Low efficiency of gene transfer is the main obstacle for a clinically effective 
gene therapy at the level of the pluripotent hematopoietic stem cell. Another 
important aspect of stem cell gene therapy, the actual expression of the 
transduced genes, has only been investigated adequately in very few studies, 
mainly for globin genes. Transcriptional silencing and position effects due to 
negative effects of surrounding chromatin on the expression of randomly 
integrated vector sequences may seriously jeopardize the success of current gene 
therapy strategies, even if transduction efficiency can be significantly 
improved. We propose the incorporation of chromatin insulators in the design of 
gene therapy vectors to overcome the problem of position effects. Chromatin 
insulators are protein-binding DNA elements that lack intrinsic 
promoter/enhancer activity but shelter genes from transcriptional influence of 
surrounding chromatin. The best characterized insulators are from Drosophila. We 
hypothesize that the important cellular function of chromatin organization is 
evolutionarily conserved and that human homologs to Drosophila insulator binding 
proteins such as the suppressor of Hairy-wing exist and can be cloned. Using 
these putative proteins, it should be possible to identify corresponding minimal 
binding sites with insulator activity. The design and incorporation of effective 
chromatin insulator sequences in the next generation of gene therapy vectors 
should lead to improved and more predictable expression of therapeutic 
transgenes and constitute an important step toward clinically effective gene 
therapy.