EDITORIAL Maternal gene therapy for placental insufficiency

eveloping therapies for diseases of when deciding whether to continue monitoring a Dis an important but challenging task. Despite pregnancy, with the risks of and neuro- maternal and perinatal conditions making up 7% developmental impairment from chronic in utero of the global burden of disease, there are few or hypoxia, or to deliver a baby preterm, with all of no evidence-based treatments for diseases of the complications that may ensue.4 pregnancy such as fetal growth restriction, pre- Anna David and preterm labour.1 There is also a Developing a maternal therapy Reader and Consultant in ‘drought’ of new therapies in development. This One potential strategy to treat placental Maternal and Fetal Medicine is partly as a result of industry underinvestment insufficiency is to increase the flow of blood but also because there are many ethical and through the mother’s uterine arteries that supply regulatory barriers to carrying out clinical trials the maternal side of the . This is the in pregnant women.2 approach taken by the EVERREST project. The EVERREST project is a multinational and Vascular endothelial growth factor (VEGF) is multidisciplinary collaboration that aims to carry important for the development of the placenta out the first trial of maternal growth factor gene and its circulation, and reduced VEGF availability therapy in affected by placental is implicated in the pathogenesis of placental insufficiency, a common cause of fetal growth insufficiency.5 Therapeutic manipulation of VEGF restriction.3 An important first step in the project and other angiogenic factors is now being studied was to explore the ethical and social acceptability as a method to improve fetal growth in placental of the proposed trial, as this would be the first use insufficiency. Gene therapy results in local and of gene therapy in pregnancy. short-term increases in the levels of growth Rebecca Spencer factors such as VEGF, and has been safely used in Placental insufficiency and fetal other vascular beds such as the coronary artery Clinical Research Fellow in growth restriction circulation.6 In pre-clinical studies VEGF gene Maternal and Fetal Medicine During pregnancy placental villous development therapy increases uterine artery blood flow in [email protected] and normal placental circulation are key to the short- and medium-term,7, 8 and it safely delivering and nutrients from the mother improves fetal growth in animal models of Institute for Women’s to the growing fetus. In placental insufficiency placental insufficiency.9,10 The EVERREST project Health, University College London there is poor placental development and proposes to give VEGF gene therapy directly insufficient maternal blood supply to the uterus. into the uterine arteries of pregnant women This leads to restricted growth of the fetus, with early onset and severe fetal growth where the estimated fetal weight (EFW) is less restriction due to placental insufficiency, using than expected and commonly small for gestational interventional radiology. age (SGA, EFW <10th centile). In placental insufficiency there may also be Doppler What do women and caregivers think? ultrasound changes in the uterine and umbilical As part of the EVERREST project we undertook arteries. a literature review exploring the ethics of In normal pregnancy the experimental medicine research in pregnant in the uterine arteries falls, increasing the flow of women, particularly in relation to the use of the mother’s blood to the womb. In placental maternal gene therapy. The findings of this review insufficiency the resistance in the uterine arteries were used as the basis for semi-structured remains high, with a pre-diastolic ‘notch’ in the qualitative interviews with 21 women who had flow pattern. There may also be high resistance to had a previous pregnancy affected by early onset blood flow in the umbilical arteries, described as severe fetal growth restriction due to placental an increased pulsatility index, reflecting a problem insufficiency.11 Similar interviews were performed with the circulation of fetal blood through the with 34 stakeholders from national and placenta. At its most severe there can be absent, international medical, midwifery, disability, and and even reversed, end-diastolic flow in the parental support organisations. Because of the umbilical arteries. multinational nature of the EVERREST project There is currently no treatment for placental women and stakeholders were interviewed from insufficiency. When it develops in mid-pregnancy Germany, Spain, Sweden and the UK. the parents and healthcare professionals face a Overall the interview studies found no constantly changing balance of