title: Restoration of hemoglobin A synthesis in erythroid cells from peripheral blood of thalassemic patients.
abstract: Mononuclear cells from peripheral blood of thalassemic patients were treated with morpholino oligonucleotides antisense to aberrant splice sites in mutant beta-globin precursor mRNAs (pre-mRNAs). The oligonucleotides restored correct splicing and translation of beta-globin mRNA, increasing the hemoglobin (Hb) A synthesis in erythroid cells from patients with IVS2-654/beta(E), IVS2-745/IVS2-745, and IVS2-745/IVS2-1 genotypes. The maximal Hb A level for repaired IVS2-745 mutation was approximately 30% of normal; Hb A was still detectable 9 days after a single treatment with oligonucleotide. Thus, expression of defective beta-globin genes was repaired and significant level of Hb A was restored in a cell population that would be targeted in clinical applications of this approach.
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lacerra
authors.forename: H
authors.initials: H
authors.lastname: Sierakowska
authors.forename: C
authors.initials: C
authors.lastname: Carestia
authors.forename: S
authors.initials: S
authors.lastname: Fucharoen
authors.forename: J
authors.initials: J
authors.lastname: Summerton
authors.forename: D
authors.initials: D
authors.lastname: Weller
authors.forename: R
authors.initials: R
authors.lastname: Kole
mesh_terms: D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D004912:Erythrocytes / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D005914:Globins / Q000235:genetics; D006441:Hemoglobin A / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017381:Spliceosomes / Q000235:genetics; D013997:Time Factors; D017086:beta-Thalassemia / Q000097:blood* / Q000235:genetics / Q000628:therapy*
chemical_list: D016376:Oligonucleotides, Antisense; D012322:RNA Precursors; D012333:RNA, Messenger; D005914:Globins; D006441:Hemoglobin A