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Innovation in modelling Placenta for Maternal and Fetal Health

Periodic Reporting for period 1 - iPLACENTA (Innovation in modelling Placenta for Maternal and Fetal Health)

Reporting period: 2018-01-01 to 2019-12-31

Many of the major complications during pregnancy are thought to stem from abnormal development and function of the placenta, an organ which grows during pregnancy and supplies the fetus with all it needs for development from the mother. However, as yet relatively little is known about the placenta’s function, nor its interaction with the maternal cardiovascular system, in the development of two of the most common complications: preeclampsia (PE) and intrauterine growth restriction (IUGR). These are complex conditions which have detrimental consequences for both the mother and fetus. The World Health Organisation have reported preeclampsia as one of the least funded areas of medical research, and there has been comparatively little progress in developing diagnostic tests and therapies. iPLACENTA aims to use advancements in technology to enhance our ability to model, visualise and assess the placenta at different levels (in vitro, in silico and in vivo), as well as its interaction with the maternal cardiovascular system, with a view to improving diagnosis and eventual treatment of major placental diseases.

Preeclampsia (PE) claims the lives of 76,000 mothers and 500,000 babies annually worldwide, and it is estimated that three out of every 100 pregnant women suffer from this disease (Preeclampsia Foundation, 2019). Its onset and clinical course are unpredictable, there are no preventative means and delivery is the only existing cure, which often necessitates medically induced preterm deliveries. Undiagnosed, or without intervention, it may lead to life-threatening complications.
Intra-uterine growth restriction (IUGR) affects 60,000 births across the EU per year and is the most common factor for stillborn babies. Yet the prediction rate is woefully poor: two thirds of the fetuses identified are small but healthy for their gestational age, while the remaining third are at high risk for mortality or cerebral malformation. This poor prediction rate places a heavy burden on the healthcare system. Delaying premature births by a week could potentially save millions per year in the UK alone (Mangham LJ et al., 2009).
For those that survive both PE and IUGR, there are life-long serious cardiovascular and neurological consequences. Altogether, these pregnancy complication have great personal, societal and economic impact.

The principal research aim of iPLACENTA is to improve our ability to study, model and visualise the placenta, in order to improve investigation and prognosis of complicated pregnancies through the development of a multidisciplinary network spanning different sectors.
A motivating force for iPLACENTA is the lack of PhD programmes in Maternal and Fetal Health in the EU and worldwide. iPLACENTA delivers doctoral-level training and coordinates collaboration among world-leading academic institutions in Europe, providing a new network of in-depth international expertise. The 15 Early-Stage Researchers participating in the programme are working with academics and clinicians to develop new placenta-on-a-chip technology, in silico placenta modelling, and new modalities of laser technology to visualize the placenta in vivo, as well as to improve maternal-cardiovascular assessment and validate novel ultrasound tools for diagnosis of complicated pregnancies. In addition, they will receive training from our partners in industry and business, and experts in the field in healthcare and science. After completion of the project, they will be fully capable of leading interdisciplinary, intersectoral translational research at an international level. These are the skills required to achieve future therapeutic breakthroughs.
iPLACENTA has recruited 11 EU-based Early-Stage Researchers (ESRs) and attracted 4 non-EU based ESRs to the EU Research area. Their network training included an introduction to clinical complications in maternal and fetal health, project management, Open Science, data management and aspects of media engagement. The ESRs have completed initial training at their institutes, developed methodologies, and begun recruitment for clinical studies. In June 2019 the ESRs presented their project progress at the 1st iPLACENTA network meeting (midterm check) at the University of Torino, Italy. There will be a session dedicated to iPLACENTA at the International Federation of Placenta Associations (IFPA) annual conference in 2021 (postponed from 2020 due to COVID-19). To date the ESRs have published 6 scientific review articles.
The ESRs are expected to become a key asset to the European Research Area to lead translational research and develop and deliver novel, high-impact technological approaches. iPLACENTA broadens the scope of the participating institutions’ research capacities by bringing together 11 institutes, and expanding academia collaboration with companies, e.g. Mimetas and Moor.

The objective in Work Package (WP) 1 is to develop state-of-the-art models to mimic the placenta in vitro. ESRs 1 and 2 will utilise Mimetas’ unique OrganoPlates® platform to create a placenta-on-a-chip model to emulate the clinical disease situation, as well as the integration of functional characteristics. This model mimics the interplay of the placenta barrier with vascular system, providing a miniaturised effective tool for mechanistic studies or drug development. ESR 3 will isolate and characterise extracellular vesicles (EV) from ex vivo placental explants, amniotic fluid, maternal plasma and placenta-on-a-chip. During pregnancy, placental-derived EVs may provide a natural placental derived biopsy available in the maternal blood to determine placenta wellbeing. ESR 4 will use gene editing technology to encapsulate the complex pathophysiological disease conditions.

WP2 will establish modularized molecular interaction network maps in the context ‘omics’ data of PE and IUGR and identify decisive factors to support early diagnosis and long-term prognosis. ESRs 5-8 are taking an interdisciplinary approach to generate genomics, epigenomics, proteomics and miRNA data of PE/IUGR, developing interactomes between biological and biophysical data, using a combination of new results, data previously stored in bio-databanks, and clinical information. The logic-based model to be developed by ESR 9 will provide a platform to prioritize prognostic/diagnostic markers that will be validated in WP3 and WP1, thus providing the ultimate opportunity for commercialisation of a systems biology placental model for therapeutic targeting or personalised medicine.

The objective of WP3 is to characterise and validate new methodologies for in vivo placenta modelling and clinical prediction of early/late onset PE and IUGR. Early prediction will not only allow targeting of resources, it will provide insight into pathological mechanisms or identification of a window or target for therapeutic intervention. ESRs 11 and 12 work on standardising protocols for in vivo models and characterising them in relation to clinical assessment, while ESR 10 works with Moor Instruments to develop a Laser Speckle Doppler imaging device to allow minimally invasive visualisation of organ perfusion such as the placenta. ESRs 13-15 are improving our ability to evaluate human placental structure and function in real time by using e.g. new advances in ultrasound in early gestation which will help determine the clinical trajectory of a patient toward the development of placental disorders like PE/IUGR.
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