risks and benefits fundamental or insurmountable objections to a infant VOLUME 12 ISSUE 3 2016 75 EDITORIAL clinical trial of maternal gene therapy for an acceptable safety profile based on 2. David A., Thornton S., Sutcliffe A., Williams P. placental insufficiency. Most respondents reproductive toxicology studies that are Scientific Impact Paper No. 50. Developing New Pharmaceutical Treatments for Obstetric Conditions. viewed the clinical trial in positive terms. currently being completed. Data from London: RCOG; 2015. Issues relating to informed consent were previous human trials of VEGF gene 3. EVERREST Consortium. EVERREST: Maternal Growth key considerations for many of the therapy in cardiovascular and peripheral Factor Therapy to Improve Fetal Growth. [Online]. respondents; both women and stake- vascular disease show good long-term Available from: www.everrest-fp7.eu [accessed 27 holders highlighted the importance of safety, and our pre-clinical studies April 2016]. having sufficient information, support and 4. Lees C., Marlow N., Arabin B. et al. Perinatal demonstrate no fetal vector transfer. The morbidity and mortality in early-onset fetal growth time in which to make a decision to take attitudes of the women and stakeholders restriction: cohort outcomes of the trial of random- part. All of the women felt that they would that were interviewed support the ized umbilical and fetal flow in Europe (TRUFFLE). have been capable of freely deciding continuation of the EVERREST project. Ultrasound Obstet Gynecol 2013;42:400-08. Andraweera P.H., Dekker G.A., Roberts CT. whether or not to participate, with most of The views expressed by the women in our 5. The the women saying that they would have vascular endothelial growth factor family in adverse study echo the findings of other qualitative pregnancy outcomes. Hum Reprod Update wanted to participate in such a trial. studies exploring women’s experiences of 2012;18:436-57. The literature review raised the issue of obstetric research, and support the 6. Hedman M., Muona K., Hedman A. et al. Eight-year whether it was ethically acceptable to give development of maternal and fetal safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer. Gene an intervention which might lead to a baby therapies in general. surviving with severe disabilities when Ther 2009;16:629-34. To find out more about the EVERREST 7. David A.L., Torondel B., Zachary I. et al. Local otherwise it would have died in utero. Over project visit www.everrest-fp7.eu delivery of VEGF adenovirus to the uterine artery half of the women interviewed felt that this increases vasorelaxation and uterine blood flow in was acceptable, as long as the disability was Funding the pregnant sheep. Gene Ther 2008;15:1344-50. 8. Mehta V., Abi-Nader K.N., Peebles D.M. et al. Long- not due to a complication of the trial Magnus Growth, a Magnus Life Science intervention. However, a minority of term increase in uterine blood flow is achieved by programme, is part of the EVERREST local overexpression of VEGF-A(165) in the uterine women did not feel that this was accep- Consortium working to support the arteries of pregnant sheep. Gene Ther 2012;19: table, because of the long-term impact on ongoing translation of maternal growth 925-35. the child and family. While most 9. Carr D., Wallace J.M., Aitken R.P. et al. factor gene therapy. The research leading to respondents were not concerned about the Uteroplacental adenovirus VEGF gene therapy these results has received funding from the use of maternal gene therapy, one of the increases fetal growth velocity in growth-restricted European Union Seventh Framework sheep pregnancies. Hum Gene Ther 2014;25:375-84. German stakeholders felt that this would Programme (FP7/2007–2013) under grant 10. Swanson A., Rossi C., Ofir K. et al. Maternal uterine be unacceptable in Germany. Interestingly agreement no. 305823. artery gene therapy with Ad.VEGF-A165 increases this opinion was not shared by the German weight at term in a guinea pig model of fetal women interviewed. References growth restriction. Hum Gene Ther 2015;26:A14. There are still many regulatory 11. Sheppard M., Spencer R.N., Ashcroft R. et al. Ethics 1. World Health Organization. The Global Burden of challenges before a trial of maternal gene and social acceptability of a proposed clinical trial Disease: 2004 Update. [Online] 2008. Available from: using maternal gene therapy to treat severe early- therapy for placental insufficiency can take www.who.int/healthinfo/global_burden_disease/ onset fetal growth restriction. Ultrasound Obstet place. Among these will be demonstrating 2004_report_update/en/ [accessed 27 April 2016]. Gynecol 2016;47:484-91.

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