In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor

Simon N Waddington, Suzanne M K Buckley, Megha Nivsarkar, Sarah Jezzard, Holm Schneider, Thomas Dahse, Geoff Kemball-Cook, Maznu Miah, Nick Tucker, Margaret J Dallman, Mike Themis, Charles Coutelle

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Abstract

The fundamental hypotheses behind fetal gene therapy are that it may be possible (1) to achieve immune tolerance of transgene product and, perhaps, vector; (2) to target cells and tissues that are inaccessible in adult life; (3) to transduce a high percentage of rapidly proliferating cells, and in particular stem cells, with relatively low absolute virus doses leading to clonal transgene amplification by integrating vectors; and (4) to prevent early disease manifestation of genetic diseases. This study provides evidence vindicating the first hypothesis; namely, that intravascular prenatal administration of an adenoviral vector carrying the human factor IX (hFIX) transgene can induce immune tolerance of the transgenic protein. Following repeated hFIX protein injection into adult mice, after prenatal vector injection, we found persistence of blood hFIX and absence of hFIX antibodies in 5 of 9 mice. Furthermore, there was substantial hFIX expression after each of 2 reinjections of vector without detection of hFIX antibodies. In contrast, all adult mice that had not been treated prenatally showed a rapid loss of the injected hFIX and the development of high hFIX antibody levels, both clear manifestations of a strong immune reaction.
Original languageEnglish
Pages (from-to)1359-1366
Number of pages8
JournalBlood
Volume101
Issue number4
DOIs
Publication statusPublished - 15 Feb 2003

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Keywords

  • adenoviridae
  • animals
  • antibodies
  • factor IX
  • female
  • fetus
  • gene expression
  • genetic vectors
  • humans
  • immune tolerance
  • kinetics
  • liver
  • mice
  • myocardium
  • pregnancy
  • recombinant proteins
  • time factors
  • transfection

Cite this

Waddington, S. N., Buckley, S. M. K., Nivsarkar, M., Jezzard, S., Schneider, H., Dahse, T., ... Coutelle, C. (2003). In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. Blood, 101(4), 1359-1366. https://doi.org/10.1182/blood-2002-03-0779