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. 1992 Dec;157(6):631–636.

Future prospects for treatment of hemoglobinopathies.

J A Stamatoyannopoulos 1
PMCID: PMC1022095  PMID: 1282285

Abstract

Strategies for the treatment of sickle cell anemia and beta-thalassemia are founded on the knowledge that these disorders result from structural or functional defects in an adult gene for which an intact fetal counterpart exists. During the past decade, several pharmacologic agents have been investigated for their potential to ameliorate sickle cell anemia and beta-thalassemia by increasing the synthesis of fetal hemoglobin in adults. Progress in understanding globin gene regulation is now being combined with advances in retrovirus-mediated gene transfer, and the once-distant goal of providing gene therapy for hemoglobinopathies is rapidly approaching reality.

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Selected References

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  1. Behringer R. R., Ryan T. M., Palmiter R. D., Brinster R. L., Townes T. M. Human gamma- to beta-globin gene switching in transgenic mice. Genes Dev. 1990 Mar;4(3):380–389. doi: 10.1101/gad.4.3.380. [DOI] [PubMed] [Google Scholar]
  2. Bodine D. M., Karlsson S., Nienhuis A. W. Combination of interleukins 3 and 6 preserves stem cell function in culture and enhances retrovirus-mediated gene transfer into hematopoietic stem cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8897–8901. doi: 10.1073/pnas.86.22.8897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Charache S., Dover G. J., Moore R. D., Eckert S., Ballas S. K., Koshy M., Milner P. F., Orringer E. P., Phillips G., Jr, Platt O. S. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992 May 15;79(10):2555–2565. [PubMed] [Google Scholar]
  4. Charache S., Dover G. J., Moyer M. A., Moore J. W. Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia. Blood. 1987 Jan;69(1):109–116. [PubMed] [Google Scholar]
  5. Charache S., Dover G., Smith K., Talbot C. C., Jr, Moyer M., Boyer S. Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4842–4846. doi: 10.1073/pnas.80.15.4842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Collis P., Antoniou M., Grosveld F. Definition of the minimal requirements within the human beta-globin gene and the dominant control region for high level expression. EMBO J. 1990 Jan;9(1):233–240. doi: 10.1002/j.1460-2075.1990.tb08100.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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 Nov 1;74(6):1963–1971. [PubMed] [Google Scholar]
  8. Constantoulakis P., Papayannopoulou T., Stamatoyannopoulos G. alpha-Amino-N-butyric acid stimulates fetal hemoglobin in the adult. Blood. 1988 Dec;72(6):1961–1967. [PubMed] [Google Scholar]
  9. Dover G. J., Charache S., Boyer S. H., Vogelsang G., Moyer M. 5-Azacytidine increases HbF production and reduces anemia in sickle cell disease: dose-response analysis of subcutaneous and oral dosage regimens. Blood. 1985 Sep;66(3):527–532. [PubMed] [Google Scholar]
  10. Dunbar C., Travis W., Kan Y. W., Nienhuis A. 5-Azacytidine treatment in a beta (0)-thalassaemic patient unable to be transfused due to multiple alloantibodies. Br J Haematol. 1989 Jul;72(3):467–468. doi: 10.1111/j.1365-2141.1989.tb07734.x. [DOI] [PubMed] [Google Scholar]
  11. Enver T., Raich N., Ebens A. J., Papayannopoulou T., Costantini F., Stamatoyannopoulos G. Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice. Nature. 1990 Mar 22;344(6264):309–313. doi: 10.1038/344309a0. [DOI] [PubMed] [Google Scholar]
  12. Forrester W. C., Thompson C., Elder J. T., Groudine M. A developmentally stable chromatin structure in the human beta-globin gene cluster. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1359–1363. doi: 10.1073/pnas.83.5.1359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Friedmann T. Progress toward human gene therapy. Science. 1989 Jun 16;244(4910):1275–1281. doi: 10.1126/science.2660259. [DOI] [PubMed] [Google Scholar]
  14. Grosveld F., van Assendelft G. B., Greaves D. R., Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987 Dec 24;51(6):975–985. doi: 10.1016/0092-8674(87)90584-8. [DOI] [PubMed] [Google Scholar]
