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Alterations in postnatal growth and metabolism following prenatal treatment of intrauterine growth restriction with Ad.VEGF gene therapy in the sheep
  1. D J Carr1,2,
  2. R P Aitken2,
  3. J S Milne2,
  4. D M Peebles1,
  5. I Zachary3,
  6. J Martin3,4,
  7. A L David1,
  8. J M Wallace2
  1. 1Prenatal Cell and Gene Therapy Group, UCL Institute for Women's Health, London, UK
  2. 2Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK
  3. 3Department of Cardiovascular Medicine, UCL, London, UK
  4. 4CSO, Ark Therapeutics plc, London, UK

Abstract

Background Adenovirus (Ad) mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine arteries of pregnant sheep increases uterine blood flow1. We recently demonstrated significantly increased fetal growth velocity following Ad. VEGF gene therapy in growth-restricted sheep fetuses2. Herein the subsequent effect on postnatal growth, metabolism and body composition in the same cohort was investigated.

Methods Growth rate was determined weekly from birth until weaning in 31 lambs born following maternal administration of Ad. VEGF (n=16) or control saline (n=15) mid-pregnancy. At 7 weeks of age, following a 3 h fast, lambs were blood-sampled at −20, −10, 0, +5, +10, +15, +20, +25, +30, +45, +60, +90 and +120 min relative to an intravenous glucose bolus (0.25 g/kg). Plasma was analysed for insulin, glucose and non-esterified fatty acids (NEFA). At 12 weeks, lambs underwent necropsy and complete dissection.

Results Postnatal growth velocity was increased in Ad. VEGF-treated lambs compared to controls (397 g/day vs 363 g/day, p=0.023). There was no difference in fractional growth rate, which was inversely related to birthweight (r=–0.910, p=<0.001) irrespective of treatment. Following glucose challenge, insulin area under the curve (AUC) was increased (p=0.04) and NEFA AUC increased (p=0.038) in Ad. VEGF versus saline groups. At necropsy there were no significant differences in perirenal fat or major organ weights.

Conclusion Prenatal gene therapy for ovine fetal growth restriction results in enhanced postnatal accretion of lean tissue and altered metabolic function. This may indicate altered fetal programming secondary to therapeutic manipulation of the intrauterine environment.

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