Angiogenic Biomarkers as Predictive Tests for Early Onset Preeclampsia: A Population-Based Study

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Cardiovascular Science

Abstract

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Technical Summary

Preeclampsia (PE) is a systemic endothelial disease characterised by hypertension, proteinuria, exacerbated inflammation, dysregulated angiogenesis and can lead to end-organ failure. There are currently no reliable means to predict in early pregnancy who will go on to develop this condition, despite the many theories for the pathogenesis of PE. Also no definitive biomarker exists with the potential for risk stratification or delineation of the mechanism of action for potential therapeutic agents. The only effective treatment for PE resolution is delivery by Caesarean section. We and others have performed a variety of retrospective studies suggesting that specific angiogenic markers, placental growth factor (PlGF) and its antagonist soluble Flt-1 (sFlt1) and novel soluble endoglin (sEng) are promising screening tools capable of predicting PE prior to it?s clinical manifestations. These biomarkers are strongly rooted in the pathology of PE. It remains unknown, however, whether the test characteristics of these biomarkers are robust in a diverse European population and whether these tests perform well utilising high-throughput, highly sensitive assays. We hypothesise that a quantifiable increase in blood sEng and sFlt, and a decrease in blood and/or urine PlGF will antedate maternal clinical symptoms of early onset ( 32 weeks gestation) PE and differentiate it from late onset PE. To verify if changes in angiogenic and anti-angiogenic proteins can be used to accurately predict women at risk of developing early onset PE, we will test blood and urine samples collected longitudinally from over 40,000 pregnant women and assay for the blood sFlt1, and sEng and blood/urine PlGF levels screening for PE amongst asymptomatic women in early pregnancy at two time points (8-12 weeks gestation and 17-20 weeks gestation). To address these important aims, we have assembled a team with expertise in the biology of angiogenic markers and PE, clinical investigators with a track record of performing high-quality prospective studies in pregnancy, and medical device and immunoassay experts from industry. We believe this proposal will lead to the development of highly economical and robust testing strategies that will allow efficient assessment of potential therapeutic interventions, permit a targeted approach concentrating on women at the highest risk and also reduce NHS cost.

Publications

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Crispi F (2008) Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses. in American journal of obstetrics and gynecology

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Bergmann A (2010) Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. in Journal of cellular and molecular medicine

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Ahmed A (2011) Multiple roles of angiopoietins in atherogenesis. in Current opinion in lipidology

 
Description Health Technology Assessment programme
Amount £700,000 (GBP)
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2012
 
Title Transgenic CSE null 
Description Generated a transgenic mouse to further study the novel pathways we have identified in preeclampsia 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Not yet. 
 
Description Irina Buhimschi - Angiogenic marker in preeclampsia 
Organisation Yale University
Department School of Medicine
Country United States 
Sector Academic/University 
PI Contribution We are one of the world's leading groups on angiogenic factors in pregnancy disorders and were able to generate the hypothesis which was tested by my student Dr Wenda Ramma (she obtained her PhD this summer). Thus we provided a student, supported her time at Yale and paid for the research consumables.
Collaborator Contribution One of my PhD student was able to go out to Yale and spend a year doing research on clinical samples which they had collected. This has resulted in a paper in Circulation and several other papers are in the pipeline.
Impact Rosenberg VA, Buhimschi IA, Lockwood CJ, Paidas MJ, Dulay AT, Ramma W, Abdel-Razeq SS, Zhao G, Ahmad S, Ahmed A, Buhimschi CS. Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy. Circulation. 2011 Nov 14. [Epub ahead of print] 2. Edinburgh PhD - Wenda Ramma (one year in Yale)
Start Year 2009
 
Description Khalid Khan - PREP Study 
Organisation Birmingham Women's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Development and validation of a Prediction model for Risk of complications in Early onset Pre eclampsia (PREP). This is based on the biomarker grant.
Impact We have been awarded a HTA grant for the PREP study, 2010
Start Year 2008
 
Title Method of hastening cervical ripening 
Description The use of an agent for controlling vascular permeability within the cervix is disclosed for controlling cervical ripening. To hasten cervical ripening, the agent is one which increases vascular permeability and is selected from VEGF121, VEGF145, VEGF165, VEGF189, VEGF206, a smaller, active VEGF fragment, and placenta growth factor (PlGF). If cervical ripening is to be delayed, the agent is one which reduces vascular permeability, e.g. a VEGF receptor antagonist or antibody. The agents of the present invention can be used as a means of managing labor. 
IP Reference US6946442 
Protection Patent granted
Year Protection Granted
Licensed No
Impact N/A
 
Title Abbott Diagnostics Inc. 
Description Established collaboration and obtained joint MRC Strategic funds in Translational Medicine. However, Abbott Diagnostics Inc. later pulled out due to financial downturn. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Closed
Impact Potentially it could lead to early diagnosis of preeclampsia which will allow StAmP trial output to provide a potential treatment for such patients. 
 
Description PreDicT 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact To establish a West Midland network of pregnancy biomarker centres.

Collaboration and subsequent grant funding from HTA.
Year(s) Of Engagement Activity 2009