Kv7 channel activators -a novel treatment for preterm labour?

Every year, over 40,000 babies are born too early. Whilst some of these babies will be healthy, many will die shortly after birth and those who survive risk developing lifelong disability or behavioural problems. Ideally, obstetricians would like to be able to predict which women are at risk of delivering their baby prematurely and prevent them going into labour too early. However, this is not yet possible and women present at hospital in preterm labour requiring drugs to stop their uterus (womb) from contracting. The drugs currently available are not very effective and there is a real need to develop better treatments. Our research has identified a new class of drugs (Kv7 channel activators) that can potentially stop the uterus from contracting. Before we can begin testing these drugs in pregnant women, we need to show that they are safe to use in pregnancy. Our project aims to do this and also to develop our understanding of how these drugs can target the uterus specifically.

Premature births (37/40 weeks of gestation) account for ~7% of the deliveries in the UK, yet 75% of neonatal deaths, and most admissions to intensive care occur in infants born before 32 weeks of gestation The cost of premature birth in the UK was recently estimated at #939 million/year and economic modelling suggests that delaying preterm birth by one week could save #260 million/year. The ultimate strategy for reducing the impact of preterm labour would be the development of a prediction tool with high sensitivity and specificity to enable early pregnancy stratification of women according to risk, and development of prophylactic therapy. However, in the absence of either, the development of effective tocolytics (drugs that inhibit uterine contractions) would be a major advance in management and prevention of preterm delivery. This application focuses on the unmet need to develop a safe and effective tocolytic therapy that can prolong gestation (when appropriate) for more than one or two days and improve neonatal outcomes for babies. The overarching goal of this project is to facilitate the translation of our recent novel animal and human in vitro data on Kv7 channels into a useful therapeutic tool for the treatment of preterm labour in women. Firstly, our aim is to provide ?proof of principle? data demonstrating that Kv7 activators can inhibit uterine contractions in vivo in pregnant mice (including preterm labour models) and that they are associated with limited side effects; an essential step in the translation pathway. Secondly, to enhance the potential for use of Kv7 channels modulators in pregnant women, the predominant Kv7 channel in myometrium from labouring women needs to be identified. Radio-telemetry will be utilised to measure uterine pressure and cardiovascular parameters and micro-ultrasound to assess uterine artery blood flow in vivo. Kv7 channel subunit composition and function will be explored, using combined electrophysiological/molecular approaches, in human myometrium from pregnant women (?labour). Together this programme of work will aid selection and development of specific Kv7 channel activators for translation to clinical studies.