Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

Abstract

The developmental regulation of globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease and b-thalassemia. Fetal hemoglobin has been shown to block sickle hemoglobin S polymerization to improve symptoms of sickle cell disease; moreover, fetal hemoglobin functions to replace inadequate hemoglobin A synthesis in b-thalassemia thus serving as an effective therapeutic target. In the perinatal period, fetal hemoglobin is synthesized at high levels followed by a decline to adult levels by one year of age. It is known that naturally occurring mutations in the g-globin gene promoters and distant cis-acting transcription factors produce persistent fetal hemoglobin synthesis after birth to ameliorate clinical symptoms. Major repressor proteins that silence g-globin during development have been targeted for gene therapy in b-hemoglobinopathies patients. In parallel effort, several classes of pharmacological agents that induce fetal hemoglobin expression through molecular and cell signaling mechanisms have been identified. Herein, we reviewed the progress made in the discovery of signaling molecules targeted by pharmacologic agents that enhance g-globin expression and have the potential for future drug development to treat the b-hemoglobinopathies.

Modulation of microRNAs expression in hematopoietic stem cells treated with sodium butyrate in inducing fetal hemoglobin expression

“…Synthesis of an abnormal bs-globin chain and the reduced rate of synthesis of normal b-globin chains result in Sickle cell diseases and b-thalassaemias, respectively (Galanello and Origa 2010, Pace et al 2015, Rees et al 2010. Sickle cell disease is a widespread group of hemoglobin disorders caused by substitution of single amino acid.…”

SIRT1 activates the expression of fetal hemoglobin genes

“…Increased proliferation or delayed differentiation of erythroid progenitor cells can contribute to elevated HbF . As SIRT1 has been shown to be involved in cell growth and apoptosis we explored the mechanism by which SIRT1 regulates HBG expression by first determining whether SIRT1 played a role in erythroid progenitor cell proliferation .…”

Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms

“…[5, 48-65] While concern has been raised regarding prolonged suppression of BCL11A on B-cell differentiation long-term in the context of gene editing approaches, these and other small molecules can be readily administered intermittently, thereby preventing sustained off-target effects. [67, 70] The findings here suggest a basis for combining pharmacologic agents to induce higher HbF expression through complementary molecular mechanisms if one alone is not adequate.…”