Efficacy of Rapamycin as Inducer of Hb F in Primary Erythroid Cultures from Sickle Cell Disease and β-Thalassemia Patients

Hemoglobin. 2015;39(4):225-9. doi: 10.3109/03630269.2015.1036882. Epub 2015 May 27.

Abstract

Phenotypic improvement of hemoglobinopathies such as sickle cell disease and β-thalassemia (β-thal) has been shown in patients with high levels of Hb F. Among the drugs proposed to increase Hb F production, hydroxyurea (HU) is currently the only one proven to improve the clinical course of these diseases. However, Hb F increase and patient's response are highly variable, indicating that new pharmacological agents could be useful for patients not responding to HU or showing a reduction of response during long-term therapy. In this study we evaluated the efficacy of rapamycin, a lypophilic macrolide used for the prevention of acute rejection in renal transplant recipients, as an inducer of Hb F production. The analyses were performed in cultured erythroid progenitors from 25 sickle cell disease and 25 β-thal intermedia (β-TI) patients. The use of a quantitative Real-Time-polymerase chain reaction ReTi-PCR technique and high performance liquid chromatography (HPLC) allowed us to determine the increase in γ-globin mRNA expression and Hb F production in human erythroid cells treated with rapamycin. The results of our study demonstrated an increase in vitro of γ-globin mRNA expression in 15 sickle cell disease and 14 β-TI patients and a corresponding Hb F increase. The induction by rapamycin, even if lower or similar in most of samples analyzed, in some cases was higher than HU. These data suggest that rapamycin could be a good candidate to be used in vivo for the treatment of hemoglobinopathies.

Keywords: Fetal hemoglobin (Hb F); hemoglobinopathies; high performance liquid chromatography (HPLC); primary erythroid cultures; rapamycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anemia, Sickle Cell / drug therapy
  • Anemia, Sickle Cell / genetics*
  • Anemia, Sickle Cell / metabolism
  • Cells, Cultured
  • Erythroid Precursor Cells / drug effects*
  • Erythroid Precursor Cells / metabolism*
  • Female
  • Fetal Hemoglobin / genetics*
  • Fetal Hemoglobin / metabolism
  • Gene Expression Regulation / drug effects*
  • Genotype
  • Humans
  • Hydroxyurea / pharmacology
  • Hydroxyurea / therapeutic use
  • Male
  • Middle Aged
  • Mutation
  • Sirolimus / pharmacology*
  • Young Adult
  • alpha-Globins / genetics
  • alpha-Globins / metabolism
  • beta-Globins / genetics
  • beta-Globins / metabolism
  • beta-Thalassemia / drug therapy
  • beta-Thalassemia / genetics*
  • beta-Thalassemia / metabolism
  • gamma-Globins / genetics
  • gamma-Globins / metabolism

Substances

  • alpha-Globins
  • beta-Globins
  • gamma-Globins
  • Fetal Hemoglobin
  • Sirolimus
  • Hydroxyurea