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Publication Detail
Ultrasound guided percutaneous delivery of adenoviral vectors encoding the beta-galactosidase and human factor IX genes to early gestation fetal sheep in utero
  • Publication Type:
    Journal article
  • Publication Sub Type:
    JOUR
  • Authors:
    David A, Cook T, Waddington S, Peebles D, Nivsarkar M, Knapton H, Miah M, Dahse T, Noakes D, Schneider H, Rodeck C, Coutelle C, Themis M
  • Publication date:
    2003
  • Pagination:
    353, 364
  • Volume:
    14
  • Issue:
    4
  • Notes:
    In utero gene therapy may provide treatment of genetic diseases before significant organ damage, allow permanent genetic correction by reaching stem cell populations and provide immune tolerance against the therapeutic transgenes and vectors. We have used percutaneous ultrasound guided injection as a minimally invasive fetal procedure. First generation adenoviruses encoding the nuclear localising -galactosidase reporter gene or the human Factor IX (hFIX) gene, or colloidal carbon were delivered via the umbilical vein (UV, n=4), heart (IC, n=2), liver parenchyma (HE, n=11), peritoneal cavity (IP, n=14), skeletal musculature (IM, n=11) or the amniotic cavity (IA, n=14) to early gestation fetal sheep (0.3 gestation = day 33-61). Post-mortem analysis was performed at 2, 9 or 28 days after injection. Although fetal survival was between 77-91% for IP, HE, IA and IM routes, no fetuses survived UV or IC procedures. The hFIX levels reaching 1900 and 401ng/ml (IP), 30ng/ml (HE), 66.5 and 39ng/ml (IA) and 83 and 65.5ng/ml (IM) respectively were determined 2 days following injection and fell at birth to 16.5ng/ml (IP), 7ng/ml (HE), 4.5ng/ml (IA) and 4 and 0ng/ml (IM). PCR and immunohistochemistry showed broadest hFIX transgene spread and highest localised -galactosidase expression respectively after IP administration. Antibodies were observed against vector but not against hFIX.
Abstract
In utero gene therapy may provide treatment of genetic diseases before significant organ damage, allow permanent genetic correction by reaching stem cell populations and provide immune tolerance against the therapeutic transgenes and vectors. We have used percutaneous ultrasound guided injection as a minimally invasive fetal procedure. First generation adenoviruses encoding the nuclear localising -galactosidase reporter gene or the human Factor IX (hFIX) gene, or colloidal carbon were delivered via the umbilical vein (UV, n=4), heart (IC, n=2), liver parenchyma (HE, n=11), peritoneal cavity (IP, n=14), skeletal musculature (IM, n=11) or the amniotic cavity (IA, n=14) to early gestation fetal sheep (0.3 gestation = day 33-61). Post-mortem analysis was performed at 2, 9 or 28 days after injection. Although fetal survival was between 77-91% for IP, HE, IA and IM routes, no fetuses survived UV or IC procedures. The hFIX levels reaching 1900 and 401ng/ml (IP), 30ng/ml (HE), 66.5 and 39ng/ml (IA) and 83 and 65.5ng/ml (IM) respectively were determined 2 days following injection and fell at birth to 16.5ng/ml (IP), 7ng/ml (HE), 4.5ng/ml (IA) and 4 and 0ng/ml (IM). PCR and immunohistochemistry showed broadest hFIX transgene spread and highest localised -galactosidase expression respectively after IP administration. Antibodies were observed against vector but not against hFIX.
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