Delivering genes to the stem cell compartment has proved difficult because stem cells are rare and difficult to purify. Our analysis of the transcriptional control of the gene encoding the stem cell antigen CD34 has revealed a potent upstream regulatory element which offers a strong candidate for a stem-cell-specific enhancer. The objectives of this pilot project are two-fold: (1) to identify the CD34 cis-acting regulatory elements capable of targeting heterologous gene expression to the mammalian hematopoietic stem cell compartment, (2) to pare these elements down to a size suitable for accommodation into bi-cistronic, retroviral vectors for use in gene therapy of sickle cell disease. The development of regulatory cassettes that permit the targeting of heterologous gene products to the hematopoietic stem cell compartment has broad biological and clinical implications. In addition to sickle cell disease, monogenic disorders of hematopoietic stem cells may themselves be prime targets for gene therapy using CD34-based retroviral vectors.
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