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European Biopharmaceutical Review

Great Expectations

Preeclampsia is a leading killer of pregnant women and a major contributor to maternal and foetal morbidity. Occurring in 3-8% of pregnant women worldwide, it is diagnosed by the new onset of high blood pressure, and either elevated protein in the urine or pulmonary edema, cerebral or visual symptoms, low platelets, or specifi c signs of kidney or liver dysfunction, beginning in the 20th week of pregnancy (1-3).

Although most affected pregnancies deliver at or close to term with good outcomes, women with preeclampsia can be at an increased risk of lifethreatening events, including stroke and grand mal seizures (eclampsia). There is also an increased incidence of placental insufficiency and foetal growth restriction. Due to these potentially adverse outcomes, a key aspect of routine prenatal care is monitoring for signs and symptoms of this disorder. Even if preeclampsia is detected in a timely manner, delivery of the child remains the only cure. Anti-hypertensive and anti-seizure medications can be given, but do not change the course of the disease. Consequently, women may need to deliver prematurely to stop disease progression and protect their life and that of their baby. The disorder may emerge as early as 20 weeks' gestation, though most cases manifest later in pregnancy, with preeclampsia accounting for 12% of premature births in the US. In the case of very premature infants, there are high rates of mortality and lifelong disability, but even infants born between 33 and 36 weeks of pregnancy have significantly higher rates of morbidity than those born at term (4).

Furthermore, the negative effects of preeclampsia on the mother were thought to resolve after pregnancy. However, in February 2014 the American Heart Association and the American Stroke Association identified preeclampsia as an independent risk factor for cardiac disease and stroke in women even decades after pregnancy – it doubles the risk of stroke and quadruples the risk of developing hypertension in later life, even if blood pressure returns to normal after delivery.

Trophoblast Invasion

The pathophysiology of preeclampsia is not clearly understood. It is thought that a dysfunctional decidual-trophoblast interface between the immunologically distinct mother and foetus – and disrupted immuno-tolerance of each for the other – are at the centre of the disease process (5,6). The successful transformation of uterine spiral arteries by invading trophoblast is critical for the optimal utero-placental blood flow, and results from complex interaction between the decidua and invading trophoblast cells. Placental trophoblast migration and invasion are wellregulated by various autocrine and paracrine factors at the maternal-foetal interface, while mesenchymal cells have been shown to produce a wide array of soluble cytokines and growth factors necessary for this process.

Trophoblast invasion is unusual in preeclampsia, and remodelling of spiral arteries is defective. The resulting abnormal blood flow is thought to lead to placental ischemia and reperfusion injury, and to the release of factors from the placenta that cause systemic inflammatory and oxidative stress in maternal circulation, as well as in the decidua and placenta. Systemic inflammation may result from placental secretion of factors such as pro- and anti-angiogenic proteins and other proinflammatory products, while deficiency in levels of anti-inflammatory IL-10 are also evident (6). Elevated production of pro-inflammatory cytokines by placenta-derived mesenchymal stromal cells from preeclamptic chorionic villi has been described, and researchers have shown that these cells elicit a preeclampsialike phenotype in physiological villous explants. These data suggest that mesenchymal stromal cells are central to placental pathology in preeclampsia, and may inform development of a treatment (7).

Therapeutic Compounds

There are several ongoing clinical trials aimed at prevention of preeclampsia in women considered high risk. These include a Phase 2 trial by Novartis to evaluate treatment with a recombinant form of human relaxin-2, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Phase 1 trial to evaluate pravastatin, a cholesterol lowering drug. Meanwhile, the Faculty at the Assistance Publique, Hôpitaux de Paris is comparing Lovenox® (enoxaparin) and Aspegic® (Aspirin) together to aspirin alone, in a Phase 3 trial in women with a history of severe preeclampsia in a prior pregnancy.

Since preeclampsia is known to be a multi-factorial condition that involves multiple organs and systems, it may be that an effective treatment will involve administration of multiple compounds in the right amounts and at the right times. This would require a sophisticated drug delivery platform capable of regulating release of therapeutic compounds in response to the needs of dysfunctional tissues.

