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Genetic discovery calls for precision approach to preterm birth therapy

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A new US study has for the first time identified genetic variants that predict whether patients will respond to treatment for preterm birth, a condition that affects one in 10 infants born in the United States. 

The findings are critical because no medication is available in the US to treat preterm birth.

In 2023, the Food and Drug Administration (FDA) pulled the only approved therapy to help prevent this condition, a synthetic form of progesterone sold under the brand name Makena, from the market, citing ineffectiveness.

The new study found that pregnant individuals with high levels of mutations in certain genes – specifically those associated with involuntary muscle contraction – were less likely to respond to the treatment.

Screening for the mutations could enable doctors to target the medication to those most likely to benefit, the authors suggest.

The study was led by Jingjing Li, PhD, associate professor in UCSF’s Department of Neurology and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.

The researcher said: “This study calls for a precision framework for future drug development.

“In addition to understanding drug effects based on population averages, we also need to take into account the drug response of each individual patient and ask why some respond and some don’t.”

Preterm birth, or babies born alive before 37 weeks of gestation, is the leading cause of infant mortality and affects some 15 million pregnancies worldwide each year.

Preterm birth also leads to a range of long-term health consequences including neurological impairments such as cerebral palsy, breathing problems, developmental disabilities, visual and hearing impairments, heart disease and other chronic illnesses.

To conduct the study, researchers developed a machine-learning framework to analyse genomes of 43,568 patients that had spontaneous preterm births.

This approach uncovered genes that had not previously been known to be associated with preterm birth.

The researchers then examined mutations in the genes among those who had received the progesterone treatment Makena.

The FDA had approved the drug in 2011 after a single clinical trial but removed it from the market last spring after concluding the drug didn’t work.

The decision left doctors without an approved medication for preterm birth and frustrated those who had found it effective for a subset of patients.

This posed the question: Could there be a genetic reason why progesterone therapy worked for some patients, but not for others?

The research team discovered that the patients in the group with low levels of mutations in the genes associated with muscle contractions were more likely to respond to Makena, but those with higher levels tended not to respond.

The finding indicates a personalised medicine approach that involves genetic screening could lead to successful results in patients without a high burden of those mutations.

First author, Cheng Wang, PhD, a postdoctoral scholar at UCSF, said: “Progesterone therapy was the only treatment for recurrent preterm birth over the past decade, and its recent withdrawal by the FDA has left a void in the medication options available for preterm birth patients,” said the study’s .

“In previous clinical practice, we did see that many patients benefited from progesterone therapy.

“We probably should re-evaluate its efficacy, if we can identify those who respond positively to the treatment.”

The researcher team included a cohort of African American patients in the study to determine whether the findings applied broadly across different races.

Black women in the US are almost twice as likely to give birth prematurely than white women.

The researchers found that the genetic burden did not vary by race, suggesting that the high rate of preterm birth among Black mothers may be due primarily to environmental factors such as elevated stress hormones, health care biases and lack of prenatal care.

The scientists then went beyond that finding to identify new targets and potential therapies to treat preterm birth.

The researchers screened more than 4,000 compounds and homed in on 10 that were predicted to interact with the genes associated with preterm birth.

Many of these therapeutic compounds are already being used to treat cancer and other diseases, which means that these drugs could possibly be repurposed to help prevent preterm labour.

A top candidate is the small molecule RKI-1447, with the drug currently being used to treat cancer, glaucoma and fatty liver disease.

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