
<ArticleTitle>Development of a stable retrovirus vector capable of long-term expression of <prot>gamma-globin</prot> mRNA in mouse erythrocytes.</ArticleTitle>
<AbstractText>Gene therapy for patients with <prot>hemoglobin</prot> disorders such has been hampered by the inability of retrovirus vectors to transfer globin genes and the locus control region (LCR) into hematopoietic stem cells without rearrangement. In addition, the expression from intact globin gene vectors has been variable in red blood cells as a result of position effects and retrovirus silencing. We hypothesized that by substituting the globin gene promoter for the promoter of another gene expressed in red blood cells, we could generate stable retrovirus vectors that would express globin at sufficient levels to treat hemoglobinopathies. Transgenic mice containing the human <prot>ankyrin</prot> (<prot>Ank</prot>) gene promoter fused to the human <prot>gamma-globin</prot> gene showed position-independent, copy number-dependent expression of a linked <prot>gamma-globin</prot> mRNA. We generated a "double-copy" <prot>Ank/A</prot> <prot>gamma-globin</prot> retrovirus vector that transferred two copies of the <prot>Ank/A</prot> <prot>gamma-globin</prot> gene into target cells. Stable gene transfer was observed in primary primary mouse progenitor cells and long-term repopulating hematopoietic stem cells. Expression of <prot>Ank/A</prot> <prot>gamma-globin</prot> mRNA in mature red blood cells was approximately 8% of the level of mouse <prot>alpha-globin</prot> mRNA. We conclude that this novel retrovirus vector may be valuable for treating a variety of hemoglobinopathies by gene therapy if the level of expression can be further increased.</AbstractText>
