Prenatal adenovirus vascular endothelial growth factor gene therapy: a promising new treatment for fetal growth restriction

Abstract

BackgroundFetal growth restriction (FGR) is an important obstetric condition that is commonly associated with reduced uterine blood flow. In normal sheep pregnancies, adenovirus (Ad) mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine arteries increases uterine blood flow. We hypothesised that enhancing uterine blood flow would improve fetal substrate delivery in a sheep model of FGR that is characterised by reduced uterine blood flow from mid-gestation. MethodsSingleton pregnancies were established with embryo transfer in 90 adolescent ewes subsequently overnourished to generate FGR (n=78) or control fed (n=12). In study 1, at a mean gestational age of 89 days (SE 0·2), 45 overnourished ewes were randomised to receive Ad-VEGF (n=18), Ad-LacZ (control vector, n=14), or saline (n=13) injected into each uterine artery. Control-fed ewes (n=12) received saline. Uterine blood flow was monitored with indwelling flowprobes until necropsy at 131 days’ gestation (0·6). Placental mRNA expression of VEGF and its receptors, Flt1/KDR, was assessed in the maternal and fetal placental compartments by quantitative reverse transcription PCR. In study 2, at 88 days’ gestation (0·7), 33 overnourished ewes received Ad-VEGF (n=17) or saline (n=16) and were allowed to deliver spontaneously at 141 days’ gestation (0·4). In both studies fetal growth and wellbeing were evaluated (blind) using serial ultrasound. FindingsIn both studies ultrasound measurements of abdominal circumference (AC) were greater in Ad-VEGF-treated FGR fetuses than in control-treated FGR fetuses at 21 days (0·3) and 28 days (0·5) post injection (p<0·001–0·047). In study 1, fewer fetuses were markedly growth-restricted (weight >2 SD below control mean) in Ad-VEGF compared with Ad-LacZ plus saline groups (5/18 vs 18/27, p=0·038). Indices of head sparing (ultrasound biparietal diameter:AC ratios, relative brain weight, and brain:liver weight ratios) were lower (p=0·001–0·046) and maternal placental Flt1/KDR mRNA expression higher (p=0·028/0·034) in Ad-VEGF than in Ad-LacZ plus saline groups, but no measurable differences in uterine blood flow were detected. In study 2, Ad-VEGF-treated lambs tended to be heavier (p=0·081) with increased placental efficiency (p=0·074). There were no maternal or fetal complications or significant differences in the level of neonatal care required to ensure lamb survival. InterpretationAd-VEGF safely increases fetal growth in this ovine model of FGR. FundingWellbeing of Women.