Scientists have found that targeting a particular group of proteins in the uterus muscle (myometrium) can suppress human uterine contractions in laboratory studies and delay preterm birth in a preclinical model.
The findings, published today in Communications Medicine, highlight a potential future avenue for developing new drugs, or repurposing existing drugs, that act on these proteins to delay early labour.
In the study led by King’s College London, researchers looked at a group of proteins in the membranes of cells in the uterus wall called KV7 channels. Using a drug that activates these channels, they were able to reduce uterine contractions in human tissue and delay preterm birth in mice.
Preterm birth, defined as birth before 37 weeks of pregnancy, affects around 1 in 12 babies in the UK and is the leading cause of neonatal death worldwide. Babies born too early are at increased risk of serious health complications from birth and throughout their lives. Despite its substantial health burden, treatment options to prevent spontaneous preterm birth (when a mother goes into labour spontaneously) remain limited, partly because the biological pathways that trigger labour are not yet fully understood.
Rachel Tribe, Professor of Maternal and Perinatal Sciences at King’s College London and senior author of the paper, said: “For many years, my research team has focused on understanding what drives preterm birth and looking for predictors of early labour. About 6-7% of all pregnancies in the UK are preterm, with about two thirds of these due to a mother going into spontaneous labour early, often without any warning or notable risk factors – these are the women we want to help treat.
“We need new treatments to delay preterm birth and improve outcomes for babies, and our findings provide a proof-of-principle that specific types of KV7 channels could offer a promising target for drug development.”
KV7 channels are present throughout the body, including in smooth muscle found in the uterus wall. Activation of these channels regulates the movement of potassium in and out of cells, helping to control the electrical activity and contraction of uterine muscle.
The researchers looked at samples of human myometrium (the muscular layer of the uterus wall) collected from women during active preterm and term labour, and during caesarean section at term and preterm. By analysing gene and protein expression, they identified several KV7 channel components that were present in the myometrium in both term and preterm pregnancies, at the end of pregnancy and after labour had started.
They identified the main type of active KV7 channel (called KV7.4) present in the uterus, providing important information for the future development or repurposing of drugs that selectively target these channels.
The team then simulated uterine contraction in the lab, using myometrium tissue from humans and mice. When human and mouse tissue samples were treated with retigabine, a drug that opens KV7 channels, contractions were reduced. In a mouse model of preterm birth, retigabine delayed preterm delivery.
Iain Greenwood, Professor of Vascular Pharmacology at City St George’s University of London and co-author on the paper, said: “KV7 channels are key regulators of cellular physiology. Research into these important players is facilitated by the existence of many chemical modifiers of KV7 channels spawned by the discovery that boosting KV7 channel activity in neurones is an effective anti-epileptic mechanism. Repurposing some of these molecules may offer the potential of new treatments for labour issues sooner rather than later.”
Women experiencing preterm labour, who do not have an underlying infection, can be given medicines to delay labour temporarily, but current treatments offer only modest benefits and can cause side effects.
Against a backdrop of limited options for preventing spontaneous preterm labour, identifying a new biological pathway involved in regulating uterine contractions could open new opportunities for treatment development. In the future, this may help provide valuable time for interventions that improve outcomes for babies born too soon.
The authors say the next steps for this work include demonstrating the benefits to neonates in addition to delaying preterm birth. The researchers hope to translate these findings towards future clinical application by working in partnership with pharmaceutical companies and collaborators to investigate more targeted KV7 activators and innovative drug-delivery systems that target the uterus.