Assessment of Potential Therapies for Pre-eclampsia and Fetal Growth Restriction using Murine Models

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

Pre-eclampsia and fetal growth restriction (babies born smaller than they should be) are complications that affect up to 1 in 10 pregnancies and are responsible for grave illness in affected mothers and babies. Each year in the UK, up to 5 women and 600 babies die because of pre-eclampsia; 1 in 4 stillbirths are caused by fetal growth restriction and this is responsible for 1 in 6 sudden infant deaths.
Babies who survive these complications are at greater risk of cerebral palsy and, later on in life as children and adults, they are at higher risk of suffering heart disease, diabetes, bone disease and mental health problems.

Babies born of pregnancies complicated by pre-eclampsia and fetal growth restriction place a heavy burden on the NHS, with 20% of all intensive care baby cots being occupied by babies from pre-eclampsia pregnancies and around #420m being spent each year on intensive care of growth restricted babies. In addition, looking after children with illnesses related to pre-eclampsia and fetal growth restriction places a heavy burden on families, the NHS and social services.

Unfortunately, there are no cures for either pre-eclampsia or fetal growth restriction and women suffering from severe problems have to undergo premature delivery of their baby, which also carries great risks of chronic illness and death. Although there have been no drugs specially designed to treat these illnesses, there are a number of possible treatments that are used to treat other illnesses and that have already been shown to be safe in people who are not pregnant. These treatments cannot be tested on pregnant women without first establishing whether they are effective and safe in treating symptoms of pre-eclampsia and fetal growth restriction in animals. We would like to test a number of existing drugs to see if they are useful at treating the symptoms of these diseases in a number of specially-bred mouse strains that display signs of pre-eclampsia and fetal growth restriction when pregnant. Once we have found which treatments have the greatest potential for treatment in mice, we will use them on blood vessels taken from human placentas and women (with informed written consent) after they have given birth to test whether they might be effective in human pregnancy. Such experiments will provide information on how to design clinical trials for the development of these treatments in pregnant women suffering from pre-eclampsia or fetal growth restriction.

Technical Summary

Pre-eclampsia (PE) and fetal growth restriction (FGR) complicate up to 10% of pregnancies and are responsible for substantial maternal and fetal morbidity. In the UK, PE causes the deaths of 3-5 women and 600 babies per annum and FGR is associated with 1 in 4 stillbirths and 1 in 6 sudden infant deaths. The effects of PE and FGR are not limited to early life; survivors are at greater risk of cerebral palsy and neurodevelopmental delay. Furthermore, babies that are born small have increased risk of developing cardiovascular disease, chronic hypertension, diabetes and schizophrenia in adulthood.
There is no curative treatment for PE/FGR and the only therapy is early delivery, which has its own risks of mortality and morbidity. PE accounts for the occupancy of 20% of all intensive care baby cots. Thus the health, social and economic burdens of PE/FGR are enormous.
Despite the heavy burden of PE/FGR, there have been few therapeutic advances; only one new class of drug has been licensed for obstetric conditions in the last 20 years. Fear of fetotoxicity is one contributor to a lack of interest in drug development. Our proposal aims to develop treatments for PE/FGR by screening potential therapies in existing, and novel, mouse models of disease. Interventions that rescue utero- and fetoplacental vascular development and function in PE/FGR have immense potential for treatment of these serious pregnancy complications and are the focus of our research proposal. Through a multi-faceted programme of work incorporating a number of inter-related projects, using diverse methodologies, we will gain a thorough understanding of the vascular disease phenotypes of PE/FGR, and then rescue the vascular abnormalities using a range of potential therapeutic interventions, focusing on those which have already been approved for human studies outside of pregnancy. Treatments found to be effective in the mouse will be evaluated on the ex-vivo vasculature of women with PE/FGR thereby facilitating the identification of therapies for patient benefit. These pre-clinical studies will significantly advance our quest to identify therapies to arrest or alleviate the pathogenesis of PE/FGR. They will lead directly to Phase0/Phase1 Trials and promising novel interventions would interest pharmaceutical companies to develop further therapies and regimens.

Publications

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Charnock JC (2016) The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction. in American journal of physiology. Endocrinology and metabolism

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Kusinski LC (2012) eNOS knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype. in American journal of physiology. Regulatory, integrative and comparative physiology

 
Description British Heart Foundation Intermediate Fellowship (for Dr. Elizabeth Cottrell)
Amount £450,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 08/2019
 
Description Career Development Award (Dr. M Dilworth)
Amount £1,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 08/2018
 
Description Collaboration for mouse studies 
Organisation University of Auckland
Country New Zealand 
Sector Academic/University 
PI Contribution Shared expertise and technqiues in mouse reproductive physiology
Collaborator Contribution As above
Impact see publications
Start Year 2009
 
Description Collaboration for mouse studies 
Organisation University of Edmonton
Country Canada 
Sector Academic/University 
PI Contribution Shared expertise and technqiues in mouse reproductive physiology
Collaborator Contribution As above
Impact see publications
Start Year 2009
 
Title Beetroot 
Description Following pre-clinical studies in mice we are testing beetroot juice as a potential modifier of blood pressure in women with pre-eclampsia. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact None until current trial complete 
URL https://clinicaltrials.gov/show/NCT02520687
 
Title sildenafil 
Description Sildenafil being tested in a clinical trial for treatnebt of fetal growth restriction. Trial funded by an MRC EME award to Alfirevic 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Confirmed the value of testing drugs in mouse models of pregnancy disease 
URL http://www.isrctn.com/ISRCTN39133303
 
Description Before you were Born 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a Public and Patient Engagement event to tell people about our research. @oo people attended the event which sparked interest in our research and how to get involved in it.
Year(s) Of Engagement Activity 2017
 
Description Local Women's Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact !0 ladies attended this session to learn more about the placenta

Increased awareness of our research and how research is done
Year(s) Of Engagement Activity 2013
 
Description Stillbirth Workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 35 plus professionals attended this workshop on understanding, preventing and management of stillbirth. This sparked new work at other specialty meetings

Workshops at meetings of pathologists and placentologists to refine diagnosis
Year(s) Of Engagement Activity 2013