title: Efficacy of Rapamycin as Inducer of Hb F in Primary Erythroid Cultures from Sickle Cell Disease and β-Thalassemia Patients.
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.
authors.affiliation: Dipartimento di Oncologia ed Ematologia, Unitá Operativa Complessa Ematologia per le Malattie Rare del Sangue e degli Organi Ematopoietici, Azienda Ospedaliera "Ospedali Riuniti Villa Sofia-Cervello" , Palermo , Italia and.
authors.forename: Alice
authors.initials: A
authors.lastname: Pecoraro
authors.forename: Antonio
authors.initials: A
authors.lastname: Troia
authors.forename: Roberta
authors.initials: R
authors.lastname: Calzolari
authors.forename: Concetta
authors.initials: C
authors.lastname: Scazzone
authors.forename: Paolo
authors.initials: P
authors.lastname: Rigano
authors.forename: Adriana
authors.initials: A
authors.lastname: Martorana
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Sacco
authors.forename: Aurelio
authors.initials: A
authors.lastname: Maggio
authors.forename: Rosalba
authors.initials: R
authors.lastname: Di Marzo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005838:Genotype; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020123:Sirolimus / Q000494:pharmacology*; D055815:Young Adult; D055542:alpha-Globins / Q000235:genetics / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism; D017086:beta-Thalassemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D055542:alpha-Globins; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D020123:Sirolimus; D006918:Hydroxyurea
keywords: Fetal hemoglobin (Hb F); hemoglobinopathies; high performance liquid chromatography (HPLC); primary erythroid cultures; rapamycin