  15. Humphries R. K., Dover G., Young N. S., Moore J. G., Charache S., Ley T., Nienhuis A. W. 5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin. J Clin Invest. 1985 Feb;75(2):547–557. doi: 10.1172/JCI111731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Karlsson S., Nienhuis A. W. Developmental regulation of human globin genes. Annu Rev Biochem. 1985;54:1071–1108. doi: 10.1146/annurev.bi.54.070185.005231. [DOI] [PubMed] [Google Scholar]
  17. Ley T. J., DeSimone J., Anagnou N. P., Keller G. H., Humphries R. K., Turner P. H., Young N. S., Keller P., Nienhuis A. W. 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. N Engl J Med. 1982 Dec 9;307(24):1469–1475. doi: 10.1056/NEJM198212093072401. [DOI] [PubMed] [Google Scholar]
  18. Ley T. J., DeSimone J., Noguchi C. T., Turner P. H., Schechter A. N., Heller P., Nienhuis A. W. 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood. 1983 Aug;62(2):370–380. [PubMed] [Google Scholar]
  19. Mavilio F., Giampaolo A., Carè A., Migliaccio G., Calandrini M., Russo G., Pagliardi G. L., Mastroberardino G., Marinucci M., Peschle C. Molecular mechanisms of human hemoglobin switching: selective undermethylation and expression of globin genes in embryonic, fetal, and adult erythroblasts. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6907–6911. doi: 10.1073/pnas.80.22.6907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nienhuis A. W., Anagnou N. P., Ley T. J. Advances in thalassemia research. Blood. 1984 Apr;63(4):738–758. [PubMed] [Google Scholar]
  21. Nienhuis A. W., Ley T. J., Humphries R. K., Young N. S., Dover G. Pharmacological manipulation of fetal hemoglobin synthesis in patients with severe beta-thalassemia. Ann N Y Acad Sci. 1985;445:198–211. doi: 10.1111/j.1749-6632.1985.tb17189.x. [DOI] [PubMed] [Google Scholar]
  22. Noguchi C. T., Rodgers G. P., Serjeant G., Schechter A. N. Levels of fetal hemoglobin necessary for treatment of sickle cell disease. N Engl J Med. 1988 Jan 14;318(2):96–99. doi: 10.1056/NEJM198801143180207. [DOI] [PubMed] [Google Scholar]
  24. Papayannopoulou T., Brice M., Stamatoyannopoulos G. Analysis of human hemoglobin switching in MEL x human fetal erythroid cell hybrids. Cell. 1986 Aug 1;46(3):469–476. doi: 10.1016/0092-8674(86)90667-7. [DOI] [PubMed] [Google Scholar]
  25. Perrine S. P., Greene M. F., Faller D. V. Delay in the fetal globin switch in infants of diabetic mothers. N Engl J Med. 1985 Feb 7;312(6):334–338. doi: 10.1056/NEJM198502073120602. [DOI] [PubMed] [Google Scholar]
  26. Perrine S. P., Miller B. A., Faller D. V., Cohen R. A., Vichinsky E. P., Hurst D., Lubin B. H., Papayannopoulou T. Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia. Blood. 1989 Jul;74(1):454–459. [PubMed] [Google Scholar]
  27. Perrine S. P., Rudolph A., Faller D. V., Roman C., Cohen R. A., Chen S. J., Kan Y. W. Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8540–8542. doi: 10.1073/pnas.85.22.8540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rodgers G. P., Dover G. J., Noguchi C. T., Schechter A. N., Nienhuis A. W. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med. 1990 Apr 12;322(15):1037–1045. doi: 10.1056/NEJM199004123221504. [DOI] [PubMed] [Google Scholar]
  29. Ryan T. M., Behringer R. R., Martin N. C., Townes T. M., Palmiter R. D., Brinster R. L. A single erythroid-specific DNase I super-hypersensitive site activates high levels of human beta-globin gene expression in transgenic mice. Genes Dev. 1989 Mar;3(3):314–323. doi: 10.1101/gad.3.3.314. [DOI] [PubMed] [Google Scholar]
  30. Stamatoyannopoulos G., Veith R., Galanello R., Papayannopoulou T. Hb F production in stressed erythropoiesis: observations and kinetic models. Ann N Y Acad Sci. 1985;445:188–197. doi: 10.1111/j.1749-6632.1985.tb17188.x. [DOI] [PubMed] [Google Scholar]
  31. Stamatoyannopoulos J. A., Nienhuis A. W. Therapeutic approaches to hemoglobin switching in treatment of hemoglobinopathies. Annu Rev Med. 1992;43:497–521. doi: 10.1146/annurev.me.43.020192.002433. [DOI] [PubMed] [Google Scholar]
  32. al-Khatti A., Umemura T., Clow J., Abels R. I., Vance J., Papayannopoulou T., Stamatoyannopoulos G. Erythropoietin stimulates F-reticulocyte formation in sickle cell anemia. Trans Assoc Am Physicians. 1988;101:54–61. [PubMed] [Google Scholar]

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