Retroviral Stem Cell Gene Therapy

Abstract

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.

Stem cell therapy and gene transfer for regeneration

“…However, progress in the field of genetic transfer or modification into human longterm repopulating stem cells mediated by retroviral vectors has been blocked by the fact that levels of transfection are too low for any likely therapeutical benefit. 51,52 Several reports have demonstrated that an important reason for the low levels of transduction might involve certain incompatible features of the vectors used and the stem cells that they target.…”

Genetically modified CD34+ cells as cellular vehicles for gene delivery into areas of angiogenesis in a rhesus model

“…[37][38][39][40][41][42][43][44] Unfortunately, maneuvers for improving transduction in vitro, such as prolonging exposure to viral vectors, stimulating cell proliferation, or culturing on stromal cells, affect the phenotypic features of progenitor cells in undesirable ways. 45,46 To explore the concept of systemic gene delivery into areas of angiogenesis, we sought to use cellular vehicles naturally endowed with angiogiogenic tropism.…”

Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector

“…The observed superiority of amphotropic producer cells is in contradiction to previous data which suggested that ecotropic viral vectors mediate significantly higher transgene expression levels than amphotropic vectors. 29 Differences in the vectors and the transduction/transplantation protocol may explain these contrasting results.…”