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Retroviral Stem Cell Gene Therapy

^a Gene Therapy Section of the Department of Medical Biochemistry, Medical Faculty, LeidenUniversity, The Netherlands;
^b IntroGene BV, Leiden, The Netherlands;
^c Department of Paediatrics, Sophia Children's Hospital, Rotterdam, The Netherlands

Key Words. Hemopoietic stem cell • Retrovirus • Gene therapy • Murine studies • Primate studies • Vector • Transduction

Dr. Helmuth H.G. van Es, IntroGene B.V., P.O. Box 2048, 2301 CA Leiden, The Netherlands.

Long-term in vivo gene transfer studies in mice have shown that recombinant murine retroviruses are able to infect murine hemopoietic stem cells with high efficiency. Taken together the results indicated that the proviral structure was present at high frequency in circulating hemopoietic cells resulting in significant expression levels. Because of the success of these murine studies, it was believed that gene therapy would soon be applicable to treat a wide variety of congenital or acquired human diseases associated with the hemopoietic system. However, results from gene transfer studies in nonhuman primates and first human clinical trails have indicated that murine retrovirus infection of primate hemopoietic stem cells is inefficient. Although there are essential differences between the murine and primate gene therapy studies with respect to the recombinant viruses and transduction protocols used, these differences cannot solely account for the differences observed in infection efficiency. Therefore, in recent years effort has been spent on the identification of factors limiting retroviral transduction of primate hemopoietic stem cells. Increasing knowledge concerning hemopoiesis and retroviral infection has helped in identifying a number of limiting factors. Novel transduction strategies and tools have been generated which attempt to circumvent these limiting factors. These factors as well as the strategies that showed increased retroviral infection of primate hemopoietic stem cells will be discussed.

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