Sickle Cell Disease at 100 Years

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Science  16 Jul 2010:
Vol. 329, Issue 5989, pp. 291-292
DOI: 10.1126/science.1194035

A 100th anniversary is often a cause for celebration. However, next week's First Global Congress on Sickle Cell Disease in Accra, Ghana, marking the centenary of the description of the disease (1), is a sober reminder that we have far to go to meet the global challenges posed by this disorder. Just over 60 years ago, sickle cell disease (SCD) was heralded as the first “molecular” disease (2), resulting from a single amino acid substitution in the β-globin chain of hemoglobin (HbA). Adult hemoglobin is a tetramer of two α-globin and two β-globin polypeptides (α2β2). Despite extensive characterization of the properties of sickle hemoglobin (HbS, α2βS2) and red blood cells containing HbS, and 30 years of analysis of globin genes, consistently effective therapy for individuals with SCD remains elusive. The World Health Organization estimates that many of the more than 200,000 babies with SCD born annually in Africa will die before the age of 5 years from anemia and infection (3, 4). In the United States, approximately 50,000 individuals are afflicted with SCD. The global need to develop uniformly effective and inexpensive therapy is enormous, and growing.

The tendency of HbS to polymerize at low oxygen tension leads to deformation of red blood cells into the characteristic sickle shape (5). These inflexible cells clog small blood vessels and cause intermittent occlusion, with ensuing tissue damage, pain, and anemia. Strokes, pulmonary infarction, and cardiovascular damage cause considerable morbidity. Therapy is mainly hydration, antibiotics, and blood transfusions, but in resource-poor countries, most patients receive little or no such care. Fifteen years ago, hydroxyurea was made available for treating SCD (6), reducing the incidence of pain in some cases, through largely unknown mechanisms. The sole “cure” for SCD is bone marrow transplantation, but it works best with matched donors. Proof-of-principle experiments in gene therapy and gene repair with induced pluripotent stem (iPS) cells (7) provide rationales for ongoing research into alternative curative strategies. Although prospects for gene therapy have improved with recent trials in patients with β-thalassemia (in which β-globin is inefficiently produced) (8), such a resource-intensive treatment is unlikely to succeed globally. Similarly, formidable hurdles in generating and expanding blood stem cells from human iPS cells prevent consideration of this regenerative medicine approach in the near future.

Although all individuals with SCD have the same mutation in the β-globin gene, disease severity varies widely. The concentration of fetal hemoglobin (HbF, α2γ2) is a major genetic contributor to this variability. HbF, the predominant hemoglobin produced during fetal life, is generally present at very low concentrations (∼1%) in adults, and is largely restricted to a small population of red blood cells (called F cells). The low concentration of HbF varies among individuals and is highly heritable as a quantitative trait. HbF reduces the tendency of HbS to polymerize, a salutary effect that has been appreciated for many years. Indeed, in 1948, it was hypothesized that residual HbF in infants with SCD explained the absence of sickle cells and disease symptoms (9).

The hemoglobin switch.

The fetal (γ) and adult (β) globin chains are expressed from genes on chromosome 11. SCD is caused by mutation of the β chain to the sickle (βS) chain. Genome-wide association studies have identified loci on chromosome 2 (BCL11A) and chromosome 6 (HBS1LMyb) that modify HbF expression. These modifiers affect the expression switch from γ to either β or βS globin. They may affect HbF levels either directly or indirectly. Targeted therapy could reverse the fetal-to-adult switch, and hence reduce disease severity.


As the switch from γ- to β-globin gene expression occurs after birth, HbF (α2γ2) is replaced by HbS (α2βS2), and symptoms of SCD ensue. Pain, the simplest measure of disease severity, is influenced by the amount of HbF present (10). HbF concentrations above ∼15% of the total adult hemoglobin are frequently associated with relatively benign disease symptoms. Thus, reactivating HbF expression in SCD patients, even to a modest degree, could be a highly effective therapy. However, a lack of understanding how the “hemoglobin switch” is regulated has thwarted progress on this front.

The hemoglobin switch results from a transition of γ- to β-globin gene expression during human development (see the figure). The DNA sequence of the human β-globin gene cluster on chromosome 11 was determined nearly 30 years ago. Much has been learned since about regulatory elements within the cluster and the individual globin genes (5). Rare germline deletions within the human β-globin gene cluster, as well as specific mutations in the γ-gene promoters, are associated with substantial HbF production in adults. Yet, transacting regulators of the hemoglobin switch have remained mysterious.

New findings provide hope that a detailed understanding of the hemoglobin switch may be forthcoming and translated into mechanism-based approaches to reactivate HbF production in SCD (as well as in the β-thalassemias). Although genome-wide association studies (GWAS) have been criticized for identifying multiple loci that each contribute only minimally to the overall genetic variation of a trait or disease (11), independent HbF GWAS studies have revealed just a few loci with very large effects (12, 13). Three genomic regions have been identified: the β-globin gene cluster itself, the gene encoding BCL11A on chromosome 2, and a region on chromosome 6 containing genes encoding HB1SL, a GTP-binding protein, and Myb, a transcription factor. Overall, these loci account for at least 40% of the genetic variation in the amount of HbF produced. The BCL11A and HBS1L-Myb regions are of particular interest because they might harbor “trans” regulators of the switch. Indirect evidence suggests that Myb, which controls hematopoiesis, rather than HBS1L, may influence HbF expression (14). The situation with BCL11A is clearer. It cooperates with other transcription factors and repressors to directly silence γ-globin genes in primary human erythroid cells, and controls the switch from fetal to adult β-like globin expression in mice and human red blood cells (15, 16). Consistent with GWAS analyses, HbF production is controlled in a dosage-sensitive manner by BCL11A.

The identification of a genetically validated regulator of HbF production has therapeutic implications for directed reactivation of HbF in adults. Presumably, additional regulators will be discovered with ongoing research. Decreasing BCL11A expression by RNA inhibition induces the production of appreciable HbF in adult-type red blood cells (15), which should spur exploration of emerging in vivo RNA interference technologies (17). Inhibiting BCL11A function, either directly or through disruption of interactions with cooperating factors, may be an alternative strategy. Because some protein complexes containing BCL11A may include proteins with enzymatic functions, inhibiting these activities might mimic the effects of decreasing BCL11A function (18). Traditionally, transcription factors have been considered “undruggable” targets, but new methods for designing inhibitory small molecules based on protein chemistry and structure, and for gene expression–based screening, open the possibility for pursuing such drugs (1921). Advances in high-throughput screening of small-molecule libraries also offer a platform for discovery and refinement of molecules that induce HbF production. Reinvigorating research for effective and hopefully low-cost therapy for SCD has never been more pressing.


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