Kv7 channel activators -a novel treatment for preterm labour?

Lead Research Organisation: King's College London
Department Name: Reproduction and Endocrinology

Abstract

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.

Technical Summary

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.
 
Description Curriculum development for a new MSc in Women and Children's health
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
URL https://www.kcl.ac.uk/study/postgraduate/taught-courses/women-and-childrens-health-msc.aspx
 
Description RO1
Amount $198,564 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 04/2018 
End 03/2023
 
Description Travel Award
Amount £700 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 02/2015 
End 04/2015
 
Description Travel Award
Amount £700 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 02/2016 
End 04/2016
 
Description Travel award
Amount £700 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 02/2014 
End 04/2014
 
Title Video recording of timing of birth 
Description Video capture of animals giving birth in cages 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2013 
Provided To Others? Yes  
Impact Reduction in use of uterine telemetry (surgical technique) 
 
Description Uterine Telemetry Collaboration 
Organisation Washington University in St Louis
Department Department of Obstetrics and Gynaecology
Country United States 
Sector Academic/University 
PI Contribution Training to undertake work planned on the grant. Training took place at the Washington University, St Louis USA.
Collaborator Contribution Provided a week long training session and continued advice for implementation of the technique in our laboratory.
Impact Technique has been implemented and data will be included in future publications More members of my team have been trained in the technique, including an MRC funded PhD student. He is now training others including colleagues from other UK institutions. We have achieved our aim which was to become an known UK hub for this technique. This has saved money as we have not needed to send others to the US to learn the technique.
Start Year 2012
 
Description Preterm Birth PCPIE group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Biannual PCPIE group to discuss all our research relating to Preterm Birth and pregnancy.
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
 
Description STEM for Girls Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Inspiring school girls to consider science subjects as a future career
Year(s) Of Engagement Activity 2018
URL https://scicommessentials.com/girls-in-stem
 
Description University College Dublin GL Brown Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Lecture to encourage early carer researchers to be interested in Physiology and research into Women's Health. Generated lots of questions and debate after the lecture and engaged with different students and academics after the lecture.
Year(s) Of Engagement Activity 2018
 
Description University of Aberdeen - Lecture to Researchers and Students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Invited research lecture - meet and discussed work with a number of academics and researchers prior to and after the lecture (approx 10).
Year(s) Of Engagement Activity 2019
 
Description University of Cambridge GL Brown Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Lecture to encourage early carer researchers to be interested in Physiology and research into Women's Health. Generated lots of questions and debate after the lecture and engaged with different students and academics before and after the lecture (whole day event)
Year(s) Of Engagement Activity 2018
 
Description University of Cardiff GL Brown Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Lecture to encourage early carer researchers to be interested in Physiology and research into Women's Health. Generated lots of questions and debate after the lecture and engaged with different students and academics before and after the lecture (whole day event). Midwifery students attended from a nearby but different institution. They emailed me afterwards asking whether they could have a PDF of my slides so they could use it for their reflective portfolio and to share with others.
Year(s) Of Engagement Activity 2017,2018
 
Description University of Edinburgh GL Brown Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Lecture to encourage early carer researchers to be interested in Physiology and research into Women's Health. Generated lots of questions and debate after the lecture and engaged with different students and academics before and after the lecture (whole day event). Following on from this undergraduates students who missed the lecture heard how good it was and asked whether I could send them my slides. i did this but also offered to meet with four students when i was next in Edinburgh and give them a seminar/tutorial. One student asked if she could keep in touch in order to maybe work with me in the future.
Year(s) Of Engagement Activity 2018
 
Description University of Manchester and Manchester Metropolitan University - GL Brown Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact This was the keynote at the all day annual Physiology symposium organised by Manchester Metropolitan University and the University of Manchester

Lecture to encourage early carer researchers to be interested in Physiology and research into Women's Health. Generated lots of questions and debate after the lecture and engaged with different students and academics before and after the lecture (whole day event).
Year(s) Of Engagement Activity 2018
 
Description University of Southampton GL Brown Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Lecture to encourage early carer researchers to be interested in Physiology and research into Women's Health. Generated lots of questions and debate after the lecture and engaged with different students and academics before and after the lecture (whole day event). There was a specific question and answer session with several PhD students afterwards to discuss careers and provide some informal mentoring.
Year(s) Of Engagement Activity 2018