The beta-globin locus control region versus gene therapy vectors: a struggle for expression.

Developmental control of gene expression has a major impact on the design of beta-globin retrovirus vectors for hematopoietic stem cell gene therapy of beta-thalassemia. It is obvious that the endogenous locus control region (LCR) elements that drive beta-globin gene expression in transgenic mice must be included in these vectors. However, the specific elements to use are not clear and require an understanding of LCR action. Moreover, retrovirus vectors contain silencer elements that function in stem cells and are dominant to LCR function. Recent studies on LCRbeta-globin transgenes and retrovirus silencing suggest ways to overcome this silencing effect after transfer into stem cells and carefully designed lentivirus vectors have exciting therapeutic benefit in animal models of beta-thalassemia. By building on 15 years of development, LCRbeta-globin vectors are now being tested in preclinical animal models and may ultimately lead to the long-sought cure for this genetic disease.