2018 ISPD Conference

Neurodevelopmental effects of maternal uterine artery Ad.VEGF-A165 treatment for fetal growth restriction in fetal guinea pigs
Tara Krishnan1, Mariya Hristova2, Owen Vaughan1, Carlo Rossi1, Jan Nouza2, Anna David3

1Institute for Women's Health, University College London, London, United Kingdom
2Institute for Women's Health, University College London, United Kingdom, London, United Kingdom
3Institute for Women's Health, University College London,, London, , United Kingdom
Objectives
Fetal growth restriction(FGR) is the failure of a fetus to achieve normal intrauterine growth. There is currently no treatment available for FGR, which can cause behavioural disorders, impaired motor function, and carries a high mortality rate. FGR fetuses have reduced brain size, altered brain-to-bodyweight ratio and increased inflammation and neural cell death when compared with normally grown fetuses. Previously we showed that maternal uterine artery administration of an adenovirus vector containing the VEGF-A165 isoform(Ad.VEGF-A165) to pregnant guinea pigs with FGR mid-gestation increases fetal weight at term. Here we studied the effects of treatment on neurodevelopment in FGR guinea pig fetuses.
Methods
To induce FGR, Dunkin Hartley guinea pigs were fed normally (control, n=7) or 70% calorie intake one month before conception and during pregnancy. FGR dams received Ad.VEGF-A165 (n=9, FGR+VEGF group) or a vehicle (pluronic gel, n=7, FGR group) externally to their uterine arteries via laparotomy on day ~30 of pregnancy (term=65=days). Control dams underwent sham laparotomy. Fetal body and brain weights were determined on day~65, at post-mortem. Brain samples were fixed and sectioned (40 mm). Regional brain volumes, microglial ramification, astrogliosis and apoptosis were analysed using cresyl violet, IBA-1, GFAP and TUNEL stained sections respectively. Groups were compared using one-way ANOVA.
Results
Brain weight was reduced in FGR fetuses (2.268g±0.064g) but was similar to control values (2.531g±0.093g) in the FGR+VEGF group fetuses (2.517g±0.063g,P=0.02). There was no significant difference in fetal weight between the three groups (P>0.05). Consequently, brain:body weight ratio was lower in the FGR group (2.693g±0.082g), compared to the FGR+VEGF group fetuses (3.040g±0.081g) that were no different to controls (2.976g±0.120g,P=0.017). Microglial ramification was increased in cortex, hippocampus, thalamus, and striatum in FGR fetuses compared with control and FGR+VEGF fetuses. Astrogliosis was increased in FGR+VEGF fetuses in all analysed brain regions when compared with control fetuses. TUNEL staining showed no difference in apoptosis across the groups.
Conclusions
Administration of maternal uterine artery Ad.VEGF-A165 gene-therapy to FGR guinea pig pregnancies in mid-gestation improves fetal brain growth, normalises microglial activation, and does not adversely affect neurological anatomy or apoptosis. These data support the safety profile of maternal uterine artery Ad.VEGF therapy for the treatment of FGR.
This research was funded by Action Medical Research.