Developing personalized nanotherapies to target placental abnormalities causing fetal growth restriction

During pregnancy, the placenta supports the growth of the developing baby. At the beginning of pregnancy, the placenta grows rapidly to establish a functional system for transferring nutrients and oxygen from the mother to the baby. At the same time, the placental tissue forms a protective barrier between the maternal and fetal blood circulations.

Despite the high quality medical care available in the western world, many fetuses fail to grow normally. This condition is called fetal growth restriction (FGR) and it has severe consequences: the smallest babies die, while those that survive will potentially have poor health, both as children and as adults. Most cases of FGR are caused by (i) a placenta that cannot transport enough nutrients to the baby or (ii) a placenta that doesn't receive enough of the mother's blood. Currently, there is no way to correct these defects. Drug companies shy away from developing drugs for use in pregnancy because they are fearful of harming unborn babies with their new products. Instead, they invest in other areas of research, leaving doctors with few alternatives for treating pregnant women.

It has recently been discovered that every organ in the body has a unique combination of molecules on its surface. These molecules act like a "postcode" and can be used to "address" packages containing drugs, so that the drugs are sent to a specific location in the body. We have recently created tiny packages called nanoparticles that have the postcode of the placenta on their surface. We have shown that these packages can deliver drugs directly to the placentas of pregnant mice, helping the placentas function better, and as a result, helping the mouse fetuses grow bigger. Importantly, we showed that the drug did not cross the placental barrier and reach the fetuses, and the drug was not detected at high levels in any of the mother's major organs. This means that our nanoparticle packages provide a safe way of delivering drugs to treat an abnormal placenta, without the risk of harming the developing baby.

In this study, we will test our drug-loaded nanoparticles in human placental tissue. As well as identifying the postcode of the placenta, we also know the postcode of the blood vessels in the womb. We can therefore use our nanoparticles to deliver drugs to treat both types of FGR: helping a placenta to transport more nutrients or by increasing the maternal blood flow, so that the placenta can receive the blood it needs. Doctors are already able to identify which type of FGR women have using blood tests and ultrasound scans, and our nanoparticles will enable doctors to correctly target the different placental abnormalities with the right drugs.

We have also identified a number of drugs, primarily used to treat diseases outside of pregnancy, that improve placental growth and blood flow in mice. For the first time, we will load these drugs into our nanoparticle packages. We will use pieces of human placental tissue collected after delivery of the baby, and blood vessels taken from the wombs of women having a Caesarean section, to study which drug-nanoparticle combinations help placentas and womb blood vessels function most effectively. Our study will also help us understand more about how the human placenta responds to, and breaks down our nanoparticles.

This research will lead to the development of safe, personalised medicines to treat FGR and collect the important data needed before clinical trials can take place. It will also help women feel confident that any drugs they receive during pregnancy will not harm their unborn child. Our ultimate aim is to find safe and effective treatments for FGR that ensure the survival of newborn babies and improve their long-term health.

Fetal growth restriction (FGR) is a serious pregnancy complication associated with significant risk of neonatal morbidity and mortality, and of non-communicable diseases in childhood and adulthood. Despite this burden of disease, there are no in utero medicines for correcting the underlying cause of disordered fetal growth: placental dysfunction. Our recent research using mouse models of FGR has identified a number of effective drugs, primarily designed for use in diseases outside of pregnancy, which have proven to be effective placental therapies. We have also developed targeted liposomes capable of selective delivery of drugs to the mouse placenta or uterine arteries, resulting in significant enhancement of fetal growth. The aim of this application is to test the hypothesis that targeted liposomes can selectively deliver drugs to either human myometrial vasculature or the placental syncytiotrophoblast (STB), improving functional effectiveness and safety, and enabling a stratified approach to treat FGR resulting from vascular or non-vascular placental pathology.

Our objectives are to:
1. Assess the effect of targeted liposomes containing appropriate drug on healthy human myometrial vascular reactivity and STB function in vitro, and compare it to the effect of freely administered drug.

2. Determine whether targeted liposomes can selectively improve function in human myometrial vessels or STB from FGR pregnancies complicated by vascular or non-vascular placental dysfunction.

3. Use human placental ex vivo dual perfusion to evaluate maternofetal transfer of targeted liposomes and potential effects on placental endocrinology, cell survival and placental barrier integrity.

This programme of study will allow us to fully exploit our proven strategy for fast tracking candidate therapies into obstetric clinical trials.

The pregnancy complication fetal growth restriction (FGR) increases the risk of fetal death and disability and also has life-long health consequences. This condition therefore leads to a considerable social and financial burden for society, as well as affected families. There are currently no treatments available, leaving obstetricians to deliver the baby prematurely, which exacerbates existing poor health outcomes. Our research is focussed on identifying safe, effective, targeted interventions that can both normalise fetal growth and improve life-long health. Consequently, our work will have a number of impacts:
1. reducing, fetal and child mortality and morbidity;
2. reducing costs associated with caring for sick mothers and babies, offering novel and affordable treatments - benefits flowing to clinicians, commissioners in the NHS, and as a result, the general public;
3. developing targeted drug delivery systems for treatment of diseases outside of pregnancy.

This will be of immediate benefit to the following groups:
Women, unborn children and infants will benefit because FGR complicates up to 10% of human pregnancies and is responsible for significant maternal and fetal morbidity. In the UK, FGR is associated with 40% of the 4000 stillbirths that occur each year. Furthermore, there is overwhelming evidence to suggest that lifelong health is programmed in utero and being born too small increases the risk of childhood obesity and diabetes and of adult cardiovascular disease, diabetes and a range of other non-communicable diseases. In turn, poor health in adulthood will affect the in utero development and wellbeing of subsequent offspring, creating a cycle of ill health for subsequent generations. Finding treatments for FGR could therefore ultimately improve the health of the whole population of the UK.
1. Obstetricians, NHS managers and commissioners will benefit as early-onset FGR accounts for 15% of the occupancy of intensive care baby cots; in combination with the enhanced neonatal requirements of FGR infants, the NHS spends in excess of £420M annually on the conditions we are focused on. The cost of providing care for people with chronic diseases, including diabetes, and cardiovascular disease, is in excess of £70 billion per year. Thus the health, social and economic burdens of FGR are substantial. The new treatments we develop will reduce these costs, and enable obstetricians, and NHS managers and commissioners to more effectively focus increasingly scarce resources.
2. Systemically delivered drugs, for any disease, can reach all tissues in the body, potentially leading to unwanted side effects. The ideal drug would only target the specific diseased tissue, and researchers in a variety of fields are trying to achieve this goal. Our work will use novel nanotechnology-based delivery systems to target drugs specifically to the placenta. However, the delivery systems we are using have broad applications, and information obtained from our work will benefit researchers outside of pregnancy.

Our ability to benefit these groups is enhanced by the strong tradition of the University of Manchester in using its research to make positive impacts on real world challenges, from informing health policy through to the commercialisation of intellectual property, guided by our ongoing dialogue with clinical colleagues and the University of Manchester Intellectual Property (UMIP) service.