EVERREST

Does vascular endothelial growth factor gene therapy safely improve outcome in severe early-onset fetal growth restriction?

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 Obiettivo del progetto (Objective)

'Fetal growth restriction (FGR) globally occurs in 8% of pregnancies, is severe and early onset in 1:500 cases, affecting 11,000 babies annually in the EU. In most cases, reduced uterine blood flow restricts substrate delivery to the fetus causing growth to slow or cease. There is no treatment. Currently the fetus is delivered very preterm before fetal death or irreversible organ damage occurs. Affected neonates suffer intracranial haemorrhage, chronic lung disease, cerebral palsy, with heart disease and diabetes as adults; mortality is high. Recent improvements in the care of premature growth restricted neonates, means that more of them survive delivery, but at great cost. Small increases in fetal growth and gestation at birth are associated with major improvements in survival and morbidity. Improving uterine blood flow is key and Vascular Endothelial Growth Factor (VEGF) is important to achieve this. In preclinical animal models we showed that local VEGF gene transfer to the uteroplacental circulation using adenovirus vectors increases uterine blood flow, attenuates constriction of uterine arteries and increases angiogenesis; these changes result in improved growth of severely growth restricted fetuses. This is the first clinically-applicable evidence based therapy that could improve perinatal outcome in severe early onset FGR in man. In collaboration with an SME experienced in gene therapy trials, our aim is to complete an agreed toxicology programme, identify specific ethical issues in stakeholders, and to perform a Phase I/II study in women with severe early onset FGR at four EU centres of excellence, using interventional radiology to deliver an adenovirus vector containing the mature processed form of human VEGF-D into the uterine artery. Data on safety, tolerability and efficacy will be analysed, and used, if successful, to inform phase II and III trials of this innovative therapy, leading to the first treatment for this intractable obstetric condition.'

Introduzione (Teaser)

In the EU alone, around 11 000 babies annually are affected as a result of placental insufficiency leading to fetal growth restriction (FGR) in the womb. Researchers are investigating the effectiveness of a promising maternal growth factor therapy during pregnancy via human clinical trials.

Descrizione progetto (Article)

Placental insufficiency leading to FGR is an incurable condition where fetal growth in the womb is unnaturally slow. In placental insufficiency there is reduced blood flow to the womb. This places babies resulting from such pregnancies at high risk of long-term health problems. Improving blood flow to the womb would significantly improve the outcome for such babies.

Women with normal pregnancies have appropriate levels of vascular endothelial growth factor (VEGF) levels in their blood, resulting in healthy blood flow to the womb. VEGF is a protein secreted by the placenta and women with FGR could benefit if the local VEGF levels in the blood supply to the womb are enhanced via techniques such as gene therapy.

Recently, use of growth factor therapy in animals dramatically enhanced fetal growth through dilating the vessels supplying the womb and by providing new blood vessel formation that increased blood flow to the womb. The http://www.everrest-fp7.eu/ (EVERREST) consortium will demonstrate the safety and efficacy of this maternal growth factor therapy via pre-clinical studies followed by clinical trials.

Initially, EVERREST members investigated the social acceptability and ethical issues involved in using gene medicine in pregnancy. Results revealed a mostly favourable mindset towards pregnant women participating in such clinical trials.

Pre-clinical studies are being carried out to demonstrate the safety of maternal growth factor therapy. Tissue from human placentas exposed in the laboratory to high doses of the gene medicine did not show any damage. Laboratory testing is ongoing to determine if gene medicine crosses the placenta, though initial animal testing did not demonstrate this. In addition, comprehensive reproductive toxicology studies will be carried out on pregnant animals to study the effects of high and low doses of the gene medicine.

Women with severe early-onset FGR are being recruited at the four study sites for an observational study aiming to collect comprehensive data about untreated affected pregnancies. EVERREST has also established a biobank of samples from women and babies with FGR. The clinical trial protocol for phase I/IIa study has been drafted.

Positive clinical trial outcomes will advance clinical research in obstetric therapy. This should facilitate faster commercialisation of gene therapy for FGR, hopefully within the next 10 to 15 years.