Cell therapy with mesenchymal stromal cells may prove capable of doing just that. These cells can be harvested from different tissue sources, such as placenta, bone marrow, fat and cord blood. They can be collected from an individual patient, expanded and then re-administered to the same patient; or produced as an ‘off-the-shelf’ treatment that needs no tissue matching. Such cells secrete multiple cytokines as central actors in the regulation of the maternal foetal interface, and their secretome could hypothetically infl uence the pathological processes at work in preeclampsia.

Placental Expanded Cells


In one development, Pluristem Therapeutics has developed placentaderived mesenchymal-like adherent stromal cells into therapies for infl ammatory and ischemic conditions. These therapeutic cells would require no tissue matching prior to administration. Immune-privileged cells taken from the placenta are expanded and modulated in three-dimensional bioreactors to develop different products to treat multiple indications. These cells, called placental expanded cells (PLX), are thought to respond to chemical signals from damaged tissue in the body by secreting a combination of therapeutic proteins including proangiogenic, immuno-modulatory and anti-infl ammatory factors into the blood stream; these can reduce inflammation and stimulate angiogenesis, as well as facilitate the body’s own mechanisms for tissue repair.

The crosstalk between damaged tissues and the PLX cells, resulting in PLX secretion of multiple compounds, may be well-suited to address complex diseases such as preeclampsia, in which multiple interrelated pathways generate pathology. Studies in toll-like receptor-induced pregnant mouse models of preeclampsia have demonstrated effi cacy for these cells in mitigating hypertension and proteinuria – key characteristics of the disease (8).

Emerging Emphasis

Preeclampsia is an unmet medical need that takes a signifi cant toll on pregnant women around the world, while also increasing the risk for premature birth, and the accompanying complications and risk of long-term morbidity for the babies. More research into the disease’s causes and potential therapies is critical. The emerging emphasis on preeclampsia in the academic, public health and commercial arenas will hopefully lead to progress in treatment and prevention.

References

1. Ananth CV, Keyes KM and Wapner RJ, Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis, BMJ 347: f6564, 2013
2. Dolea C and AbouZahr C, Global burden of hypertensive disorders of pregnancy in the year 2000, Evidence and Information for Policy, World Health Organization, Geneva, July 2003
3. Wallis AB, Saftlas AF, Hsia J and Atrash HK, Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987-2004, Am J Hypertens 21(5): pp521-526, May 2008
4. Wang ML, Dorer DJ, Fleming MP and Catlin EA, Clinical outcomes of near-term infants, Pediatrics 114(2): pp372-376, August 2004
5. Hsu P, Kay R and Nanan H, Innate and adaptive immune reactions at the fetal-maternal interface in healthy human pregnancy and preeclampsia, Journal of Immunology, published online 28 March 2014
6. Staff AC and Redman CWG, IFPA Award in Placentology Lecture: Preeclampsia, the decidual battleground and future maternal cardiovascular disease, Placenta 35, Supplement A, Trophoblast Research Vol 28 S26-S31, 2014
7. Rolfo A, Giuffrida D, Nuzzo AM, Pierobon D, Cardaropoli S, Piccoli E et al, Pro-inflammatory profile of preeclamptic placental mesenchymal stromal cells: New insights into the etiopathogenesis of preeclampsia, PLOSone, 19 March 2013
8. Pinzur L, Chiasson V, Chatterjee P, Hatahet M, Abraham E, Chajut A et al, PLX-PAD cell treatment mitigate tolllike receptor induced preeclampsia symptomology in mice, Cytotherapy 16(4): S101, April 2014

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Karine Kleinhaus, MD, MPH, is the Divisional Vice President, North America, for Pluristem Therapeutics. Prior to her joining Pluristem, Karine practiced obstetrics and completed two fellowships at Columbia University, before holding the role of Assistant Professor in the Departments of Obstetrics and Gynaecology and Psychiatry at the New York University School of Medicine. She received her Medical degree from Tel Aviv University, earned a Master of Public Health from Columbia’s Mailman School of Public Health, and a Bachelor’s degree from Princeton University.


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