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Research Opportunities and Forecast: Hemoglobinopathies
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1.
Steinberg MH. Management of sickle cell disease.  N Engl J Med.1999;340:1021-1030.
2.
Platt O, Brambilla DJ, Rosse WF.  et al.  Mortality in sickle cell disease.  N Engl J Med.1994;330:1639-1644.
3.
Olivieri NF. The β-thalassemias.  N Engl J Med.1999;341:99-109.
4.
Ehlers KH, Giardina PJ, Lesser ML, Engle MA, Hilgartner MW. Prolonged survival in patients with beta-thalassemia major treated with deferoxamine.  J Pediatr.1991;118:540-545.
5.
Gaston MH, Verter JI, Woods G.  et al.  Prophylaxis with oral penicillin in children with sickle cell anemia.  N Engl J Med.1986;314:1593-1599.
6.
Mentzer WC. Bone marrow transplantation for hemoglobinopathies.  Curr Opin Hematol.2000;7:95-100.
7.
Arcasoy MO, Gallagher PG. Molecular diagnosis of hemoglobinopathies and other red cell disorders.  Semin Hematol.1999;36:328-339.
8.
Cao A, Galanello R, Rosatelli MC, Argiolu F, De Virgiliis S. Clinical experience of management of thalassemia: the Sardinian experience.  Semin Hematol.1996;33:66-75.
9.
Loukopoulos D. Current status of thalassemia and the sickle cell syndromes in Greece.  Semin Hematol.1996;33:76-86.
10.
Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z. First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia.  JAMA.1999;281:1701-1706.
11.
Hebbel RP. Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies.  N Engl J Med.2000;342:1910-1912.
12.
Paszty C. Transgenic and gene knock-out mouse models of sickle cell anemia and the thalassemias.  Curr Opin Hematol.1997;4:88-93.
13.
Osarogiagbon UR, Choong S, Belcher JD, Vercellotti GM, Paller MS, Hebbel RP. Reperfusion injury pathophysiology in sickle transgenic mice.  Blood.2000;96:314-320.
14.
Olivieri NF. Reactivation of fetal hemoglobin in patients with β-thalassemia.  Semin Hematol.1996;33:24-42.
15.
Flake AW, Zanjani ED. In utero hematopoietic stem cell transplantation: ontogenic opportunities and biologic barriers.  Blood.1999;94:2179-2191.
16.
Persons DA, Nienhuis AW. Gene therapy for the hemoglobin disorders: past, present, and future.  Proc Natl Acad Sci U S A.2000;97:5022-5024.
17.
May C, Rivella S, Callegari J.  et al.  Therapeutic haemoglobin synthesis in B-thalassaemic mice expressing lentivirus-encoded human β-globin.  Nature.2000;406:82-86.
18.
Peterson BE, Bowen WC, Patrene KD.  et al.  Bone marrow as a potential source of hepatic oval cells.  Science.1999;284:1168-1170.
19.
Gussoni E, Soneoka Y, Strickland CD.  et al.  Dystrophin expression in the mdx mouse restored by stem cell transplantation.  Nature.1999;401:390-394.
20.
Bjornson CRR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo.  Science.1999;283:534-537.
21.
Yoon K, Cole-Strauss A, Kmiec EB. Targeted gene correction of episomal DNA in mammalian cells mediated by a chimeric RNA-DNA oligonucleotide.  Proc Natl Acad Sci U S A.1996;93:2071-2076.
22.
Kren BT, Parashar B, Bandyopadhyay P, Chowdhury NR, Chowdhury JR, Steer CJ. Correction of the UDP-glucuronosyltransferase gene defect in the Gunn rat model of Crigler-Najjar syndrome type I with a chimeric oligonucleotide.  Proc Natl Acad Sci U S A.1999;96:10349-10354.
23.
Corash L. Inactivation of viruses, bacteria, protozoa, and leukocytes in platelet concentrates: current research perspectives.  Transfus Med Rev.1999;13:18-30.
24.
Cheung MC, Goldberg JD, Kan YW. Prenatal diagnosis of sickle cell anemia and thalassemia by analysis of fetal cells in maternal blood.  Nat Genet.1996;14:264-268.
Research Opportunities for Specific Diseases and Disorders
February 7, 2001

Prospects for Research in Hematologic DisordersSickle Cell Disease and Thalassemia

Author Affiliations

Author Affiliations: Departments of Pediatrics (Dr Mentzer) and Laboratory Medicine (Dr Kan), Cardiovascular Research Institute, and Howard Hughes Medical Institute Laboratory, University of California, San Francisco.

