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Developmental Biology - Preterm Birth

Can Acid Reflux Drugs Curb Preterm Births?

Research identifies a dozen drugs that reduce inflammation, as slowing the onset of pre-term birth...


Lansoprazole, an over-the-counter acid reflux drug often taken by pregnant women, may be a promising therapy to reduce preterm birth, according to a computational drug repurposing study testing several of the drugs on mice.

The study, published in JCI Insight, also identified 12 other FDA-approved drugs deemed safe in pregnancy. While these drugs include a variety of modalities, researchers found they all appear to affect the immune response implicated in preterm birth.
"Inflammation clearly plays a role in initiating labor and preterm birth. Immune pathways are significantly dysregulated in women who end up delivering preterm. They are also dysregulated in babies who are born early. However, we have seen from our previous work there is an interaction between the maternal and fetal immune systems and a breakdown in maternal-fetal tolerance."

Marina Sirota PhD, Assistant Professor, Pediatrics; member, Bakar Computational Health Sciences Institute, UCSF; and senior author of the study.

To identify candidate drugs that might be effective in preventing preterm birth, they first looked at which genes were increasing or decreasing production of blood cells in women experiencing spontaneous preterm birth. This was done to identify that gene's "expression signature."

They then looked for the opposite gene expression signature in cells exposed to 1,309 different drugs. Their reasoning being that if a drug could correct the effects preterm birth had on a woman's blood cells, that drug might also prevent preterm birth itself.

They identified 83 drug candidates after excluding any found to have risks to pregnancy in animal or human studies. This produced a list of 13 drugs, ranked according to their "reversal score," a measure of the extent to which that drug was able to reverse the gene expression signature of preterm birth.
Drugs identified for a "Pre-term Reversal Score"

Progesterone in use against recurrent preterm birth
Folic Acid given in pregnancy to prevent birth defects
3 Antibiotics
1 Antifungal
1 Antidepressant
1 Anti-Diabetic
1 Blood Pressure control medication.

That predictable drugs like progesterone came up in this screening gave researchers confidence these drugs may be effective when tested in pregnant women. Folic acid, clotrimazole and metformin have also been shown in previous studies to be effective against preterm birth.
"Finding progesterone on the list was a promising validating step. Four of the drugs on our list have seen effectiveness in past studies that were either experimental or retrospective. This leads us to believe in the biology behind their identification."

Brian Le PhD, postdoctoral scholar, UCSF Department of Pediatrics, the Bakar Computational Health Sciences Institute and first author of the study.

Researchers chose lansoprazole for further testing as in addition to its high reversal score, it is available over the counter. It is also known, from their prior research, as an affective stress-response protein against heme oxygenase-1, previously linked with pregnancy disorders. Lansoprazole is a proton-pump inhibitor marketed as Prevacid. It had the second-highest reversal score of the 13 drugs identified as safe and effective. Progesterone was further down that list.

The scientists tested lansoprazole in pregnant mice given a bacteria to induce inflammation. This caused some fetuses to die in utero, where they were reabsorbed. When the same mice were treated with lansoprazole, they had more viable fetuses. Lansoprazole also gave better results than progesterone.

Although a good measure of how inflammation affects pregnancy in mice, this mouse model isn't adequate as a model of human preterm birth without more work, including human trials. Much more work has to be done before lansoprazole or any of the dozen other drugs identified can be proven effective in pregnant women.
"This is basically a "proof of concept" that this drug has anti-inflammatory properties which are not properties the drug was designed for. This is a short way to get to new therapeutics for known diseases."

David K. Stevenson MD, Professor, Pediatrics, Stanford University, author on the study.

Abstract
Few therapeutic methods exist for preventing preterm birth (PTB), or delivery before completing 37 weeks of gestation. In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness, working in only approximately one-third of cases. Computational drug repositioning leverages data on existing drugs to discover novel therapeutic uses. We used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, had significantly reversed differential gene expression compared with that found for PTB. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B indicating no known risk in human pregnancy. We focused our validation efforts on lansoprazole, a proton-pump inhibitor, which has a strong reversal score and a good safety profile. We tested lansoprazole in an animal inflammation model using LPS, which showed a significant increase in fetal viability compared with LPS treatment alone. These promising results demonstrate the effectiveness of the computational drug repositioning pipeline to identify compounds that could be effective in preventing PTB.

Authors
Brian L. Le, Sota Iwatani, Ronald J. Wong, David K. Stevenson and Marina Sirota.


Aknowledgments
The authors thank Aolin Wang, Idit Kosti, and Bianca Vora for useful discussions. This project was in part supported by the March of Dimes and NIH grant NLM K01LM012381. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the March of Dimes.


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Feb 20 2020   Fetal Timeline   Maternal Timeline   News 



Partial differential gene expression heat map. A meta-analysis of 10 computationally identified drugs
in pregnancy. Each row corresponds to a gene (top to bottom). A rank-based coloring scheme ordered from left to right by inflamation reversal score (most negative to least negative). Bluer color corresponds to more downregulated genes, and redder color corresponds to more upregulated genes.
CREDIT The Authors.


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