Perinatal and long-term effects of maternal uterine artery adenoviral VEGF-A165 gene therapy in the growth-restricted guinea pig fetus

Vaughan, Owen; Rossi, Claudia; Ginsberg, Yuval; White, Alicia; Hristova, Mariya; Sebire, Neil J.; Martin, James S.; Zachary, I; Peebles, Donald; David, Anna L.

doi:10.1152/ajpregu.00210.2017

Cited by 15 publications

(7 citation statements)

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“…29 Experiments were performed in normal pregnant sheep, [30][31][32] FGR pregnant sheep, 33,34 and FGR pregnant guinea pigs. 29,35,36 We chose pregnant sheep in which to first assess the effect of maternal gene therapy on uterine blood flow and fetal growth because many aspects of sheep fetal and vascular physiology are similar to the human and because the ovine fetus is similar in size to the human. Moreover, ultrasound quantification of uterine blood flow, fetal growth, and well-being is a validated technique for monitoring normal and FGR sheep pregnancy, and which allows comparison with human FGR.…”

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%

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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“…A potential treatment for FGR is maternal gene therapy which aims to increase the local availability of Vascular Endothelial Growth Factor (VEGF) in the maternal uteroplacental circulation. Preclinical studies have shown that maternal uterine artery administration of adenovirus vectors containing the VEGF gene in pregnancy increases uterine blood flow, angiogenesis and fetal growth [3–6].…”

Section: Introductionmentioning

confidence: 99%

Pregnant women’s experiences and perceptions of participating in the EVERREST prospective study; a qualitative study

Harvey¹,

David²,

Dyer³

et al. 2019

BMC Pregnancy Childbirth

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Background The EVERREST Prospective Study is a multicentre observational cohort study of pregnancies affected by severe early-onset fetal growth restriction. The study recruits women with singleton pregnancies where the estimated fetal weight is less than the 3rd centile and below 600 g, between 20 + 0 and 26 + 6 weeks of pregnancy, in the absence of a known chromosomal, structural or infective cause. Method The reported study was retrospective descriptive qualitative interview study of women who had participated in the EVERREST Prospective Study. The aim of this study was to explore the experiences and perceptions of pregnant women taking part in research during a pregnancy affected by severe early-onset fetal growth restriction. Audio-recorded semi-structured telephone interviews were conducted with a purposive sample of 12 women, at least 1 year after delivery of their baby. Two of these pregnancies had ended in stillbirth and one in neonatal death, reflecting the outcomes seen in the EVERREST Prospective Study. Participants gave informed consent, were 16 years or older and were interviewed in English. A topic guide was used to ensure a consistent approach. Questions focused on pregnancy experiences, involvement with the EVERREST study and potential involvement in future research. Recordings were transcribed verbatim for thematic analysis using NVivo10. Results Four broad themes were identified; ‘before joining the EVERREST Prospective Study’, ‘participating in research’, ‘information and support’ and ‘looking back and looking forwards’. Each broad theme incorporated several subthemes. All participants recalled their reaction to being told their baby was smaller than expected. The way this news was given had a lasting impact. A range of benefits of participation in the EVERREST Prospective Study were described and the participants were positive about the way it was conducted. As a consequence, they were receptive to participating in future research. However, the findings suggest that research teams should be sensitive when approaching families at a difficult time or when they are already participating in other research. Conclusions This study highlights the willingness of pregnant women to participate in research and identifies strategies for researchers to engage participants. Electronic supplementary material The online version of this article (10.1186/s12884-019-2277-8) contains supplementary material, which is available to authorized users.

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“…The medical plausibility for maternal VEGF gene therapy is based on the observation that reduced uterine blood flow is a key pathology in placental insufficiency, and that manipulation of VEGF expression can improve uterine blood flow, increase uterine artery relaxation and endothelial nitric oxide synthase production, and increase local angiogenesis . In preclinical animal models we have previously shown that local maternal VEGF gene transfer to the utero–placental circulation using adenovirus vectors increases uterine blood flow, attenuates constriction of the uterine arteries and increases angiogenesis; these changes result in improved growth of severely growth restricted fetuses …”

Section: Discussionmentioning

confidence: 99%

“…56,57 In preclinical animal models we have previously shown that local maternal VEGF gene transfer to the utero-placental circulation using adenovirus vectors increases uterine blood flow, attenuates constriction of the uterine arteries and increases angiogenesis; 58 these changes result in improved growth of severely growth restricted fetuses. [59][60][61][62]…”

Section: Additional Requirements For Ema Orphan Drug Designationmentioning

confidence: 99%

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

Spencer

Rossi

Lees

et al. 2019

BJOG

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Objective To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. Design Incidence estimation based on literature review and published national and EU statistics. Setting and population European Union. Methods Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. Results The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93–3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07–3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. Conclusions Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life‐threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. Tweetable abstract Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

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Perinatal and long-term effects of maternal uterine artery adenoviral VEGF-A165 gene therapy in the growth-restricted guinea pig fetus

Cited by 15 publications

References 74 publications

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

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

Pregnant women’s experiences and perceptions of participating in the EVERREST prospective study; a qualitative study

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

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