In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor.
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.
Waddington
Simon N
SN
Gene Therapy, Section of Cell and Molecular Biology, Imperial College School of Science, Technology and Medicine, London, United Kingdom. s.waddington@ic.ac.uk
Buckley
Suzanne M K
SM
Nivsarkar
Megha
M
Jezzard
Sarah
S
Schneider
Holm
H
Dahse
Thomas
T
Kemball-Cook
Geoff
G
Miah
Maznu
M
Tucker
Nick
N
Dallman
Margaret J
MJ
Themis
Mike
M
Coutelle
Charles
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D005164:Factor IX / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D007108:Immune Tolerance; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D011247:Pregnancy; D011994:Recombinant Proteins / Q000276:immunology; D013997:Time Factors; D014162:Transfection
D000906:Antibodies; D011994:Recombinant Proteins; D005164:Factor IX