MICA: MRC EVERREST: A Pre-clinical Efficacy Study for FGR

胎儿生长受限是一种可能危及生命的妊娠并发症，影响约8%的妊娠，导致全球50%的死产。生长受限妊娠所生的婴儿不仅面临围产期死亡和脑瘫等并发症的风险增加，而且会产生长期的健康后果，包括糖尿病和心血管疾病。近年来对早产儿产后护理的改进意味着更多的早产儿能在分娩后存活下来，但代价高昂。最常见的是子宫血流不足，称为“胎盘不通畅”，是潜在的异常。这限制了营养物质和氧气在子宫内向婴儿的输送，这意味着它生长不良。目前还没有治疗和干预措施可以改善子宫血流和恢复胎儿生长。大约每500例中就有1例婴儿在怀孕中期生长受限。一旦发现这种严重的早发性胎儿生长受限，夫妇们目前面临着一个严峻的选择，要么在知道他们可能会在新生儿重症监护室死亡的情况下过早地分娩他们的婴儿，要么允许怀孕继续，婴儿很可能会在子宫内死亡。这些早产儿中有许多在出生后要在医院呆上几个月，这对父母来说是一种压力，对NHS来说也是一种昂贵的负担。在过去的12年里，UCL的研究人员与Trizell Limited进行的研究发现，在正常妊娠中，通过向子宫动脉输送含有血管内皮生长因子（VEGF）的基因药物，可以增加流向胎盘的母体血流量。在生长受限妊娠的临床前研究中，基因药物安全地增加了胎儿生长和出生体重。最有希望的是，胎儿生长和分娩时胎龄的相对较小的增加与存活率和发病率的重大改善有关。例如，随着怀孕时间的延长，怀孕24至27周，出生后的存活率提高了2%。研究人员与利益相关者团体和受胎儿生长受限影响的患者进行了讨论，以评估在怀孕期间使用这种基因药物的伦理和社会可接受性。这种治疗被认为是积极的，没有任何伦理问题。基因药物的临床前毒理学研究显示了令人放心的安全性。临床试验基因药物现在已经为第一批病人生产好了。该团队将使用临床试验基因药物在经过充分验证的胎儿生长受限动物模型（母体营养限制豚鼠）中进行临床前研究。豚鼠幼仔在妊娠中期生长受限。我们将发现在豚鼠妊娠中期应用这种新药是否安全有效地增加妊娠末期的胎儿生长。我们将研究药物是如何起作用的，它是否穿过胎盘到达豚鼠幼崽，以及是否有任何伤害的证据。我们计划测试两种剂量的基因药物，看看最佳剂量是什么。如果成功，我们将利用这些数据寻求监管和伦理批准，进行首次人体临床试验，以确定干预的安全性和有效性。这项研究可以在产科领域开发一种高度创新的新疗法，这是一个目前缺乏新治疗投资的专业。这项研究的好处可能包括减少死产和新生儿死亡，以及改善受胎儿生长受限影响的妊娠结局。

Fetal growth restriction is a potentially life-threatening pregnancy complication affecting about 8% of all pregnancies, contributing to 50% of stillbirths globally. Babies born from growth restricted pregnancies are not only at increased risk of perinatal death and complications such as cerebral palsy, but have long term health consequences including diabetes and cardiovascular disease. Recent improvements in the postnatal care of premature growth restricted babies means that more of them survive delivery, but at great cost.Most commonly inadequate uterine blood flow, termed 'placental insufficiency', is the underlying abnormality. This restricts delivery of nutrients and oxygen to the baby in the womb meaning that it grows poorly. There is no therapy available and no intervention that can improve uterine blood flow and restore fetal growth.In around 1 in 500 cases the baby is found to be growth restricted in mid pregnancy. Once this severe early onset fetal growth restriction is identified, couples currently face a stark choice between delivering their baby very prematurely in the knowledge that they might die in the neonatal intensive care unit, or allowing the pregnancy to continue with the strong likelihood that the baby will die in the womb. Many of these premature, very small babies stay in hospital for months after birth, which is stressful for parents and very costly for the NHS.Studies performed over the last twelve years by researchers at UCL with Trizell Limited have identified that maternal blood flow to the placenta could be increased in normal pregnancies by delivering a gene medicine containing the Vascular Endothelial Growth Factor (VEGF) to the uterine arteries. In pre-clinical studies of growth restricted pregnancies, the gene medicine safely increased fetal growth and birthweight. What is most promising is that relatively small increases in fetal growth and gestational age at delivery are associated with major improvements in survival and morbidity. For example, as each day of pregnancy advances between 24 and 27 weeks of gestation, there is a two per cent improvement in survival after birth.The researchers have discussed with stakeholder groups and patients affected by fetal growth restriction to evaluate the ethical and social acceptability of using this gene medicine in pregnancy. The treatment was viewed positively with no ethical concerns. Pre-clinical toxicology studies on gene medicine have shown reassuring safety. The clinical trial gene medicine is now manufactured ready for the first patients. The team will perform a pre-clinical study using the clinical trial gene medicine in a well validated animal model of fetal growth restriction, the maternal nutrient restricted guinea pig. Guinea pig pups become growth restricted in mid-pregnancy. We will find out if the application of this novel medicine in the middle of guinea pig pregnancy safely and effectively increases fetal growth at the end of pregnancy. We will study how the drug works, if it crosses the placenta to the guinea pig pups, and if there is any evidence of harm. We plan to test out two doses of the gene medicine to see what the best dose may be.If successful we will use this data to seek regulatory and ethical approval to conduct the first-in-human clinical trial to determine the safety and efficacy of the intervention.This research could enable the development of a highly innovative new therapy in the field of obstetrics, a specialty in which there is currently a lack of investment in new treatments.Benefits from this research could include reduced stillbirths and neonatal deaths, and improved outcome in pregnancies affected by fetal growth restriction.