JAMA. 2001;285(5):640-642. doi:10.1001/jama.285.5.640
Abstract

Sickle cell anemia and thalassemia constitute the most common genetic diseases in the world. Affected patients carry a heavy burden of morbidity and early mortality. With improved understanding of the pathophysiology and molecular basis of these diseases, treatment is evolving from management of symptoms to more effective strategies that aim to modify diseased red blood cells or replace them with normal cells. Available treatment options include red blood cell transfusions, pharmacologic interventions to increase fetal hemoglobin levels, and stem cell transplantation. Improvements in these approaches or the development of means to replace defective genes with normal ones using techniques of gene transfer offer hope for the future.

Sickle cell disease and thalassemia are inherited disorders of hemoglobin that have a worldwide impact on health and longevity. Sickle cell disease, characterized by lifelong hemolytic anemia and a wide variety of painful and debilitating vaso-occlusive events, occurs in 70 000 to 80 000 Americans of African, Mediterranean, or Middle Eastern extraction.1 In the United States, the life expectancy for patients with sickle cell disease is shortened by about 30 years,2 while in Africa, where comprehensive medical care is less available, death in early childhood is usual.

Thalassemia is the most common human single gene disorder3 and occurs in people of Mediterranean, Middle Eastern, and Asian origin. Heterozygous carriers of the thalassemia trait are clinically normal and largely unaware of their genetic condition. Inheritance of thalassemia from 2 carrier parents produces a life-threatening anemia, with death occurring in utero (ie, with inheritance of 2 deletion α-thalassemia from each parent) or in early childhood (β-thalassemia) unless regular transfusions of normal red blood cells are given. Intermediate clinical forms of thalassemia exist, characterized by anemia and an occasional need for red blood cell transfusions. The median life expectancy for patients with severe β-thalassemia treated with red blood cell transfusions and aggressive management of complications is about 30 years in industrialized countries,4 but far less than this in underdeveloped regions of the world.

Recent Advances

The past 25 years have witnessed real advances in the management of hemoglobinopathies. In sickle cell disease, prevention of overwhelming bacterial infection by immunizations and prophylactic antibiotics have almost eliminated deaths from these infections during infancy.5 Treatment is evolving from management of symptoms to strategies that modify diseased red blood cells or replace them with normal cells. High fetal hemoglobin levels reduce the clinical severity of sickle cell disease or thalassemia, sparking a search for drugs that increase fetal hemoglobin levels in red blood cells. One, hydroxyurea, is a mainstay of treatment in sickle cell disease1 and reduces the frequency of hospitalization in some patients. Monthly red blood cell transfusions can prevent most disease-associated morbidity,1,3 but transfusion complications such as iron overloading, which injures heart, liver, and endocrine tissues, remain a challenge. If used consistently, an iron chelator, deferoxamine, can reduce the body iron burden to safe levels; however, the drug is expensive and its administration is so cumbersome that good compliance is uncommon.3 Both sickle cell disease and thalassemia can be cured by stem cell transplantation, but transplant-associated complications, expense, and a paucity of suitable donors have limited its application.6

Lack of a widely available cure underscores the importance of disease prevention. DNA testing of fetal blood or tissues to identify sickle cell disease or thalassemia allows elective termination of affected pregnancies. In Italy and Greece, where thalassemia is the most common genetic disease, prenatal diagnosis has reduced the disease burden to families and to the health care system.79 A costly and labor-intensive alternative approach, preimplantation diagnosis, relies on in vitro fertilization and DNA testing of embryos to select those free of disease for implantation.10

Current Scientific Foundation

Sickle hemoglobin polymerizes when deoxygenated, forming rigid structures that deform red blood cells into sickle shapes that block the flow of blood.1 The presence of certain nonsickle hemoglobins (ie, fetal hemoglobin) within red blood cells retards the sickling process. Other factors such as red blood cell dehydration1 or the increased adherence of sickle red blood cells to vascular endothelium11 initiate occlusive events. Agents that can favorably affect erythrocyte deformability, adherence, hydration, hemoglobin composition, or the polymerization of sickle hemoglobin need to be identified.1 The availability of transgenic mice that have red blood cells largely filled with human sickle hemoglobin has made it possible to investigate new agents in an animal model of sickle cell disease.12 This model is also likely to provide insight into the complex basis for the vaso-occlusive process and the organ damage that ensues.13

