Abstract
Our study aimed to target adenoviral gene therapy to the uteroplacental circulation of pregnant guinea pigs in order to develop a novel therapy for fetal growth restriction. Four methods of delivery of an adenovirus encoding β-galactosidase (Ad.LacZ) were evaluated: intravascular injection using phosphate-buffered saline (PBS) into (1) uterine artery (UtA) or (2) internal iliac artery or external administration in (3) PBS or (4) pluronic F-127 gel (Sigma Aldrich). Postmortem examination was performed 4 to 7 days after gene transfer. Tissue transduction was assessed by X-gal histochemistry and enzyme-linked immunosorbent assay. External vascular application of the adenovirus vector in combination with pluronic gel had 91.7% success rate in terms of administration (85% maternal survival) and gave the best results for maternal/fetal survival and local transduction efficiency without any spread to maternal or fetal tissues. This study suggests an optimal method of gene delivery to the UtAs of a small rodent for preclinical studies.
Highlights
Fetal Growth Restriction (FGR) is an obstetric complication in which the fetus does not achieve its genetically determined growth potential
We have previously shown that in pregnant sheep, there was a significant increase in uterine blood flow (UBF) for up to one month after injection of adenovirus vectors containing the VEGFA165 gene when compared with uterine arteries (UtAs) injected with a control adenovirus containing the -galactosidase gene[7,8]
Recent data from sheep pregnancies affected by fetal growth restriction demonstrates that mid-gestation maternal UtA injection of Ad.VEGF-A165 vector led to fewer instances of marked FGR, defined as fetal weight more than two standard deviations from the contemporaneous non growth restricted control mean, at term[9]
Summary
Fetal Growth Restriction (FGR) is an obstetric complication in which the fetus does not achieve its genetically determined growth potential. Recent data from sheep pregnancies affected by fetal growth restriction demonstrates that mid-gestation maternal UtA injection of Ad.VEGF-A165 vector led to fewer instances of marked FGR, defined as fetal weight more than two standard deviations from the contemporaneous non growth restricted control mean, at term[9]. There was a fall in ratio of the head (biparietal diameter, BPD) to abdominal size (abdominal circumference, AC) over gestation, which was significantly lower at term than control untreated FGR fetuses, and no different to non growth restricted control fetuses. There was no significant difference in the BPD measurements, suggesting that the “brain sparing” that is seen in this paradigm of fetal growth restriction had been ameliorated[9]
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