Fetal hemoglobin reactivation and cell engineering in the treatment of sickle cell anemia

Abstract

The natural history of severe hemoglobinopathies like sickle cell disease (SCD) is rather variable, depending on the circumstances, but the main influence on such variability is the level of fetal hemoglobin (HbF) in the patient’s red cells. It is well known that a significant HbF level is associated with a milder course of disease and fewer complications. Therefore, attempts have been made to reactivate using various means the HbF production, which is normally switched off perinatally. A pharmacological approach has been attempted since the 1980s, ranging from drugs like 5-azacytidine and its derivative, decitabine, to a series of compounds like hydroxyurea and a number of histone deacetylase inhibitors like butyrate, which seem to act as epigenetic modifiers. Many other disparate agents have been tried with mixed results, but hydroxyurea remains the most effective compound so far available. Combinations of different compounds have also been tried with some success. Established treatments like bone marrow or cord blood transplantation are so far the only real cure for a limited number of patients with severe hemoglobinopathies. Improved chemotherapy regimens of milder toxicity than those employed in the past have made it possible recently to obtain a stable, mixed donor-recipient chimerism, with reversal of the SCD phenotype. However, great effort is directed to cell engineering, searching for an effective gene vector by which a desired gene can be transferred into new classes of vectors for autologous hemopoietic stem cells. Recent studies are also aiming at targeted insertion of the therapeutic gene into hemopoietic cells, which can also be “induced” human stem cells, obtained from somatic dedifferentiated cells. Attention in this area must be paid to the possibility of undesired effects, like the emergence of potentially oncogenic cell populations. Finally, an update is presented on improved HbF determination methods, because common international standards are becoming mandatory.

Comparing segmented ASL perfusion of vascular territories using manual versus semiautomated techniques in children with sickle cell anemia

“…Additionally, there was a trend toward significance with hemoglobin F in the left PCA WM as well. Indeed, the amount of fetal hemoglobin expression is associated with a milder clinical phenotype of the disease, and is an area of active research (41, 42). These significant hematological associations are clinically relevant relationships, and may in part demonstrate complex pathophysiologic changes that contribute to observed clinical variation in CBF (14), although this needs to be validated in a prospective study.…”

Reactivation of Fetal Hemoglobin in Thalassemia and Sickle Cell Disease

“…It can be reminded that HDAC inhibitors are among the agents suggested for clinical treatment of SCD. 45 Other events not to be underestimated as regulatory mechanisms are epigenetic changes, such as histone modifications and DNA methylation. Histone modifications by acetylation, methylation, phosphorylation, sumoylation, and ubiquitination and DNA methylation on CpG residues are among the most important epigenetic mechanisms.…”

“…Histone modifications by acetylation, methylation, phosphorylation, sumoylation, and ubiquitination and DNA methylation on CpG residues are among the most important epigenetic mechanisms. 45 DNA methylation is apparently the best-characterized epigenetic modifier of HbF level. Methylation of CpG dinucleotides within the gglobin promoter has been associated with gene silencing by inhibiting the transcription of gglobin genes in adult bone marrow.…”

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

“…Before birth until 32 weeks of gestation, HbF is the predominant hemoglobin type in production and circulation. At 32 weeks of gestation, globin chain production begins to switch from production of γ‐globin chains to the production of β‐globin chains, causing the formation of HbA . In SCD, a mutation occurs in the gene responsible for β‐globin production that causes increased hydrophobicity and, subsequently, reduced solubility of HbS.…”

“…At 32 weeks of gestation, globin chain production begins to switch from production of c-globin chains to the production of b-globin chains, causing the formation of HbA. 3,5,6 In SCD, a mutation occurs in the gene responsible for b-globin production that causes increased hydrophobicity and, subsequently, reduced solubility of HbS. Polymerization also occurs that distorts RBCs into a sickle shape.…”