Jefferson Investigates: Neonatal Opioid Withdrawal Syndrome, Amyotrophic Lateral Sclerosis, & Herniated Discs

As the opioid crisis continues, the number of babies born with neonatal opioid withdrawal syndrome (NOWS) – a condition that affects infants whose mothers used opioids during pregnancy – has risen 5-fold over the past 20 years. According to the Centers for Disease Control (CDC), there are 20,000 infants a year in the United States born with signs of NOWS. These infants often require extended hospital stays and, in some cases, treatment with medications like morphine to relieve withdrawal symptoms.

A new study from Walter Kraft, MD, an internist and clinical pharmacologist at Thomas Jefferson University, and his team further explored the potential of ondansetron, a medication commonly used to treat nausea and considered safe during pregnancy, to help reduce withdrawal symptoms in newborns with NOWS.

The research expands on data from Dr. Kraft's previous work, along with collaborators at Stanford University, of a clinical trial conducted at Jefferson and other sites. That study explored the impact of ondansetron in 90 infants and found that it significantly reduced the severity of withdrawal symptoms. 

The current investigation, led by first author Kevin Lam, PharmD, used Bayesian population pharmacokinetic modeling – a mathematical method that describes how different patients process a drug – to identify the concentration of ondansetron that would lead to symptom relief. The model can be used to simulate optimized ondansetron doses.

“In the past, we might have used gut intuition and said, ‘Let’s just double the dose,’” Dr. Kraft said. “Now we can use mathematical modeling to be much more likely to find an effective dose and require fewer patients to enroll in a clinical trial.”

Dr. Kraft, who is also a faculty member at Sidney Kimmel Medical College, says his team is seeking funding for future clinical trials to explore whether ondansetron can reduce the number of symptoms experienced by infants with NOWS or shorten their hospital stay.

“This is a complex medical and societal issue. There’s unlikely to be a single solution," Dr. Kraft said. "We’re optimistic that ondansetron may be part of a multi-pronged approach to improving care for these infants.”

By Queen Muse

Amyotrophic lateral sclerosis (ALS) is a disease that destroys the nerves necessary for movement. About 30,000 people in the United States are affected, and doctors still don’t know what causes it. To lay the groundwork for better tests, Thomas Jefferson University researchers Phillipe Loher, Eric Londin, PhD, and Isidore Rigoutsos, PhD are taking a computational biology approach to see how ALS affects molecules in the blood.

In a study published in Molecular Neurobiology, the team analyzed blood samples from about 300 people with and without ALS. The research focused on small non-coding RNAs (sncRNAs), short molecules that help regulate gene expression and other important cellular processes. Past work from Dr. Rigoutsos and his team at the Jefferson Computational Medicine Center had shown that Parkinson’s disease affected sncRNA levels in the blood. Dr. Rigoutsos wanted to see if that was true for ALS as well.

The team discovered that people with ALS had different combinations of sncRNAs compared to people without, and certain sncRNAs were even associated with how long a person lived after being diagnosed.

Interestingly, the analyses also revealed some sncRNAs that didn’t belong to the human genome.

“A lot of the molecules that change with the disease come from bacteria or fungi,” Dr. Rigoutsos said. While the team doesn’t know whether these changes are a cause or the effect of ALS, the results point towards the microbiome playing an important role in the condition.

Dr. Rigoutsos says that a computational biology approach, which analyzes massive quantities of data to find hidden patterns of sncRNAs, will be key for understanding neurodegenerative diseases like ALS and creating better diagnostics and prognostics for more accurate survival times.

“We can do tests on the computer that would take many months, if not years, to do in the lab,” he said. “It goes beyond the kinds of things that a person can do simply by looking at a spreadsheet.”

By Marilyn Perkins

As people grow older, changes in the spine can lead to low back pain, which in turn, can become a chronic disability. Understanding how spinal discs – soft cushions tucked in between the vertebrae – function is crucial to inform clinical practice. With injury or age-related degeneration, the disc’s soft center bulges out and presses on nerves, resulting in pain.

A new animal model of disc pathology may provide important answers, according to new research by a Thomas Jefferson University team led by Makarand Risbud, PhD, James J Maguire Jr. Professor of Spine, Research and a musculoskeletal cell biologist. “The spinal disc is an understudied tissue,” Dr. Risbud says. “But disc herniation is a huge clinical problem.”

In the study published in Science Advances, Dr. Risbud and his colleagues, including a former M.D., Ph.D. student Emanuel Novais and recent Ph.D. graduate Olivia Ottone, describe a specific strain of inbred mice that form bulging or herniated discs naturally, and is accompanied by pain, cellular changes, and altered immune responses.

“It was a surprise to find a mouse strain that spontaneously develops herniated discs,” Dr. Risbud says. Previous models have used injury to actively trigger the condition in mice, but this does not necessarily mimic the spontaneous disease process seen in people.

For instance, the researchers detected changes in the immune system that occurred prior to the disc troubles. This was surprising because immune responses are typically thought to come after injury or infection, not precede it. Dr. Risbud will continue to study whether this immune dysregulation is triggering disc herniation in some way. The model also allows his team to explore possible genetic influences that predispose animals to disc pathology.

In addition to enabling researchers to study the biology of disc herniation, the new animal model might reveal how disc problems can progress to chronic pain. This is a big unknown in clinical medicine. “Out of 10 patients with pain from herniated discs, 7 or 8 will resolve,” Dr. Risbud says. “But the other 2 or 3 will not and that leads to chronic pain. We do not yet understand why.”

By Jill Adams