and the EVERREST EU-project...• Early-onset severe IUGR associated with reduced uterine blood flow...

Supported by the EC under the FP7 Programme

Copyright © 2013 EVER

REST Consortium

– All rights reserved



REST Consortium


Interventions aiming to treat fetal growth restriction

and the EVERREST EU-project

14/01/2015

Karel Maršál Lund University

Sweden



REST Consortium




REST Consortium


Fetal Growth Restriction

• Complicates ~8% of pregnancies (severe 1:500) • Major cause of perinatal mortality & morbidity • No effective treatment • Outcome dependent on gestational age • Early-onset severe IUGR associated with

reduced uterine blood flow

14/01/2015



REST Consortium




REST Consortium


Uteroplacental perfusion Uteroplacental blood flow is proportional

to fetal size Uteroplacental insufficiency

Sheep pregnancy

(Konje et al. 2003)

Ute

rine

bloo

d flo

w (m

l/m

in)

Gestational Age (Weeks)

Human pregnancy



REST Consortium




REST Consortium


Baschat et al 2007

Neonatal outcome in fetal growth restriction

Gestational age at birth

%

total survival

survival without disability

Between 23 and 26 weeks of gestation, an increase in birthweight of 100g reduces the risk of dying by 40%.



REST Consortium




REST Consortium


Very preterm IUGR – high survival: - Lund / Malmö 90% - TRUFFLE study 94 %

HOWEVER

- both the short-term and long-term morbidity is considerably high !

• cognitive impairment • behavioural disturbances • reduced lung function • changes in cardiovascular function



REST Consortium




REST Consortium


Early-onset IUGR

Postnatal growth stimulation of IUGR infants difficult.

It is desirable to improve fetal growth and to prolong

pregnancy.

Need for intrauterine therapy.



REST Consortium




REST Consortium


Therapies that do not work • Bedrest • Maternal oxygen supplementation • Maternal nutritional supplements • Low-dose aspirin • β-mimetics (RCTs show no effect) • Calcium channel blockers • Plasma volume expansion • Vitamin C



REST Consortium




REST Consortium


Interventions aimed at increasing uterine blood flow

L-arginine (aminoacid, nitric oxide donor)

• Maternal intravenous infusions

• L-arginine readily available and safe in pregnant women, however, conflicting data on increase in birth weight

• Currently not recommended for treatment of IUGR



REST Consortium




REST Consortium


Interventions aimed at increasing uterine blood flow

Sildenafil citrate (nitric oxide donor)

• Temporary smooth muscle relaxation in vessels • Works in animal models and tested in humans • In severe, early-onset IUGR thrice daily

maternal treatment with 25 mg sildenafil until delivery = ↑ AC growth velocity

• Randomized controlled trial data required



REST Consortium




REST Consortium


Growth hormone treatment

• Animal models

• Maternal and fetal supplementation • Risk of adverse effects (hydranencephaly

in fetuses)



REST Consortium




REST Consortium


Insulin-Like Growth Factor-1 (IGF-1)

• Implicated in regulation of normal placental function and of appropriate fetal and postnatal growth

• Anabolic effect, stimulates substrate

uptake and inhibits protein breakdown



REST Consortium




REST Consortium


IGF-1 treatment

Maternal Guinea pigs • Increased placental mass and functional

capacity of placenta = ↑ fetal growth • Significant effects on maternal physiology

14/01/2015



REST Consortium




REST Consortium


IGF-1 treatment Fetal infusion Sheep and non-human primates • Increased aminoacid utilization and alteration

in fetal protein accretion • Adequate substrate supply necessary for

effective tissue growth • Organ specific increases in growth, however

no significant effect on body size and growth

14/01/2015



REST Consortium




REST Consortium


IGF-1 treatment

Intra-amniotic

Sheep

• Increased total fetal growth rate and organ growth in growth restricted fetal sheep

• Up-regulates placental amino acid transporters

• Promising approach (?)

14/01/2015



REST Consortium




REST Consortium


Maternal uterine artery VEGF gene therapy ...and the EVERREST study

Vascular Endothelial Growth Factor (VEGF)



REST Consortium




REST Consortium


VEGF angiogenesis vasodilatation vascular protection

sFlt-1 ↑

Pre-eclampsia

VEGF ↓ PlGF ↓ endothelial dysfunction

IUGR

Reduced endothelial derived vasodilatation

VEGF implicated in trophoblast invasion

Over-expression of sFlt1 in pregnant mice using adenovirus causes PE-like syndrome & IUGR

Vascular Endothelial Growth Factor



REST Consortium




REST Consortium


….uses genetic material as a drug delivery vehicle to facilitate the expression of

therapeutic proteins

Gene therapy……

Achieve targeted protein expression • Uteroplacental circulation

Short term protein expression • Adenovirus vectors



REST Consortium




REST Consortium


VEGF levels are reduced in fetal growth restriction

Sustained local levels of VEGF will treat fetal growth restriction

“Maternal growth factor gene therapy”



REST Consortium




REST Consortium


Hypothesis Delivery of adenovirus containing VEGF gene to

uteroplacental circulation

Local over-expression of VEGF

Increase uterine blood flow Alter uterine artery vascular tone &

angiogenesis

Increase fetal growth in severe FGR



REST Consortium




REST Consortium


Short-term changes in uterine artery volume flow 4 – 7 days after vector injection

14/01/2015



REST Consortium




REST Consortium


Long-term changes in uterine artery blood flow after vector injection

14/01/2015



REST Consortium




REST Consortium


Correcting growth restriction in animal models of IUGR

14/01/2015

IUGR guinea pig: maternal nutrient restriction model - fetal growth, vector dose and safety

