1. Anna David Reader in Obstetrics and Maternal Fetal Medicine
The EVERREST Project: Developing a maternal gene therapy for severe early onset fetal growth restriction
Anna David
Reader in Obstetrics and Maternal Fetal Medicine
27/02/2019

2. Fetal Growth Restriction
Failure to achieve your growth potential in utero
8% pregnancies
Contributes to 50% of stillbirths
Mostly due to placental insufficiency
No treatment
27/02/2019

3. Placental insufficiency
Trophoblast invades the spiral arteries converting them into high flow, low resistance vessels
In FGR there is less trophoblast invasion, reduced uterine artery perfusion
Moffett-King A, 2002
Non-pregnant FGR Pregnant
27/02/2019

4. Utero-placental perfusion
Placental insufficiency
Uteroplacental blood flow is proportional to fetal size
(Konje et al. 2003)
Uterine blood flow (ml/min)
Gestational Age (Weeks)
FGR = fetal growth restriction
AGA = appropriately grown for gestation
Sheep pregnancy

5. Neonatal outcomes in fetal growth restriction
Between 23 and 26 weeks of gestation, an increase in birthweight of 100g reduces the risk of dying by 40%.
total survival
Increasing the gestational age by 1 week will reduce costs by 30% over the preterm range %
survival without disability
median survival gained per day in utero is 2% (range 1.1–2.6) between 24 and 27 weeks of gestation.
Baschat et al 2007
Gestational age at birth

6. The cost of severe Fetal Growth Restriction
The cost of caring for babies to discharge
£39,483 / €45,397, this is 50% higher than babies born weighing over 1000g
Increasing the gestational age at birth by 1 week will reduce costs by 30% over the early preterm range
27/02/2019

7. Hypothesis behind the EVERREST treatment
Delivery of adenovirus vector containing VEGF gene to maternal uterine artery
Local over-expression of VEGF
Normal and FGR sheep ✔
Normal and FGR guinea pigs ✔
Increase fetal growth in severe FGR
Increase uterine blood flow
Normal sheep ✔
Alter uterine artery vascular tone & angiogenesis
Normal and FGR sheep ✔
Normal and FGR guinea pigs ✔
FGR sheep ✔
FGR guinea pigs ✔
27/02/2019

8. ethical & regulatory approval Phase I/IIa safety/efficacy study
scientific advice
original idea
ethical & regulatory approval
Phase I/IIa safety/efficacy study
bioethics
27/02/2019

9. EVERREST
Does vascular endothelial growth factor gene therapy safely improve outcome in severe early-onset fetal growth restriction?
Bioethics study - completed
Reproductive toxicology - ongoing
Prospective observational study - ongoing
First-in-woman phase I/IIa safety/efficacy study – late 2016

10. First-in-woman trial
Prospective study on untreated patients collecting data on affected pregnancies
Clinical trial
Inclusion criteria:
Severe early onset FGR
>22 weeks and <26 weeks of gestation
Uteroplacental insufficiency
Exclude other causes of FGR
Vector instilled into uterine artery for 5 minutes using interventional radiology
Primary outcome is safety
Secondary efficacy and exploratory outcomes

11. EVERREST Prospective Study
Putting together a:
Clinical database and
Biobank of samples
from pregnancies affected by severe early onset Fetal Growth Restriction to
Provide detailed information on adverse events to inform the clinical trial
Develop methods to provide prognostic information at the time of diagnosis
27/02/2019

12. What the prospective study involves
Collecting information about the woman
27/02/2019

13. What the prospective study involves
Collecting samples
Maternal blood
( 30ml)
Maternal blood ( 30ml)
Cord blood
Placenta & umbilical cord
Myometrial & placental bed biopsy (Caesarean only)

14. What the prospective study involves
Collecting information about the fetus/baby
Maternal blood
( 30ml)
Maternal blood ( 30ml)
Cord blood
Placenta & umbilical cord
Myometrial & placental bed biopsy (Caesarean only)
As per routine clinical care
27/02/2019

15. EFW <3rd centile & <600g
How you can help
Live singleton fetus
20+0 – 26+6
EFW <3rd centile & <600g
Refer to UCLH FMU
For more details / any questions:
Ask the team: phone,
Look at the website
27/02/2019

16. Summary
Severe early onset fetal growth restriction has high mortality and morbidity, and a high cost
An effective treatment is needed
Maternal VEGF growth factor gene therapy improves fetal growth in pre-clinical studies
EVERREST prospective study is carefully collecting data on outcomes of severe early onset FGR
EVERREST clinical trial will study safety and efficacy of maternal VEGF growth factor gene therapy
27/02/2019

17. www.everrest-fp7.eu PI: Anna David Twitter @FP7EVERREST