Production of Genetically Stable High - Titer Retroviral Vectors That Carry a Human y - Globin Gene Under the Control of the a - Globin Locus Control Region

The a b i l i to generate stable high-titer vectors that give rise to high levels of expression of transduced globin genes in erythroid dls is a prerequisite for dfective retrovird-diated globin gene therapy. The human #%globin gene with its immediate flanking sequences does not contain all the regulatory elements necessary for regulated high-level and position-independent expression in erythroid cells. The regulatory element known as the 8-globin locus control region WLCRl can provide a linked @globin gene with those properties. However, addition of 8LCR sequences to a retrovirus camying a &globin gene increases its genetic instability. We have developed a new generation of retroviral vectors in which a human yglobin gene is placed under the control of the aLCR, the major regulatory element ofthe a-globin gene