Ultrasound-guided percutaneous delivery of adenoviral vectors encoding the β-galactosidase and human factor IX genes to early gestation fetal sheep in utero

David A, Cook T, Waddington S, Peebles D, Nivsarkar M, Knapton H, Miah M, Dahse T, Schneider H, Noakes D, Rodeck C, Coutelle C, Themis M (2003)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2003

Journal

Human Gene Therapy Mary Ann Liebert

Book Volume: 14

Pages Range: 353-364

Journal Issue: 4

DOI: 10.1089/104303403321208952

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 localizing β-galactosidase reporter gene or the human factor IX (hFIX) gene, or colloidal carbon were delivered via the umbilical vein (UV, n = 4), heart (intracardiac [IC], n = 2), liver parenchyma (intrahepatic [HE], n = 11), peritoneal cavity (intraperitoneal [IP], n = 14), skeletal musculature ([intramuscular [IM], n = 11), or the amniotic cavity (intra-amniotic [IA], n = 14) to early-gestation fetal sheep (0.3 gestation = day 33-61). Postmortem analysis was performed at 2, 9, or 28 days after injection. Although fetal survival was between 77% and 91% for IP, HE, IA, and IM routes, no fetuses survived UV or IC procedures. The hFIX levels reaching 1900 and 401 ng/ml (IP), 30 ng/ml (HE), 66.5 and 39 ng/ml (IA), and 83 and 65.5 ng/ml (IM), respectively, were determined 2 days after injection and decreased at birth to 16.5 ng/ml (IP), 7 ng/ml (HE), 4.5 ng/ml (IA), and 4 and 0 ng/ml (IM). Polymerase chain reaction (PCR) and immunohistochemistry showed broadest hFIX transgene spread and highest localised β-galactosidase expression, respectively, after IP administration. Antibodies were observed against vector but not against hFIX.

Authors with CRIS profile

Holm Schneider Department of Paediatrics and Adolescent Medicine

Involved external institutions

University College London (UCL) GB United Kingdom (GB) Imperial College London / The Imperial College of Science, Technology and Medicine GB United Kingdom (GB)

How to cite

APA:

David, A., Cook, T., Waddington, S., Peebles, D., Nivsarkar, M., Knapton, H.,... Themis, M. (2003). Ultrasound-guided percutaneous delivery of adenoviral vectors encoding the β-galactosidase and human factor IX genes to early gestation fetal sheep in utero. Human Gene Therapy, 14(4), 353-364. https://doi.org/10.1089/104303403321208952

MLA:

David, Anna, et al. "Ultrasound-guided percutaneous delivery of adenoviral vectors encoding the β-galactosidase and human factor IX genes to early gestation fetal sheep in utero." Human Gene Therapy 14.4 (2003): 353-364.

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