MICA: MRC EVERREST: A Pre-clinical Efficacy Study for FGR
Lead Research Organisation:
University College London
Department Name: Maternal & Fetal Medicine
Abstract
Fetal growth restriction is a potentially life-threatening pregnancy complication affecting about 8% of all pregnancies, contributing to 50% of stillbirths globally. Babies born from growth restricted pregnancies are not only at increased risk of perinatal death and complications such as cerebral palsy, but have long term health consequences including diabetes and cardiovascular disease. Recent improvements in the postnatal care of premature growth restricted babies means that more of them survive delivery, but at great cost.
Most commonly inadequate uterine blood flow, termed 'placental insufficiency', is the underlying abnormality. This restricts delivery of nutrients and oxygen to the baby in the womb meaning that it grows poorly. There is no therapy available and no intervention that can improve uterine blood flow and restore fetal growth.
In around 1 in 500 cases the baby is found to be growth restricted in mid pregnancy. Once this severe early onset fetal growth restriction is identified, couples currently face a stark choice between delivering their baby very prematurely in the knowledge that they might die in the neonatal intensive care unit, or allowing the pregnancy to continue with the strong likelihood that the baby will die in the womb. Many of these premature, very small babies stay in hospital for months after birth, which is stressful for parents and very costly for the NHS.
Studies performed over the last twelve years by researchers at UCL with Trizell Limited have identified that maternal blood flow to the placenta could be increased in normal pregnancies by delivering a gene medicine containing the Vascular Endothelial Growth Factor (VEGF) to the uterine arteries. In pre-clinical studies of growth restricted pregnancies, the gene medicine safely increased fetal growth and birthweight.
What is most promising is that relatively small increases in fetal growth and gestational age at delivery are associated with major improvements in survival and morbidity. For example, as each day of pregnancy advances between 24 and 27 weeks of gestation, there is a two per cent improvement in survival after birth.
The researchers have discussed with stakeholder groups and patients affected by fetal growth restriction to evaluate the ethical and social acceptability of using this gene medicine in pregnancy. The treatment was viewed positively with no ethical concerns. Pre-clinical toxicology studies on gene medicine have shown reassuring safety. The clinical trial gene medicine is now manufactured ready for the first patients.
The team will perform a pre-clinical study using the clinical trial gene medicine in a well validated animal model of fetal growth restriction, the maternal nutrient restricted guinea pig. Guinea pig pups become growth restricted in mid-pregnancy. We will find out if the application of this novel medicine in the middle of guinea pig pregnancy safely and effectively increases fetal growth at the end of pregnancy. We will study how the drug works, if it crosses the placenta to the guinea pig pups, and if there is any evidence of harm. We plan to test out two doses of the gene medicine to see what the best dose may be.
If successful we will use this data to seek regulatory and ethical approval to conduct the first-in-human clinical trial to determine the safety and efficacy of the intervention.
This research could enable the development of a highly innovative new therapy in the field of obstetrics, a specialty in which there is currently a lack of investment in new treatments.
Benefits from this research could include reduced stillbirths and neonatal deaths, and improved outcome in pregnancies affected by fetal growth restriction.
Most commonly inadequate uterine blood flow, termed 'placental insufficiency', is the underlying abnormality. This restricts delivery of nutrients and oxygen to the baby in the womb meaning that it grows poorly. There is no therapy available and no intervention that can improve uterine blood flow and restore fetal growth.
In around 1 in 500 cases the baby is found to be growth restricted in mid pregnancy. Once this severe early onset fetal growth restriction is identified, couples currently face a stark choice between delivering their baby very prematurely in the knowledge that they might die in the neonatal intensive care unit, or allowing the pregnancy to continue with the strong likelihood that the baby will die in the womb. Many of these premature, very small babies stay in hospital for months after birth, which is stressful for parents and very costly for the NHS.
Studies performed over the last twelve years by researchers at UCL with Trizell Limited have identified that maternal blood flow to the placenta could be increased in normal pregnancies by delivering a gene medicine containing the Vascular Endothelial Growth Factor (VEGF) to the uterine arteries. In pre-clinical studies of growth restricted pregnancies, the gene medicine safely increased fetal growth and birthweight.
