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Evaluation of Prenatal Adenoviral Vascular Endothelial Growth Factor Gene Therapy in the Growth-Restricted Sheep Fetus and Neonate

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Evaluation of Prenatal Adenoviral Vascular Endothelial Growth Factor Gene Therapy in the Growth-Restricted Sheep Fetus and Neonate Evaluation of Prenatal Adenoviral Vascular Endothelial Growth Factor Gene Therapy in the Growth-Restricted Sheep Fetus and Neonate David John Carr University College London 2013 A thesis submitted for the degree of Doctor of Philosophy 1 Declaration I, David Carr, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Background Fetal growth restriction (FGR) is associated with reduced uterine blood flow (UBF). In normal sheep pregnancies, adenovirus (Ad) mediated over-expression of vascular endothelial growth factor (VEGF) in the uterine arteries (UtA) increases UBF. It was hypothesised that enhancing UBF would improve fetal substrate delivery in an ovine paradigm of FGR characterised by reduced UBF from mid-gestation. Methods Singleton pregnancies were established using embryo transfer in adolescent ewes subsequently overnourished to generate FGR (n=81). Ewes were randomised mid-gestation to 11 receive bilateral UtA injections of 5x10 particles Ad.VEGF-A165 or inactive treatment (saline or 5x1011 particles Ad.LacZ, a control vector). Fetal growth/wellbeing were evaluated using serial ultrasound. Late-gestation study: UBF was monitored using indwelling flowprobes until necropsy at 0.9 gestation. Vasorelaxation, neovascularisation in perivascular adventitia and placental mRNA expression of angiogenic factors/receptors were examined. A group of control-fed ewes with normally-developing fetuses was included (n=12). Postnatal study: Pregnancies continued until spontaneous delivery near to term. Lambs were weighed and measured weekly and underwent metabolic challenge at 7 weeks, dual-energy X-ray absorptiometry at 11 weeks, and necropsy at 12 weeks postnatal age. DNA methylation of somatotropic genes was examined in hepatic tissues. Results Ultrasonographic fetal growth velocity was greater in Ad.VEGF-A165-treated versus control- treated FGR fetuses at 3-4 weeks post-injection. In late gestation fewer fetuses were markedly growth-restricted following Ad.VEGF-A165 therapy. There was evidence of mitigated brain sparing. No effect was seen on UBF/neovascularisation although Ad.VEGF-A165-transduced vessels showed enhanced vasorelaxation. Flt1/KDR expression was increased in the maternal placental compartment. At birth Ad.VEGF-A165-treated lambs tended to be heavier with increased placental efficiency. Postnatal growth, lean tissue accretion and insulin secretion were also increased, however no epigenetic changes were observed. Conclusions Ad.VEGF-A165 safely increases fetal growth in this ovine model of FGR. This work has supported a successful application to translate this therapy into the clinic. 3 Table of Contents Title Page.......................................................................................................................................1 Declaration ...................................................................................................................................2 Abstract.........................................................................................................................................3 Table of Contents..........................................................................................................................4 List of Figures..............................................................................................................................13 List of Tables................................................................................................................................17 Publications.................................................................................................................................20 Acknowledgements.....................................................................................................................21 List of Abbreviations....................................................................................................................22 Chapter 1 - General Introduction................................................................................................26 1.1 Fetal growth restriction .............................................................................................. 26 1.1.1 Terminology.......................................................................................................... 26 1.1.2 Causes of FGR ....................................................................................................... 26 1.1.2.1 Fetal factors ...................................................................................................... 27 1.1.2.2 Maternal factors ............................................................................................... 28 1.1.2.3 Uteroplacental factors...................................................................................... 30 1.1.3 Consequences of FGR ........................................................................................... 34 1.1.3.1 Metabolic impact ............................................................................................. 34 1.1.3.2 Endocrine effects .............................................................................................. 36 1.1.3.3 Haematological changes .................................................................................. 36 1.1.3.4 Cardiovascular redistribution ........................................................................... 38 1.1.3.5 Perinatal mortality............................................................................................ 39 1.1.3.6 Neonatal morbidity .......................................................................................... 39 1.1.3.7 Impact on child health ...................................................................................... 41 1.1.3.8 Impact on adult health ..................................................................................... 41 1.1.3.9 Financial implications ....................................................................................... 43 1.1.4 Management of FGR ............................................................................................ 44 1.1.4.1 Prevention ........................................................................................................ 44 1.1.4.2 Prediction ......................................................................................................... 46 1.1.4.3 Diagnosis .......................................................................................................... 48 1.1.4.4 Investigation ..................................................................................................... 48 1.1.4.5 Treatment ......................................................................................................... 50 4 1.1.4.6 Surveillance ...................................................................................................... 53 1.1.5 Animal models of FGR .......................................................................................... 56 1.1.5.1 Sheep models of fetal growth restriction ........................................................ 57 1.1.5.2 The overnourished adolescent sheep paradigm .............................................. 57 1.2 Prenatal Ad.VEGF gene therapy ................................................................................. 61 1.2.1 Adenoviral vectors ................................................................................................ 62 1.2.2 Vascular endothelial growth factor ...................................................................... 62 1.2.3 Work that has led up to the project ..................................................................... 64 1.3 Aims of thesis ............................................................................................................. 65 2.1 Animal Procedures ..................................................................................................... 66 2.1.1 Establishment of singleton pregnancies .............................................................. 66 2.1.1.1 Oestrus synchronisation and ovulation induction ........................................... 66 2.1.1.2 Laparoscopic intrauterine insemination .......................................................... 67 2.1.1.3 Embryo recovery .............................................................................................. 68 2.1.1.4 Embryo transfer................................................................................................ 69 2.1.1.5 Pregnancy diagnosis ......................................................................................... 71 2.1.2 Nutritional management ...................................................................................... 71 2.1.3 Ultrasound examination ....................................................................................... 73 2.1.3.1 Fetal biometry .................................................................................................. 73 2.1.3.2 Umbilical artery Dopplers................................................................................. 76 2.1.3.3 Placentation and amniotic fluid volume .......................................................... 78 2.1.4 Gene therapy administration ............................................................................... 79 2.1.4.1 Vectors.............................................................................................................
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