IUGR sheep: adolescent overfed ewe, Rowett Institute, Aberdeen - efficacy, fetal growth, neonatal outcome and safety



REST Consortium




REST Consortium


Fetal Growth Velocity - abdominal circumference

14/01/2015

Gestation (days)

Abd

omin

al c

ircum

fere

nce

(mm

)

***

***

***

***

A

B

140

160

180

200

220

240

260

280

300

80 85 90 95 100 105 110 115 120 125 130

Control (n=12)VEGF (n=18)Saline (n=13)LacZ (n=14)

Mean surgery day

*** p=<0.001



REST Consortium




REST Consortium


Proportion of very small sheep fetuses >2SD below control mean

0

5

10

15

20

VEGF Saline+LacZ

YesNo

p = 0.033 (Fisher’s exact test)

(Control mean = 5084g , SD = 431g, -2SD cut-off = 4222g)

Severe FGR >2SD

Mild FGR <2SD

Saline+LacZ VEGF

Num

ber o

f fet

uses



REST Consortium




REST Consortium


No significant changes in:

Maternal heart rate, blood pressure

Fetal heart rate, blood pressure

No vector spread

No fetal abnormalities 60

70

80

90

100

110

120

130

140

12/0

2/20

08

13/0

2/20

08

14/0

2/20

08

15/0

2/20

08

16/0

2/20

08

17/0

2/20

08

18/0

2/20

08

19/0

2/20

08

20/0

2/20

08

21/0

2/20

08

22/0

2/20

08

23/0

2/20

08

24/0

2/20

08

25/0

2/20

08

26/0

2/20

08

27/0

2/20

08

28/0

2/20

08

29/0

2/20

08

01/0

3/20

08

02/0

3/20

08

03/0

3/20

08

04/0

3/20

08

05/0

3/20

08

Daily

BP

at 9

am

SystolicDiastolicMean

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Day after flow probe placement

vector injection

Total n = 4

Pre

ssur

e (m

m H

g)

0

20

40

60

80

100

120

140

04/07/200809:00

05/07/200809:00

06/07/200809:00

07/07/200809:00

08/07/200809:00

11/07/200809:00

12/07/200809:00

13/07/200809:00

14/07/200809:00

15/07/200809:00

16/07/200809:00

17/07/200809:00

Systolic

Diastolic

Mean Arterial Pressure

Vector Injection

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 10

Day 8

Day 9

Day 11

Day 12

Safety

Abi-Nader et al, Lab Animals, 2011



REST Consortium




REST Consortium


EVERREST

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

Our aim • To translate a novel gene medicine delivered to

mothers, into the clinic, so as to improve fetal growth in severe early-onset fetal growth restriction

14/01/2015



REST Consortium




REST Consortium


EVERREST

• Reproductive toxicology • Bioethics study • First-in-woman phase I/IIa safety/efficacy study

14/01/2015



REST Consortium




REST Consortium


Human placenta toxicology studies

14/01/2015

After regeneration of syncytiotrophoblast, placental villous explants are exposed to high dose adenovirus vector

Perfusion experiments in normal and IUGR human placentae with high dose adenovirus vector



REST Consortium




REST Consortium


First-in-woman trial



REST Consortium




REST Consortium


First-in-woman trial • 4 EU recruiting centres

(London, Hamburg, Lund, Barcelona)

• Inclusion criteria:

• Severe early-onset IUGR

• ≥22 weeks of gestation

• Uteroplacental insufficiency (abnormal blood flow)

• Other causes of IUGR excluded

• Vector delivered via interventional radiology

14/01/2015



REST Consortium




REST Consortium


Treatment

• Vector instilled into uterine artery for 2 minutes using interventional radiology approach

14/01/2015



REST Consortium




REST Consortium


EVERREST outcome measures Primary outcome

• Assessment of patient safety and tolerability Secondary outcomes

• Uterine artery volume blood flow • Abdominal and head circumference (ultrasound) • Gestational age at delivery • Birth centile • Maternal blood pressure and proteinuria • Composite clinical outcomes • Myometrial artery contractility and placental

phenotype



REST Consortium




REST Consortium


Summary • Local expression of VEGF in the uterine arteries

• increases uterine blood flow • alters vascular reactivity • increases angiogenesis • improves fetal growth in IUGR pregnancies • without apparent maternal or fetal harm

• VEGF gene therapy promising as a therapy for

severe early-onset IUGR



REST Consortium




REST Consortium


2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

original idea

bioethics

ethical & regulatory approval

Phase I/IIa safety/efficacy

study



REST Consortium




REST Consortium


Thank you !

14/01/2015



REST Consortium




REST Consortium




REST Consortium


www.everrest-fp7.eu



REST Consortium


14/01/2015



REST Consortium




REST Consortium


2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

original idea

University College London, UK A David et al, Gene Therapy 2008 V Mehta et al, Gene Therapy 2011

Increase uterine artery blood flow short and long term Relax uterine arteries Increase endothelial nitric oxide synthase Increase endothelial cell proliferation in uterine artery adventitia No vector spread to fetus No acute haemodynamic changes



REST Consortium




REST Consortium


2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

original idea

University College London, UK D Carr et al, Hum Gene Ther 2014 V Mehta et al, PLoS One 2014

Increase fetal growth velocity Mitigate “brain sparing” No adverse events at delivery or up to 3 months postnatally Planned clinical vector has similar effects

Date post:	24-Mar-2020
Category:	Documents
Upload:	others
View:	1 times
Download:	0 times

and the EVERREST EU-project...• Early-onset severe IUGR associated with reduced uterine blood flow...

Documents