THAL for THAL?

In this issue of Blood, Aerbajinai and colleagues establish that thalidomide can increase fetal γ-globin gene expression in human adult erythroid cells in an ex vivo culture system.

Sickle cell disease and β-thalassemias are the most common monogenic diseases of man. They are found in the “malaria belt” that extends from the Mediterranean and sub-Saharan Africa through southeast Asia and southern China. These hemoglobin mutations occur at high incidences in these regions because heterozygotes have a selective advantage against infection with Plasmodium falciparum.

Sickle cell disease is prevalent in sub-Saharan Africa, parts of the Middle East, and the Indian subcontinent, and is also found in the United States and elsewhere. While thalassemias are uncommon in North America, they remain a disease of worldwide public health importance (particularly in many developing countries).¹  It is estimated that up to half a million infants are born annually with severe forms of thalassemia.

Investigations elucidating the molecular basis of sickle cell disease and thalassemias ushered in the explosion of new knowledge in genetics and molecular medicine that occurred over the past half-century.²  In spite of this remarkable progress in understanding the genetic and physicochemical basis of these disorders, there has been a disappointing lack of success in the development of disease-specific treatments that improve patient outcomes. While patients live longer and have a much better quality of life than previously—largely due to the availability of improved supportive medical care—many afflicted persons still die young even with the best possible care (see www.thalassemia.ca).

Hydroxyurea is now approved for the treatment of sickle cell anemia.³  Some patients benefit from this medication to varying degrees. Treatment options for thalassemias are even fewer, with patient survival depending largely upon regular transfusions and their accompanying complications. Antenatal diagnosis is still touted to be the most important medical intervention for thalassemia care. Hematopoietic stem-cell transplantation is curative in relatively few fortunate patients. Gene therapy has yet to become a reality.

Reactivation of fetal hemoglobin production to prevent sickle hemoglobin polymerization and to compensate for the lack of adult hemoglobin in β-thalassemias is an attractive therapeutic possibility. 5′-azacytidine was used in 1982 to treat patients with thalassemia and sickle cell disease. These reports heralded the first glimpse of hope that this approach was possible.^4,5  Hydroxyurea was later shown to up-regulate fetal hemoglobin synthesis.

The use of arginine butyrate in patients with sickle cell disease and thalassemias was reported in 1993.⁶  Since then, other short-chain fatty acids, histone deacetylase (HDAC) inhibitors, and cytokines such as erythropoi-etin and stem cell factor have been found to enhance fetal hemoglobin production to varying degrees. However, none of these agents has demonstrated clear and consistent clinical efficacy.

A brief clinical report on 5 patients treated for myelodysplasia hinted that thalidomide might enhance fetal hemoglobin production.⁷  In this issue of Blood, Aerbajinai and colleagues report that thalidomide increases γ-globin mRNA, protein, and fetal hemoglobin-containing cells (F cells) in a human erythroid-cell ex vivo culture system. It appears that the thalidomide effect is mediated through generation of reactive oxygen species (ROS), phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), and subsequent signaling. This mechanism is reminiscent of the pathway mediated by HDAC inhibitors.

The cellular and molecular mechanisms acounting for the thalidomide effect remain to be fully understood, as is the case for all other agents known today to be capable of up-regulating γ-globin gene expression. Thalidomide is likely to be unsuitable for treatment of patients with hemoglobin disorders, given its teratogenic and other side effects. Nonetheless, Aerbajinai and colleagues have now identified yet another compound capable of augmenting fetal hemoglobin synthesis in adult erythroid cells.

Will structural modeling and refinement of this and other compounds yield more ef-fective and safer candidate drugs for clinical trials? Will genomic research uncover additional targets for drug development? Will combination therapy be more efficacious? This is a fertile and important area for research that may ultimately benefit the many patients living with devastating hemoglobin disorders worldwide.