Induction of stable prenatal tolerance to β-galactosidase by in utero gene transfer into preimmune sheep fetuses

Long-term transgene expression by administration of a lentivirus-based vector to the fetal circulation of immuno-competent mice

“…33 This contrasts with the prolonged transgene expression observed in preimmune fetal sheep 11,13 and with the experiments reported here. Tran et al 13 also observed that a three-fold increase in titre of an MLV vector only yielded a two to eight-fold increase in stable transduction, implying the operation of additional factors.…”

“…Another important factor influencing the persistence of gene expression is the development of immune reactions against vector and the transgenic protein. Tran et al 13 have recently shown the development of postnatal tolerance to b-galactosidase after expression of this transgenic protein in preimmune fetal sheep. We have demonstrated a similar effect in mice after prenatal yolk sac vessel application of an The lack of gene expression after delivery into adult mice was not unexpected.…”

“…They have been used in several fetal studies in different animal models to explore various application routes and have demonstrated successful transgene expression in the fetal airways, gut, liver, adrenal glands, and vascular system. [2][3][4][5][6][7][8][9][10][11][12][13][14] Their immunogenicity has been exploited to study the possibility of fetal immune tolerance after prenatal administration. [15][16][17] However, loss of these episomal DNA vectors during subsequent cell divisions following infection severely curtails their applicability to long-term fetal gene therapy.…”

Reduced toxicity of F-deficient Sendai virus vector in the mouse fetus

“…6,19 Advancing therapeutic application of virus to the fetal period has been shown to overcome immunological obstacles by pre-empting the development of a mature immune system. Studies have shown that, following prenatal injection, tolerance can be induced to marker 20 and therapeutic transgenic proteins. 16 However, our observed loss of expression after in utero administration of SeV does not support the hypothesis of persistent infection and therefore expression with this vector at this time.…”

Fetal Gene Therapy

“…Given the pivotal role of the thymus during the development of the fetal immune system's ability to distinguish self from non-self, we undertook studies to ascertain the immunologic significance of the presence of these transgene-positive cells within the thymus. In our first set of studies, [106] we demonstrated that in utero gene transfer successfully induced durable immune tolerance to the vectorencoded -galactosidase. This tolerance induction appeared to involve both cellular and humoral mechanisms, since both antibody responses and cellular responses were blunted in these animals even several years after in utero gene transfer, providing strong evidence that IUGT induces immune tolerance to the protein product of the transgene.…”