Fetal Globin Induction—Can It Cure ß Thalassemia?

http://asheducationbook.hematologylibrary.org/cgi/content/full/2005/1/38
Abstract

The ß thalassemias are one of a few medical conditions in which reactivation of a gene product that is expressed during fetal life can functionally replace a deficiency of essential proteins expressed at a later developmental stage. The fetal globin genes are present and normally integrated in hematopoietic stem cells, and at least one fetal gene appears accessible for reactivation, particularly in ß° thalassemia. However, rapid cellular apoptosis from globin chain precipitation, and relatively low levels of endogenous erythropoietin (EPO) in some ß+ thalassemia patients contribute to the anemia in ß thalassemia syndromes.

In clinical trials, three classes of therapeutics have demonstrated proof-of-principle of this approach by raising total hemoglobin levels by 1–4 g/dL above baseline in thalassemia patients: EPO preparations, short chain fatty acid derivatives (SCFADs), and chemotherapeutic agents. Although thalassemic erythrocytes survive only for a few days, the magnitude of these responses is similar to those induced by rhu-EPO in anemic conditions of normal erythrocyte survival. New oral therapeutic candidates, which stimulate both fetal globin gene expression and erythropoiesis, and combinations of therapeutics with complementary molecular actions now make this gene-reactivation approach feasible to produce transfusion independence in many patients. Development of the candidate therapeutics is hindered largely by costs of drug development for an orphan patient population.

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The Appeal of Therapeutic Fetal Globin Gene Reactivation
The ß thalassemia syndromes are caused by more than 175 molecular mutations affecting the ß globin gene complex, which result in decreased synthetic ratios of non- to globin chains, precipitation of excess unbalanced globin chains, and programmed cell death of erythroblasts early in their development (review1). It is well-established that affected patients do not become anemic until the fetal () globin genes are developmentally silenced, and that patients with persistent high levels of fetal globin typically have less severe anemia, have milder clinical syndromes, and are often transfusion-independent.2 The ß thalassemias are thus one of a few clinical conditions in which a gene that is transiently expressed during fetal life can functionally replace a mutant gene normally expressed later in development.1 Reactivation of fetal globin expression is appealing as a therapeutic approach to the ß thalassemias, as the fetal globin genes are universally present and appropriately contextually integrated in the ß-globin locus in hematopoietic stem cells in virtually all humans.

Several mechanisms for optimal correction of ß thalassemia at the molecular and cellular levels are established, as illustrated in Figure 1. Three classes of potential therapeutic agents have been investigated in ß thalassemia syndromes: chemotherapeutic agents, short-chain fatty acid derivatives (SCFADs) (of which some are histone deacetylase [HDAC] inhibitors), and the recombinant growth factor erythropoietin (EPO). Fetal globin gene expression has been induced by chemotherapy and SCFADs in animal models, and proof-of-principle has been demonstrated in small clinical trials of these agents. Perhaps due to the molecular and clinical diversity of the ß thalassemia syndromes, and the need for therapeutics that are tolerable long-term, large collaborative trials of agents to reactivate fetal globin gene expression to high levels have not yet been undertaken in thalassemia, unlike sickle cell disease. Nonetheless, although the clinical trials have been small, patients with diverse thalassemia syndromes have been included, and significant hematologic responses have been observed, as shown in Table 1. In combination with preclinical molecular, cellular, and animal studies, the data from these trials now provide a critical base of information with which to design rational strategies for inducing globin gene expression and enhancing survival of thalassemic erythroblasts to an extent sufficient to render many subjects transfusion-independent.

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Figure 1. Therapeutic actions for -globin gene induction in the ß-thalassemias
Abbreviations: EPO, erythropoietin: SCFAD, short chain fatty acid derivative, HDACi, histone deacetylase inhibitor; AC, acetyl group; R, repressor; SSP, stage selector protein(s)

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Table 1. Hematologic responses to fetal globin gene inducers or erythropoietin (EPO) in ß-thalassemia patients.

Pathophysiologic Features of ßThalassemia That Must Be Overcome
It has been generally assumed that reduction of the globin chain imbalance and resulting globin excess by increasing expression of fetal or ß globin, or by decreasing globin, are all that is necessary to improve red cell survival and blood counts in ß thalassemia. Recent studies, however, indicate that a number of factors collectively contribute to the anemia.15,22–27 For example, EPO levels in thalassemia subjects are surprisingly often not elevated to a degree appropriate for the degree of hypoxia.22,23 This lack of a compensatory EPO response may be especially problematic in the ß thalassemia syndromes with vastly accelerated apoptosis of erythroblasts.22,25–28 In addition to stimulating proliferation of erythroid cells, EPO decreases apoptosis and prolongs erythroid cell survival through induction of the Bcl-2 family proteins, Bcl-xL and Mcl-1. 28,29 A red cell survival advantage of increased endogenous EPO in ß thalassemia that may facilitate effective globin induction was suggested by the intriguing observation of Collins and colleagues that hematologic responses to the fetal globin inducer sodium phenylbutyrate occurred only in those subjects who had high endogenous EPO levels (> 160 mU/mL), and was unrelated to any particular pattern of globin gene mutation.11 A subset of subjects with inappropriately low levels of endogenous EPO has responded to combined therapy with butyrate plus EPO, whereas each agent alone had a lesser or minimal effect in the same time-frame.24 These findings together strongly suggest that the exogenously administered EPO might be acting as a survival factor, in addition to an erythropoietic stimulant. Prolonging erythroid precursor cell survival for a sufficient interval may allow a fetal globin inducer to be able to act to correct the pro-apoptotic chain imbalance.
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