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Fetal Medicine Posters
Local administration of AD.VEGF-A165 to the utero-placental circulation reduces brain sparing and may enhance fetal growth in an FGR model of guinea pig pregnancy
  1. V Mehta1,
  2. M Boyd4,
  3. H Barker4,
  4. A Avdic-Belltheus4,
  5. D Carr1,
  6. J Martin2,3,
  7. I Zachary2,
  8. DM Peebles1,
  9. AL David1
  1. 1Institute for Women's Health, UCL, London, United Kingdom
  2. 2Centre for Cardiovascular Biology and Medicine, Division of Medicine, UCL, London, United Kingdom
  3. 3Ark Therapeutics Ltd., London, United Kingdom
  4. 4Royal Veterinary College, London, United Kingdom

Abstract

Introduction Fetal growth restriction (FGR) is commonly caused by impaired utero-placental perfusion. Adenovirus (Ad) mediated over-expression of VEGF-A165 in the uterine arteries (UtAs) of pregnant sheep significantly increases UtA blood flow, compared with UtAs transduced with a control adenovirus encoding β-galactosidase (Ad.LacZ). In FGR sheep, UtA injection of Ad.VEGF-A165 significantly improves fetal growth velocity.

Aim To study if Ad.VEGF-A165 transduction enhances fetal growth in the FGR guinea pig.

Methods To create FGR, virgin Dunkin-Hartley guinea pigs were nutrient restricted peri-conceptually. Under general anaesthesia at mid-gestation (30-34 days), sonographic fetal measurements were recorded in FGR guinea pigs and control ad lib fed sows. At laparotomy the UtAs and radial arteries on each side were transduced externally with Ad.VEGF-A165 or Ad.LacZ (5x109 viral particles), using a thermosensitive pluronic gel. Guinea pigs were sacrificed 31-34 days post-surgery but before birth. Fetal organ weights and biometry were recorded.

Results Nutrient restriction reduced fetal weight by 40%, with brain sparing. In FGR pregnancies, administration of Ad.VEGF-A165 increased fetal weight(94.5 ± 2.01g, n=11) compared to control Ad.LacZ treated fetuses (84.9 ± 2.81g, n=10, p=0.061). The liver and kidneys were significantly heavier in the Ad.VEGF-A165 group (5.6 ± 0.23g v/s 4.7 ± 0.18g, p=0.019 and 0.74 ± 0.065g v/s 0.37 ± 0.021g, p<0.001 respectively), and the brain/liver weight ratio was significantly lower (0.45 ± 0.019 v/s 0.53 ± 0.017, p=0.021), suggesting an attenuated brain sparing effect.

Conclusion VEGF gene therapy targeted to the utero-placental vasculature reduces brain sparing and may enhance fetal growth in FGR guinea pig pregnancy, and is a potential treatment for severe FGR.

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