RETROVIRAL STEM-CELL GENE-THERAPY

Long-term in vivo gene transfer studies in mice have shown that recomb inant murine retroviruses are able to infect murine hemopoietic stem c ells with high efficiency. Taken together the results indicated that t he proviral structure was present at high frequency in circulating hem opoietic 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 acq uired human diseases associated with the hemopoietic system. However, results from gene transfer studies in nonhuman primates and first huma n clinical trails have indicated that murine retrovirus infection of p rimate hemopoietic stem cells is inefficient. Although there are essen tial differences between the murine and primate gene therapy studies w ith respect to the recombinant viruses and transduction protocols used , these differences cannot solely account for the differences observed in infection efficiency. Therefore, in recent Sears effort has been s pent on the identification of factors limiting retroviral transduction of primate hemopoietic stem cells. Increasing knowledge concerning he mopoiesis 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 f actors as well as the strategies that showed increased retroviral infe ction of primate hemopoietic stem cells will be discussed.