Maternal uterine artery Ad.VEGF-A165 gene therapy improves fetal brain weight and does not adversely affect neurological anatomy in FGR Guinea pigs
Tara Krishnan (AU), Anna David (GB), Owen Vaughan (GB), Mariya Hristova (GB), Jan Nouza (GB)
[Krishnan] University College London, [David] University College London, [Vaughan] University College London, [Hristova] University College London, [Nouza] University College London
Context:Fetal growth restriction(FGR) is the failure of a fetus to achieve normal intrauterine growth. FGR has no treatment, can impair motor function, cause behavioural disorders & has high mortality-rates. FGR fetuses have reduced brain size & increased neural cell inflammation. Evidence shows that uterine artery application of a VEGF-A165 adenoviral vector(Ad.VEGF-A165) to pregnant guinea pigs(GP) with FGR increases term fetal weight. Objective:Is maternal Ad.VEGF-A165 gene therapy neuroprotective in FGR GP fetuses? Methods:Patients- Dunkin Hartley GPs were fed normally (control=n=7) or 70% their diet to induce FGR one month before conception & during pregnancy. Interventions-FGR dams received Ad.VEGF-A165(n=9 FGR+VEGF group) or pluronic gel(n=7 FGR group) to their uterine arteries via laparotomy on day ~30 of pregnancy. Control dams underwent sham laparotomy. Main Outcome Measures-Evidence of fetal brain sparing from body & brain weights calculated at term post-mortem(~65days). Brain volumes, microglial ramification & apoptosis analysis was conducted in cresyl violet, IBA1 & TUNEL stained sections. Groups were compared using one-way ANOVA. Results:Brain weight was reduced in FGR fetuses(2.268g±0.064g) but control(2.531g±0.093g) & FGR+VEGF groups were similar(2.517g±0.063g). Fetal weight was similar between the three groups(P>0.05). Brain sparing was lower in FGR fetuses(2.693g±0.082g) but FGR+VEGF group(3.040g±0.081g) was similar to controls(2.976g±0.120g). Microglial activation was increased in cortex, hippocampus, thalamus & striatum in FGR fetuses compared with control & FGR+VEGF groups. TUNEL staining showed no difference in apoptosis across the groups. Conclusion:Mid-gestation uterine artery Ad.VEGF-A165 gene-therapy in FGR GP pregnancies improves fetal brain growth, normalises microglial activation & does not cause apoptosis or adversely affect neuroanatomy.