Hemolytic anemia in thalassemia is due to unbalanced production of α-globin and β-globin chains. Excess globin chains produced by the nonthalassemic normal allele accumulate within and ultimately destroy red blood cells.3 A spectrum of genetic defects, ranging from large deletions to point mutations located in regulatory regions or in globin coding sequences, lead to thalassemia, accounting for its remarkable clinical variability. Genetic or environmental factors that reduce the imbalance in globin chain synthesis mitigate clinical severity. For example, agents that increase fetal hemoglobin production may reduce the clinical severity of thalassemia.14 These agents seem to be less effective in thalassemia than in sickle cell disease, however, and none are in routine clinical use. As in sickle cell disease, transgenic mouse models of thalassemia are useful to the understanding of disease mechanisms and screening for potential therapeutic agents.12 (Figure 1)

Promising Research Initiatives

Current research initiatives in stem cell transplantation focus on reducing the toxicity of pretransplant conditioning regimens and expanding the stem cell donor pool.6 Under evaluation are stem cells from unrelated adult or cord blood donors and from partially compatible, T-cell–depleted parental or sibling donors. The utility of such donors may be limited by graft failure, graft-vs-host disease, or delayed immune reconstitution unless these problems become manageable. In utero stem cell transplantation in sickle cell disease or thalassemia fetuses identified by prenatal diagnosis has been unsuccessful thus far because donor stem cells are not able to replace enough recipient stem cells.15

Recent progress has increased hope for the future of gene therapy for hemoglobinopathies. Although it is possible to introduce intact β-globin genes into murine hematopoietic stem cells using retroviral vectors, efficiency of transfer is low, expression of the transgene suboptimal, and long-term stability limited by gene silencing and position effects.16 Use of a lentivirus vector derived from human immunodeficiency virus 1 and carrying a large fragment of the human β-globin gene and its locus control region yields better and more stable expression, in the range that would be expected to be therapeutically effective.17

Needed Research Advances

To take advantage of the ability of fetal hemoglobin to inhibit the sickling process in sickle cell disease and to replace missing hemoglobin molecules in thalassemia requires greater understanding of how the globin genes are regulated. Such an understanding may lead to the development of pharmacological agents that allow the continued expression of the fetal hemoglobin gene. The ideal treatment of genetic defects is, of course, their full correction. To achieve this, 2 major hurdles need to be overcome. The first is the identification of a stem cell capable of perpetual renewal and differentiation into mature blood cells. Discovery of the conversion of stem cells from the blood to liver and muscle cells,18,19 and from the brain to blood cells20 are most encouraging, and research in this area should receive high priority. The second is the actual correction of genetic defects within the stem cell by introduction of a normal gene into the cell. Harmless vectors should be designed to introduce normal genes efficiently. The inserted genes should also function at an appropriate and adequate level throughout life. One approach is correction of the mutation itself by homologous recombination with a piece of DNA that contains the normal sequence.21,22 Although feasible, the frequency of successful recombination is currently too low for practical application.

Until there is a cure, treatment modalities used for these patients need to be improved. For example, simpler ways of obtaining pathogen-free blood will make transfusions safer.23 Iron chelators that can be given orally or injected infrequently should encourage patient compliance. Noninvasive imaging techniques that can measure iron accumulation in the liver, heart, and endocrine glands will improve monitoring of chelation therapy.

A frequent complication of sickle cell disease, especially during childhood, is cerebral infarction.1 A better understanding of the mechanisms that cause adherence of sickle cells to vessel walls and activation of blood clotting may suggest new therapies to prevent damage to the brain and other vital organs.

Research Prospects and Opportunities

Although eradication of a genetic disease by manipulating the gene in the germ line is not yet possible, more effective somatic cell treatments will become available. The most desirable form of therapy is to correct defective genes with normal ones in hematopoietic stem cells. Although many barriers remain to be overcome, gene therapy, perhaps involving homologous recombination currently in use in animal models,22 might be available within the next 25 years. In less developed countries where these diseases are common, the widespread application of gene therapy may be constrained by cost factors. Similar constraints apply to stem cell transplantation, although outpatient transplantation following minimal conditioning may reduce cost. New pharmacological agents to increase fetal hemoglobin levels, increase red blood cell hydration, and directly inhibit the sickling process in vivo are needed. Combination chemotherapy, as in the treatment of cancer, may be more effective than single agents. The pharmacological agents envisioned would need to be administered throughout the lifetime of the patient, so that even if daily cost is small, long-term costs might be equivalent to or even greater than stem cell transplantation or gene therapy.

