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Effort seeks to improve safety of drugs given during pregnancy

Jul. 18, 2019, 9:53 AM

 

by Bill Snyder

A 19-year-old student at Vanderbilt University is leading a multi-institutional collaboration to identify — using computer-based approaches — drugs that can be prescribed safely to pregnant women without harming the fetus.

Anup Challa

Called MADRE, for Modeling Adverse Drug Reactions in Embryos, the effort is melding structure-based predictions of adverse drug outcomes with real-life data from electronic medical records and insurance claims. The goal is to avoid bad outcomes caused by exposure to medications in the womb.

Physicians are often unsure whether they can safely prescribe drugs for chronic conditions to women once they become pregnant. “We anticipate our tool will help solve that uncertainty,” said Anup Challa, MADRE’s principal investigator, who is working simultaneously on his bachelor’s and master’s degrees in chemical engineering at Vanderbilt.

“Pregnancy has long been a ‘third rail’ in drug development,” added Challa’s mentor and colleague, David Aronoff, MD, the Addison B. Scoville Jr. Professor of Medicine and director of the Division of Infectious Diseases in the Vanderbilt University School of Medicine.

“There aren’t a lot of clinical trials including pregnant women or new drugs for pregnancy-specific problems such as preeclampsia (pregnancy-associated hypertension) or gestational diabetes, in large part because there is great fear … about (harming) the developing fetus,” said Aronoff, who also is a professor of Obstetrics and Gynecology.

“What could be transformative would be to have tools that tell us that an existing, safe drug might be ‘repurposed’ to prevent an adverse pregnancy outcome,” he said. “I think (MADRE) is a really wonderful way to leverage our new science of ‘omics’ and informatics to improve maternal-child health.”

Aronoff directs the Preventing Adverse Pregnancy Outcomes & Prematurity (Pre3) Initiative, an interdisciplinary group of faculty and students who are working to prevent adverse pregnancy outcomes and prematurity through education, research and innovation.

MADRE is pushing those frontiers by developing a suite of predictive tools that integrate more than 2 million electronic medical records at Vanderbilt University Medical Center with the chemical structures of all known drug molecules. It also works to supplement these models with nearly 60 million insurance claims housed at Harvard Medical School.

“We already have a well-working model for predicting fetal toxicity from (a drug’s) structural information,” Challa said. “The idea that you can take the inherent structure of a drug and predict its ability to harm the fetus is really powerful.”

MADRE collaborators include the following:

  • Andrew Beam, PhD, Department of Epidemiology, Harvard T.H. Chan School of Public Health;
  • Jeffery Goldstein, MD, PhD, Department of Pathology, Feinberg School of Medicine at Northwestern University;
  • Ethan Lippmann, PhD, Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering;
  • Lisa Bastarache and Joshua Denny, MD, Vanderbilt Center for Precision Medicine; and
  • Robert Lavieri, PhD, and Jana Shirey-Rice, PhD, Vanderbilt Institute for Clinical and Translational Research (VICTR).

Last year Aronoff, Denny, and colleagues reported on a concept they dubbed “PregOMICS,” the application of systems biology and bioinformatics to repurpose drugs already on the market as a rapid and low-cost way to identify new therapies for the rising tide of obstetrical diseases.

Challa began working with VICTR’s drug repurposing team in late 2017 during his freshman year at Vanderbilt. A stand-out science student at White Station High School in Memphis, he’d already first-authored a scientific paper on the use of informatics to identify gene expression therapy for breast cancer patients.

Encouraged to pursue science as a career by his father, an entomologist, and his mother, a biochemist by training, Challa chose to come to Vanderbilt because of what he describes as “a very productive and very fertile place for cross-institutional research.”

This summer he’s working in Rockville, Maryland, at the National Center for Advancing Translational Sciences, part of the National Institutes of Health, which is funding the MADRE project through VICTR.

Challa “is an all-star, a fantastic thinker,” Aronoff said. “We’re on the same page of trying to think more creatively about how to protect the health of the developing fetus while improving the health of pregnant women. The world could use more people like Anup.”

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