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SUMMARY:Drug development for fetal growth restriction: can we improve feta
 l growth before birth? - Anna David\, Professor and Consultant in Obstetri
 cs and Maternal Fetal Medicine\, University College London 
DTSTART:20241105T160000Z
DTEND:20241105T170000Z
UID:TALK222748@talks.cam.ac.uk
CONTACT:120118
DESCRIPTION:*This talk is part of the Loke CTR Seminar Series\, available 
 in person and online. For details visit https://www.trophoblast.cam.ac.uk/
 seminars/loke-ctr-seminars/2024-loke-ctr-seminars*\n\nABSTRACT\n\nFetal gr
 owth restriction (FGR) is a serious obstetric pathology affecting around 8
 % of pregnancies. Commonly\, impaired placental function and uterine blood
  flow restricts nutrient and oxygen delivery to the fetus. In severe early
 -onset FGR (estimated fetal weight <3rd centile)\, fetal growth can cease 
 <28 weeks of gestation\, but modest increases in birthweight (e.g from 500
  to 600g) and gestation at delivery (e.g from 26 to 27 weeks) significantl
 y reduces mortality and morbidity. \n\nTo treat FGR my lab is focusing on 
 the normal early physiological increased uterine blood flow\, maternal car
 diac output and trophoblast-driven modification of the uterine spiral arte
 ries into a low-pressure\, high-volume circulation. Vascular Endothelial G
 rowth Factor (VEGF) is vital in this process.\nIn sheep and guinea pig FGR
  pregnancy increasing local VEGF expression in the uteroplacental circulat
 ion using adenovirus (Ad) vectors significantly improves fetal growth velo
 city and reduced cerebral redistribution. Mechanistically we observe incre
 ased uterine blood flow\, attenuated uterine artery vasoconstriction and i
 ncreased angiogenesis. Maternal and fetal haemodynamics were unchanged and
  there is no vector spread to the fetus.\n\nIn the EC funded EVERREST stud
 y\, reproductive toxicology studies in the ex vivo human placenta and in v
 ivo pregnant rabbit showed no toxicity and minimal/no Ad vector fetal tran
 sfer. \n\nA patient and stakeholder bioethical study found no objections t
 o a clinical trial of maternal gene therapy to treat FGR\; patients desper
 ately want therapy. \nAlong the journey to clinical trial we have defined 
 the trial inclusion criteria and identified ultrasound parameters and seru
 m biomarkers at diagnosis of severe early-onset FGR that predict pregnancy
  outcomes of importance to patients and clinicians. We secured orphan dise
 ase designation for FGR and developed the first comprehensive safety taxon
 omy to define and grade maternal and fetal Adverse Events “MFAET”. \nT
 he clinical-grade Ad vector is undergoing final safety/efficacy testing in
  FGR guinea pigs prior to clinical application if successful.\n \nBiograph
 y \n\nAnna is a clinician scientist and Director of the Elizabeth Garrett 
 Anderson Institute for Women’s Health at University College London. She 
 was awarded an NIHR Senior Lectureship in 2008 and is now Professor and Co
 nsultant of Obstetrics and Maternal Fetal Medicine at UCL and UCL Hospital
 . Clinically she specializes in fetal medicine\, severe congenital disease
 \, fetal growth restriction and prevention of preterm birth. Her research 
 team is developing novel prenatal therapies using stem cells and gene ther
 apy\, treating diseases such as severe fetal growth restriction. She is pa
 rt of the BOOSTB4 consortium performing the first clinical of in utero ste
 m cell transplantation for osteogenesis imperfecta. She has led developmen
 t of the first standardized Maternal and Fetal Adverse Event Terminology: 
 MFAET version 1.0\, for use in clinical trials of pregnancy interventions.
 \n \n
LOCATION:Hodgkin-Huxley room\, PDN
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