Until inexpensive and effective curative treatment becomes available, the greatest impact on the burden of hemoglobinopathies worldwide will continue to be their prevention by prenatal diagnosis and elective termination of pregnancies found to be affected. Simplification of techniques for prenatal diagnosis, perhaps using gene chip technology, may make them more widely available. One promising approach is isolation of fetal cells from the maternal circulation, followed by polymerase chain reaction–based DNA diagnosis.24 This approach must be simplified to keep costs down and to reduce the level of technical expertise required to obtain reliable results.

References
1.
Steinberg MH. Management of sickle cell disease.  N Engl J Med.1999;340:1021-1030.
2.
Platt O, Brambilla DJ, Rosse WF.  et al.  Mortality in sickle cell disease.  N Engl J Med.1994;330:1639-1644.
3.
Olivieri NF. The β-thalassemias.  N Engl J Med.1999;341:99-109.
4.
Ehlers KH, Giardina PJ, Lesser ML, Engle MA, Hilgartner MW. Prolonged survival in patients with beta-thalassemia major treated with deferoxamine.  J Pediatr.1991;118:540-545.
5.
Gaston MH, Verter JI, Woods G.  et al.  Prophylaxis with oral penicillin in children with sickle cell anemia.  N Engl J Med.1986;314:1593-1599.
6.
Mentzer WC. Bone marrow transplantation for hemoglobinopathies.  Curr Opin Hematol.2000;7:95-100.
7.
Arcasoy MO, Gallagher PG. Molecular diagnosis of hemoglobinopathies and other red cell disorders.  Semin Hematol.1999;36:328-339.
8.
Cao A, Galanello R, Rosatelli MC, Argiolu F, De Virgiliis S. Clinical experience of management of thalassemia: the Sardinian experience.  Semin Hematol.1996;33:66-75.
9.
Loukopoulos D. Current status of thalassemia and the sickle cell syndromes in Greece.  Semin Hematol.1996;33:76-86.
10.
Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z. First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia.  JAMA.1999;281:1701-1706.
11.
Hebbel RP. Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies.  N Engl J Med.2000;342:1910-1912.
12.
Paszty C. Transgenic and gene knock-out mouse models of sickle cell anemia and the thalassemias.  Curr Opin Hematol.1997;4:88-93.
13.
Osarogiagbon UR, Choong S, Belcher JD, Vercellotti GM, Paller MS, Hebbel RP. Reperfusion injury pathophysiology in sickle transgenic mice.  Blood.2000;96:314-320.
14.
Olivieri NF. Reactivation of fetal hemoglobin in patients with β-thalassemia.  Semin Hematol.1996;33:24-42.
15.
Flake AW, Zanjani ED. In utero hematopoietic stem cell transplantation: ontogenic opportunities and biologic barriers.  Blood.1999;94:2179-2191.
16.
Persons DA, Nienhuis AW. Gene therapy for the hemoglobin disorders: past, present, and future.  Proc Natl Acad Sci U S A.2000;97:5022-5024.
17.
May C, Rivella S, Callegari J.  et al.  Therapeutic haemoglobin synthesis in B-thalassaemic mice expressing lentivirus-encoded human β-globin.  Nature.2000;406:82-86.
18.
Peterson BE, Bowen WC, Patrene KD.  et al.  Bone marrow as a potential source of hepatic oval cells.  Science.1999;284:1168-1170.
19.
Gussoni E, Soneoka Y, Strickland CD.  et al.  Dystrophin expression in the mdx mouse restored by stem cell transplantation.  Nature.1999;401:390-394.
20.
Bjornson CRR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo.  Science.1999;283:534-537.
21.
Yoon K, Cole-Strauss A, Kmiec EB. Targeted gene correction of episomal DNA in mammalian cells mediated by a chimeric RNA-DNA oligonucleotide.  Proc Natl Acad Sci U S A.1996;93:2071-2076.
22.
Kren BT, Parashar B, Bandyopadhyay P, Chowdhury NR, Chowdhury JR, Steer CJ. Correction of the UDP-glucuronosyltransferase gene defect in the Gunn rat model of Crigler-Najjar syndrome type I with a chimeric oligonucleotide.  Proc Natl Acad Sci U S A.1999;96:10349-10354.
23.
Corash L. Inactivation of viruses, bacteria, protozoa, and leukocytes in platelet concentrates: current research perspectives.  Transfus Med Rev.1999;13:18-30.
24.
Cheung MC, Goldberg JD, Kan YW. Prenatal diagnosis of sickle cell anemia and thalassemia by analysis of fetal cells in maternal blood.  Nat Genet.1996;14:264-268.
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