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

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.
LanguageEnglish
Pages1359-1366
Number of pages8
JournalBlood
Volume101
Issue number4
DOIs
Publication statusPublished - 15 Feb 2003

Fingerprint

Gene transfer
Transfer Factor
Factor IX
Blood Coagulation Factors
Human engineering
Genes
Transgenes
Immune Tolerance
Antibodies
Fetal Therapies
Antigen-antibody reactions
Gene therapy
Inborn Genetic Diseases
Injections
Human Development
Stem cells
Viruses
Genetic Therapy
Amplification
Proteins

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
Waddington, Simon N ; Buckley, Suzanne M K ; Nivsarkar, Megha ; Jezzard, Sarah ; Schneider, Holm ; Dahse, Thomas ; Kemball-Cook, Geoff ; Miah, Maznu ; Tucker, Nick ; Dallman, Margaret J ; Themis, Mike ; Coutelle, Charles. / In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. In: Blood. 2003 ; Vol. 101, No. 4. pp. 1359-1366.
@article{de8c93d5cbcd43d09edf9c55b70fd3c1,
title = "In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor",
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.",
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",
author = "Waddington, {Simon N} and Buckley, {Suzanne M K} and Megha Nivsarkar and Sarah Jezzard and Holm Schneider and Thomas Dahse and Geoff Kemball-Cook and Maznu Miah and Nick Tucker and Dallman, {Margaret J} and Mike Themis and Charles Coutelle",
year = "2003",
month = "2",
day = "15",
doi = "10.1182/blood-2002-03-0779",
language = "English",
volume = "101",
pages = "1359--1366",
journal = "Blood",
issn = "0006-4971",
number = "4",

}

Waddington, SN, Buckley, SMK, Nivsarkar, M, Jezzard, S, Schneider, H, Dahse, T, Kemball-Cook, G, Miah, M, Tucker, N, Dallman, MJ, Themis, M & Coutelle, C 2003, 'In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor' Blood, vol. 101, no. 4, pp. 1359-1366. https://doi.org/10.1182/blood-2002-03-0779

In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. / Waddington, Simon N; Buckley, Suzanne M K; Nivsarkar, Megha; Jezzard, Sarah; Schneider, Holm; Dahse, Thomas; Kemball-Cook, Geoff; Miah, Maznu; Tucker, Nick; Dallman, Margaret J; Themis, Mike; Coutelle, Charles.

In: Blood, Vol. 101, No. 4, 15.02.2003, p. 1359-1366.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor

AU - Waddington, Simon N

AU - Buckley, Suzanne M K

AU - Nivsarkar, Megha

AU - Jezzard, Sarah

AU - Schneider, Holm

AU - Dahse, Thomas

AU - Kemball-Cook, Geoff

AU - Miah, Maznu

AU - Tucker, Nick

AU - Dallman, Margaret J

AU - Themis, Mike

AU - Coutelle, Charles

PY - 2003/2/15

Y1 - 2003/2/15

N2 - 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.

AB - 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.

KW - adenoviridae

KW - animals

KW - antibodies

KW - factor IX

KW - female

KW - fetus

KW - gene expression

KW - genetic vectors

KW - humans

KW - immune tolerance

KW - kinetics

KW - liver

KW - mice

KW - myocardium

KW - pregnancy

KW - recombinant proteins

KW - time factors

KW - transfection

U2 - 10.1182/blood-2002-03-0779

DO - 10.1182/blood-2002-03-0779

M3 - Article

VL - 101

SP - 1359

EP - 1366

JO - Blood

T2 - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -

Waddington SN, Buckley SMK, Nivsarkar M, Jezzard S, Schneider H, Dahse T et al. In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. Blood. 2003 Feb 15;101(4):1359-1366. https://doi.org/10.1182/blood-2002-03-0779