What is most promising is that relatively small increases in fetal growth and gestational age at delivery are associated with major improvements in survival and morbidity. For example, as each day of pregnancy advances between 24 and 27 weeks of gestation, there is a two per cent improvement in survival after birth.
The researchers have discussed with stakeholder groups and patients affected by fetal growth restriction to evaluate the ethical and social acceptability of using this gene medicine in pregnancy. The treatment was viewed positively with no ethical concerns. Pre-clinical toxicology studies on gene medicine have shown reassuring safety. The clinical trial gene medicine is now manufactured ready for the first patients.
The team will perform a pre-clinical study using the clinical trial gene medicine in a well validated animal model of fetal growth restriction, the maternal nutrient restricted guinea pig. Guinea pig pups become growth restricted in mid-pregnancy. We will find out if the application of this novel medicine in the middle of guinea pig pregnancy safely and effectively increases fetal growth at the end of pregnancy. We will study how the drug works, if it crosses the placenta to the guinea pig pups, and if there is any evidence of harm. We plan to test out two doses of the gene medicine to see what the best dose may be.
If successful we will use this data to seek regulatory and ethical approval to conduct the first-in-human clinical trial to determine the safety and efficacy of the intervention.
This research could enable the development of a highly innovative new therapy in the field of obstetrics, a specialty in which there is currently a lack of investment in new treatments.
Benefits from this research could include reduced stillbirths and neonatal deaths, and improved outcome in pregnancies affected by fetal growth restriction.
Technical Summary
Fetal growth restriction (FGR) is a potentially life-threatening pregnancy complication affecting about 8% of all pregnancies; it contributes to 50% of stillbirths globally. Pregnancies diagnosed with FGR, about 1 in 500 occur <28 weeks of gestation, classified as severe early onset. FGR can be due to fetal structural abnormalities, aneuploidy, maternal medical disorders and congenital infection. Most commonly however impaired uteroplacental function restricts delivery of nutrients and oxygen to the fetus, termed placental insufficiency. The underlying pathology is inadequate trophoblast invasion of the myometrial spiral arteries in early gestation causing reduced uterine artery (UtA) perfusion when compared to normal pregnancy. Animal studies confirm that fetal growth correlates with UtA blood flow. In FGR the UtAs remains in a state of high resistance causing generalised endothelial cell injury. There is reduced bioavailability of Vascular Endothelial Growth Factor (VEGF), which is essential for vasculogenesis and angiogenesis during development. There is currently no FGR therapy, and no intervention that can improve UtA perfusion and increase fetal growth.
Our solution, maternal UtA gene therapy, is a promising therapeutic strategy for FGR using adenoviral vectors (Ad) encoding VEGF. Over a decade our pre-clinical research shows that UtA VEGF gene transfer improves fetal growth and neonatal outcome. Mechanistically it increases UtA blood flow, enhances vascular relaxation short term and reduces vascular contractility long term. Transduced UtAs are remodelled with increased endothelial cell proliferation in the perivascular adventitia. Safety and reproductive toxicology assessments show no vector spread to the fetus and no adverse risk to the mother or fetus. Using the proposed clinical trial Drug Product, an Ad. encoding the VEGF-D gene manufactured to GMP, we will study the safety and efficacy of this intervention in a well validated guinea pig model of FGR.
Our solution, maternal UtA gene therapy, is a promising therapeutic strategy for FGR using adenoviral vectors (Ad) encoding VEGF. Over a decade our pre-clinical research shows that UtA VEGF gene transfer improves fetal growth and neonatal outcome. Mechanistically it increases UtA blood flow, enhances vascular relaxation short term and reduces vascular contractility long term. Transduced UtAs are remodelled with increased endothelial cell proliferation in the perivascular adventitia. Safety and reproductive toxicology assessments show no vector spread to the fetus and no adverse risk to the mother or fetus. Using the proposed clinical trial Drug Product, an Ad. encoding the VEGF-D gene manufactured to GMP, we will study the safety and efficacy of this intervention in a well validated guinea pig model of FGR.
