr Top Med Chem 2009; 9:257.
  30. Weinberg RS, Ji X, Sutton M, et al. Butyrate increases the efficiency of translation of gamma-globin mRNA. Blood 2005; 105:1807.
  31. Fathallah H, Weinberg RS, Galperin Y, et al. Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin. Blood 2007; 110:3391.
  32. Stamatoyannopoulos G, Blau CA, Nakamoto B, et al. Fetal hemoglobin induction by acetate, a product of butyrate catabolism. Blood 1994; 84:3198.
  33. Faller DV, Perrine SP. Butyrate in the treatment of sickle cell disease and beta-thalassemia. Curr Opin Hematol 1995; 2:109.
  34. Perrine SP, Rudolph A, Faller DV, et al. Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching. Proc Natl Acad Sci U S A 1988; 85:8540.
  35. Constantoulakis P, Knitter G, Stamatoyannopoulos G. On the induction of fetal hemoglobin by butyrates: in vivo and in vitro studies with sodium butyrate and comparison of combination treatments with 5-AzaC and AraC. Blood 1989; 74:1963.
  36. Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 1993; 328:81.
  37. Liakopoulou E, Blau CA, Li Q, et al. Stimulation of fetal hemoglobin production by short chain fatty acids. Blood 1995; 86:3227.
  38. Reich S, Bührer C, Henze G, et al. Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta-thalassemia. Blood 2000; 96:3357.
  39. Sher GD, Ginder GD, Little J, et al. Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies. N Engl J Med 1995; 332:1606.
  40. Archer N, Galacteros F, Brugnara C. 2015 Clinical trials update in sickle cell anemia. Am J Hematol 2015; 90:934.
  41. Okam MM, Esrick EB, Mandell E, et al. Phase 1/2 trial of vorinostat in patients with sickle cell disease who have not benefitted from hydroxyurea. Blood 2015; 125:3668.
  42. Goldberg MA, Brugnara C, Dover GJ, et al. Treatment of sickle cell anemia with hydroxyurea and erythropoietin. N Engl J Med 1990; 323:366.
  43. al-Khatti A, Umemura T, Clow J, et al. Erythropoietin stimulates F-reticulocyte formation in sickle cell anemia. Trans Assoc Am Physicians 1988; 101:54.
  44. Nagel RL, Vichinsky E, Shah M, et al. F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study. Blood 1993; 81:9.
  45. Rodgers GP, Dover GJ, Uyesaka N, et al. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993; 328:73.
  46. el-Hazmi MA, al-Momen A, Kandaswamy S, et al. On the use of hydroxyurea/erythropoietin combination therapy for sickle cell disease. Acta Haematol 1995; 94:128.
  47. Little JA, McGowan VR, Kato GJ, et al. Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review. Haematologica 2006; 91:1076.
  48. Eaton WA, Bunn HF. Treating sickle cell disease by targeting HbS polymerization. Blood 2017.
  49. Oder E, Safo MK, Abdulmalik O, Kato GJ. New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Br J Haematol 2016; 175:24.
  50. Abdulmalik O, Safo MK, Chen Q, et al. 5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells. Br J Haematol 2005; 128:552.
  51. https://clinicaltrials.gov/ct2/show/record/NCT01987908 (Accessed on March 06, 2017).
  52. Oksenberg D, Dufu K, Patel MP, et al. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol 2016; 175:141.
  53. Brugnara C, de Franceschi L, Alper SL. Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J Clin Invest 1993; 92:520.
  54. De Franceschi L, Saadane N, Trudel M, et al. Treatment with oral clotrimazole blocks Ca(2+)-activated K+ transport and reverses erythrocyte dehydration in transgenic SAD mice. A model for therapy of sickle cell disease. J Clin Invest 1994; 93:1670.
  55. Brugnara C, Gee B, Armsby CC, 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 1996; 97:1227.
  56. Ataga KI, Reid M, Ballas SK, 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 2011; 153:92.
  57. Brugnara C, Tosteson DC. Inhibition of K transport by divalent cations in sickle erythrocytes. Blood 1987; 70:1810.
  58. De Franceschi L, Beuzard Y, Jouault H, Brugnara C. Modulation of erythrocyte potassium chloride cotransport, potassium content, and density by dietary magnesium intake in transgenic SAD mouse. Blood 1996; 88:2738.
  59. De Franceschi L, Bachir D, Galacteros F, et al. Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest 1997; 100:1847.
  60. De Franceschi L, Bachir D, Galacteros F, et al. Oral magnesium pidolate: effects of long-term administration in patients with sickle cell disease. Br J Haematol 2000; 108:284.
  61. Brousseau DC, Scott JP, Badaki-Makun O, et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood 2015; 126:1651.
  62. Stocker JW, De Franceschi L, McNaughton-Smith GA, et al. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood 2003; 101:2412.
  63. McNaughton-Smith GA, Burns JF, Stocker JW, et al. Novel inhibitors of the Gardos channel for the treatment of sickle cell disease. J Med Chem 2008; 51:976.
  64. Rosa RM, Bierer BE, Thomas R, et al. A study of induced hyponatremia in the prevention and treatment of sickle-cell crisis. N Engl J Med 1980; 303:1138.
  65. Hankins J, Aygun B. Pharmacotherapy in sickle cell disease--state of the art and future prospects. Br J Haematol 2009; 145:296.
  66. Wambebe C, Khamofu H, Momoh JA, et al. Double-blind, placebo-controlled, randomised cross-over clinical trial of NIPRISAN in patients with Sickle Cell Disorder. Phytomedicine 2001; 8:252.
  67. Cordeiro NJ, Oniyangi O. Phytomedicines (medicines derived from plants) for sickle cell disease. Cochrane Database Syst Rev 2004; :CD004448.
  68. Fawibe AE. Managing acute chest syndrome of sickle cell disease in an African setting. Trans R Soc Trop Med Hyg 2008; 102:526.
  69. Oniyangi O, Cohall DH. Phytomedicines (medicines derived from plants) for sickle cell disease. Cochrane Database Syst Rev 2010; :CD004448.
  70. Iyamu EW, Turner EA, Asakura T. In vitro effects of NIPRISAN (Nix-0699): a naturally occurring, potent antisickling agent. Br J Haematol 2002; 118:337.
  71. Iyamu EW, Turner EA, Asakura T. Niprisan (Nix-0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions. Br J Haematol 2003; 122:1001.
  72. Perampaladas K, Masum H, Kapoor A, et al. The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan. BMC Int Health Hum Rights 2010; 10 Suppl 1:S11.
  73. Telen MJ, Wun T, McCavit TL, 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 2015; 125:2656.
  74. Maitre B, Djibre M, Katsahian S, et al. Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study. Intensive Care Med 2015; 41:2121.
  75. Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 2011; 305:893.