Maternal uterine artery Ad.VEGF-D ΔNΔC gene therapy for placental insufficiency shows no evidence of harm in a rabbit model

Dauzat, Caroline; Bansard, Carine; Decheix-Nguyen, Armelle; Bentz, Sandrine; Spézia, François; Forster, Roy; Lees, Mark; Heikura, Tommi; David, Anna L.

doi:10.1016/j.reprotox.2017.06.146

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“…45 Using this technique, we observed that the Ad.VEGF-D DNDC vector did not appear to adversely affect rabbit dam or pup survival and there was no evidence of vector spread across the placenta to the pups. 46 The endothelial cell (EC)-funded EVERREST project proposed a first-in-woman uncontrolled, open-label, dose finding safety and tolerability (to mother and neonate) clinical trial using a Good Manufacturing Practicesmanufactured replication-deficient Ad.VEGF-D DNDC vector. 47 Entry criteria would be designed to identify the most severe early-onset FGR fetuses with the highest perinatal mortality and morbidity: (1) estimated fetal weight <3rd centile for gestational age, 48 singleton fetus with (2) confirmed gestational age >22 weeks and <26 + 0 weeks at vector administration, (3) evidence of placental insufficiency defined as raised mean uterine artery Doppler Pulsatility Index, and (4) raised umbilical artery Pulsatility Index.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Efficiency and Function of Vascular Endothelial Growth Factor Adenovirus Vectors in Endothelial Cells for Gene Therapy of Placental Insufficiency

et al. 2020

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Severe fetal growth restriction (FGR) affects 1:500 pregnancies, is untreatable and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) and lack of bioavailable VEGF due to placental insufficiency is a major cause. Transduction of uterine arteries in normal or FGR sheep and guinea pigs using an adenovirus (Ad) encoding VEGF isoforms A (Ad.VEGF-A 165 ) and a FLAG-tagged pre-processed short form D (D DNDC , Ad.VEGF-D DNDC -FLAG) increases endothelial nitric oxide expression, enhances relaxation and reduces constriction of the uterine arteries and their branches. UBF and angiogenesis are increased long term, improving fetal growth in utero. For clinical trial development we compared Ad.VEGF vector transduction efficiency and function in endothelial cells (ECs) derived from different species. We aimed to compare the transduction efficiency and function of the pre-clinical study Ad. constructs (Ad.VEGF-A 165 , Ad.VEGF-D DNDC -FLAG) with the intended clinical trial construct (Ad.VEGF-D DNDC ) where the FLAG tag is removed. We infected ECs from human umbilical vein, pregnant sheep uterine artery, pregnant guinea pig aorta and non-pregnant rabbit aorta, with increasing multiplicity of infection (MOI) for 24 or 48 hours of three Ad.VEGF vectors, compared to control Ad. containing the LacZ gene (Ad.LacZ). VEGF supernatant expression was analysed by ELISA. Functional assessment used tube formation assay and Erk-Akt phosphorylation by ELISA. VEGF expression was higher after Ad.VEGF-D DNDC -FLAG and Ad.VEGF-D DNDC transduction compared to Ad.VEGF-A 165 in all EC types (*p < 0.001). Tube formation was higher in ECs transduced with Ad.VEGF-D DNDC in all species compared to other constructs (***p < 0.001, *p < 0.05 with rabbit aortic ECs). Phospho-Erk and phospho-Akt assays displayed no differences between the three vector constructs, whose effect was, as in other experiments, higher than Ad.LacZ (***p < 0.001). In conclusion, we observed high transduction efficiency and functional effects of Ad.VEGF-D DNDC vector with comparability in major pathway activation to constructs used in pre-clinical studies, supporting its use in a clinical trial.

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Section: Introductionmentioning

confidence: 99%