Is kynurenine pathway manipulation a novel therapeutic strategy for ameliorating features of pre-eclampsia?

Pre-eclampsia (PE) - a condition where pregnant women develop high blood pressure (hypertension) and protein in the urine (proteinuria) - affects up to 5% of pregnancies. PE causes 70,000 maternal deaths and 500,000 fetal deaths every year. The only effective treatment for PE is delivery of the baby, which often results in babies being born prematurely; 1 in 5 neonatal cots in the UK are occupied by babies born to a mother with PE. These babies experience long-term disabilities and lifelong increased risks of heart disease and diabetes. A treatment for PE which would allow pregnancy to continue longer is highly desirable.

The kynurenine (KYN) pathway is a natural route for the breakdown of the amino acid tryptophan within the body. This pathway is highly active in normal pregnancy, but for unknown reasons is less active in PE. In laboratory experiments, components of the KYN pathway can relax blood vessels, reduce immune activation and protect cells from damage -this suggests that increasing activity of the KYN pathway could reduce some of the underlying problems that lead to the development of PE. This project will test the hypothesis that increasing KYN pathway activity is a useful new approach for treating PE.

Firstly, I will determine how KYN causes blood vessels to relax and compare the KYN pathway between women with normal pregnancy and PE. Understanding how this pathway is controlled and how it is altered in PE will identify ways to change the activity of this pathway in future experiments. I will increase the activity of the KYN pathway in blood vessels from women with PE and in cells with similar properties to those seen in PE to determine if this can alleviate the features similar to PE. The final stage will determine the effects of manipulating the KYN pathway in a pregnant mouse model of PE. The use of animals for investigating potential treatments for pregnancy problems is essential in order to assess the effects of therapeutics on maternal, fetal and placental function and to ensure therapies are safe. I will determine if manipulating the KYN pathway can improve hypertension, proteinuria and immune features of PE in these mice, and other effects of treatment on fetal growth and survival.

Following this project I will continue to investigate this area of research with a plan to translate the findings of these studies into clinical trials in women with PE. My long-term aim is to identify a new treatment for PE, which could be used to treat patients within 10 years of this project. An effective treatment for PE would reduce maternal and fetal deaths and allow pregnancies complicated by PE to continue longer, reducing the number of babies who experience complications due to being born prematurely or small. It is likely that the findings of this research project will also be of benefit to scientists who are investigating the KYN pathway in other conditions such as obesity, infection and cancer.

This work will take place within the Maternal and Fetal Health Research Centre (MFHRC), University of Manchester, in collaboration with research groups led by Dr Daniel Vaiman (The Cochin Institute, France) and Dr Vikki Abrahams (Yale School of Medicine, USA). The MFHRC is the largest pregnancy-based research group in Europe and has a long-standing reputation as a world-class research facility. The group is comprised of scientists, obstetricians and midwives who work on a wide range of research projects with the combined aim of making pregnancy safer for both mother and baby. There is particular experience in investigating new treatments for PE and the use of mouse models to develop treatments for pregnancy problems. In conjunction with Central Manchester Foundation Trust, MFHRC offers a number of specialist antenatal services for women at high risk of pregnancy complications, including a vascular clinic (MAViS) for women with hypertension, which provides an interface between research and clinical practice.

In normal pregnancy, the kynurenine (KYN) pathway of tryptophan degradation is highly active in the placenta where it has a physiological role in preventing immune rejection of the fetus. This pathway is less active in pre-eclampsia (PE), a pregnancy-specific disease of maternal hypertension and proteinuria accompanied by inflammatory activation, endothelial dysfunction and increased vascular tone. The principal pathway enzyme (IDO1) causes T-cell suppression and is also a potent free radical scavenger that reduces oxidative stress. KYN administration to hypertensive mice causes systemic blood pressure reduction and my preliminary data demonstrate that KYN can relax human maternal blood vessels. This CRTF will test the hypothesis that KYN pathway manipulation can ameliorate maternal features of PE.

Using human placental and maternal biopsies, this study will compare KYN pathway expression, activity and vascular effects in normal pregnancy and PE. These data will facilitate the design of strategies aimed at increasing KYN pathway activity in models of PE using commercially-available KYN pathway metabolites or activators/inhibitors of target enzymes. I will determine if manipulation of the KYN pathway can rescue the dysfunctional phenotypes of arteries and cultured endothelial cells in well-characterised in vitro models of PE. Strategies for manipulating the KYN pathway that successfully rescue the PE phenotype in vitro will be translated to a murine model of PE. Using the STOX1 model of PE, which recapitulates many features observed in the human disease, I will determine if KYN pathway manipulation can ameliorate maternal features of PE; the primary outcome will be maternal hypertension with secondary outcomes including; proteinuria and histological renal changes. It is anticipated that this research will lead to further investigations translating findings into human clinical trials, with the long-term objective of identifying a new treatment for PE.

Academic:
-As discussed in 'Academic Beneficiaries', it is anticipated that scientific knowledge about the regulation and manipulation of the KYN pathway arising from this project will be of significant interest beyond the field of pregnancy research and may have broad applications across scientific and translational research in a range of human clinical conditions, including; sepsis, trauma, stroke, obesity and cancer.

Skills and Training:
- Robust training opportunities within this CRTF will allow me to undertake a period of focussed research to complete a PhD and build upon existing skills and experience in order to develop as a clinical academic. I will learn new skills in the investigation of immune activation within models of PE and the use of murine models to investigate potential treatments for pregnancy disorders. During the fellowship I will complete Home Office Training modules necessary for conducting experiments using animals. The training provided in laboratory, mouse and clinical investigations of vascular function will equip me with the necessary skills to apply for a NIHR Lectureship to pursue translation of this research towards a clinical treatment for PE.

- During this CRTF I will gain additional experience at two internationally renowned research laboratories and forge new collaborations with researchers with skills complimentary to those in MFHRC. I will exploit networking opportunities associated with the RCOG in order to establish a network of collaboration and support within the field of obstetrics. This CRTF will be a vital step towards establishing myself as an independent researcher, gaining a Clinician Scientist Fellowship Award and ultimately becoming a future research leader.

Health of the Nation:
- Success of this experimental programme may be translated into a novel treatment for PE, a condition affecting up to 5% of pregnancies, within 10 years of this CRTF. PE contributes to 70,000 maternal deaths and 500,000 fetal deaths every year. Babies born premature or small as a consequence of PE experience short-term complications, long-term disabilities and lifelong increased risks of cardiovascular disease and diabetes. A clinically effective treatment for PE would reduce the morbidity and mortality associated with this condition for pregnant women and their offspring with obvious and important psychological, social and economic benefits to patients and their families.

Commercial and Economic:
- PE accounts for approximately 20% of neonatal cot occupancy. Advancements in the treatment of PE that reduce maternal and neonatal morbidity could be expected to have a significant impact on the financial burden of obstetric and neonatal care, and reduce healthcare and other economic costs arising from long-term complications and disabilities.

- Development of a novel treatment, which would most likely be achieved in collaboration with a commercial pharmaceutical partner, could yield economic benefit for stakeholders. The University of Manchester (UoM) Research to Enterprise Centre facilitates translation of basic scientific research into effective biotechnological applications by assisting researchers with business plans, marketing strategies, and interactions with the commercial sector. The UoM Intellectual Property Company provides assistance for early licensing of intellectual property generated by research. If this project progresses towards development of a therapeutic intervention, these resources will provide the necessary support and guidance for timely and effective exploitation of my research for maximal benefit to researchers and patients.