Gene Transfer to Hematopoietic Progenitor and Stem Cells: Progress and Problems
The hematopoietic stem cell has been an obvious target for gene therapy technologies because of its ability to permanently reconstitute all the lineages of the hematopoietic and immune systems after transplantation. Many different congenital and acquired diseases could theoretically be treated by introducing a new gene into stem cells.1–4 Retroviral vectors are currently the only gene transfer system with the appropriate characteristics of chromosomal integration and stable helper-free producer cell lines that can be used clinically in protocols targetted at hematopoietic stem cells. In rodent models, investigators have demonstrated efficient and reproducible gene transfer to a high percentage of long-term repopulating stem cells and achieved long-term expression of introduced genes in appropriate lineages.4–7 In large animal and primate models, retroviral gene transfer has been much less efficient, with reproducibly less than 1% of circulating cells containing the transferred gene long-term. 8–12 Efficient gene transfer to primitive human progenitor cells such as CFU-GEMM or long-term culture initiating cells has been reported, with gene transfer efficiencies greatly increased by exposing target cells to hematopoietic growth factors during transduction with viral vectors.I3–15 Over the past four years, investigators have begun to apply retroviral gene transfer technology directed at hematopoietic stem cells in preliminary human clinical trials.
KeywordsHematopoietic Stem Cell Gauche Disease Autologous Transplantation Gene Transfer Efficiency Exogenous Growth Factor
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