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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-03-0779.
Submitted March 13, 2002
Accepted September 17, 2002
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, Geoffrey Kemball-Cook, Maznu Miah, Nick Tucker, Margaret J Dallman, Mike Themis, and Charles Coutelle
Gene Therapy, Cell and Molecular Biology, Imperial College School of Science, Technology and Medicine, London, United Kingdom
Childrens Hospital, University of Erlangen-Nuernberg, Erlangen, Germany
Faculty of Medicine, Hammersmith Campus, Imperial College, MRC Clinical Sciences Centre, London, United Kingdom
Dept. Biological Sciences, Imperial College School of Science, Technology and Medicine, London, United Kingdom
* Corresponding author; email: s.waddington{at}ic.ac.uk.
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 which 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 4) To prevent early disease manifestation of genetic diseases. This study provides evidence vindicating the first principle; namely, that intra-vascular 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 6 out of 11 mice. Furthermore, there was substantial hFIX expression after each of two re-injections 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.
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