Drug development for fetal growth restriction: can we improve fetal growth before birth?

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• Anna David, Professor and Consultant in Obstetrics and Maternal Fetal Medicine, University College London
• Tuesday 05 November 2024, 16:00-17:00
• Hodgkin-Huxley room, PDN.

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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

ABSTRACT

Fetal growth 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

To treat FGR my lab is focusing on the normal early physiological increased uterine blood flow, maternal cardiac output and trophoblast-driven modification of the uterine spiral arteries into a low-pressure, high-volume circulation. Vascular Endothelial Growth Factor (VEGF) is vital in this process. In sheep and guinea pig FGR pregnancy increasing local VEGF expression in the uteroplacental circulation using adenovirus (Ad) vectors significantly improves fetal growth velocity and reduced cerebral redistribution. Mechanistically we observe increased uterine blood flow, attenuated uterine artery vasoconstriction and increased angiogenesis. Maternal and fetal haemodynamics were unchanged and there is no vector spread to the fetus.

In the EC funded EVERREST study, reproductive toxicology studies in the ex vivo human placenta and in vivo pregnant rabbit showed no toxicity and minimal/no Ad vector fetal transfer.

A patient and stakeholder bioethical study found no objections to a clinical trial of maternal gene therapy to treat FGR ; patients desperately want therapy. Along the journey to clinical trial we have defined the trial inclusion criteria and identified ultrasound parameters and serum biomarkers at diagnosis of severe early-onset FGR that predict pregnancy outcomes of importance to patients and clinicians. We secured orphan disease designation for FGR and developed the first comprehensive safety taxonomy to define and grade maternal and fetal Adverse Events “MFAET”. The clinical-grade Ad vector is undergoing final safety/efficacy testing in FGR guinea pigs prior to clinical application if successful.

Biography

Anna 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 Consultant 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 therapy, treating diseases such as severe fetal growth restriction. She is part of the BOOSTB4 consortium performing the first clinical of in utero stem cell transplantation for osteogenesis imperfecta. She has led development of the first standardized Maternal and Fetal Adverse Event Terminology: MFAET version 1.0, for use in clinical trials of pregnancy interventions.

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