Important FDA-approved drugs to treat HIV and cancer can save lives, but they come with their own risks. Some drugs used clinically are known to cause neurological side effects in up to half of patients, ranging from confusion and memory problems to permanent nerve damage. Kamal Seneviratne, assistant professor of chemistry and biochemistry, has been studying exactly how these drugs harm the brain, in an effort to mitigate their negative effects.
Last year, Seneviratne’s lab published the first study to reveal disruptions to brain lipid metabolism in response to the HIV drug efavirenz. The study began to show how the drug throws the brain’s lipid chemistry out of balance in specific brain regions.
Now, the Maryland Stem Cell Research Fund (MSCRF) has awarded Seneviratne a $350,000 grant to continue this promising line of work. He and his students will investigate how drugs currently in use such as efavirenz, dolutegravir (another HIV drug), and a common chemotherapy agent (oxaliplatin) can damage brain cells over time.
Nav Phulara, a Ph.D. candidate in Seneviratne’s lab, was first author on the 2024 paper and will again take a leading role in the upcoming work, alongside other UMBC graduate and undergraduate students.
From ‘what’ to ‘how’
Work supported by the new grant will take advantage of Seneviratne’s collaboration with neurologist Jinchong Xu at Johns Hopkins University, who works with human neural cells. The research team will run their trials in miniature human “brain organoids”—clusters of human brain cells grown in the lab from stem cells. Organoids mimic the physiology of a human brain far better than animal models ever could.
“Animal studies are useful, but there are major limitations due to species differences. It is extremely difficult to obtain human brain tissues,” Seneviratne says. “That’s why our collaboration with Dr. Xu has been a game-changer. With the organoids, we will finally see how these drugs behave inside human brain tissue.”
A high-resolution approach Seneviratne’s lab employed for their 2024 paper visualizes molecules directly in intact tissues, whereas other methods require grinding up the samples. The technique, a type of mass spectrometry imaging (MSI) called MALDI MSI, allows researchers to determine not only how much of various molecule types are present in the brain, but exactly where.
Seneviratne and his collaborators will be using this technique in combination with proteomics—the large-scale study of all proteins in a cell or tissue—in their MSCRF-funded work to track exactly where the drugs and their breakdown products travel inside the brain organoids and how they disturb the brain’s lipid balance. Lipids are essential for brain cells to communicate and survive, so when their function is impaired, brain cells can die, contributing to long-term neurodegeneration.
“We want to understand the ‘how’ behind the damage,” says Seneviratne. “If we can pinpoint the exact molecular warning signs, clinicians and drug companies could one day screen new medicines early in their development to help avoid these risks.”
A holistic approach
The team’s approach is deliberately holistic, extending beyond lipids to other metabolites and key proteins. For example, the 2024 study found that efavirenz disrupts the level of ceramides, a class of lipids. Ceramide synthases are key proteins that produce structurally diverse ceramides, so in their upcoming work, the researchers will track changes in ceramide synthase expression across different brain cell types in the organoids. They hope to reveal broader molecular pathways affected by the drugs and identify potential early biomarkers of neurotoxicity.
“I’m driven by the scientific questions, not any single technique,” Seneviratne explains. “We’ll use whatever tools—imaging, proteomics, molecular biology, biochemical analyses—best let us answer them.”
By combining high-resolution MALDI MSI and proteomics with human brain organoids that contain the full neighborhood of neural cells, the project offers a highly relevant picture of drug-induced damage—helping bridge the gap between scientific discoveries and patient outcomes.
The grant also opens a path for future impact. Part of the goal of the MSCRF is to encourage technology transfer, meaning discoveries could eventually lead to a startup company and new tools for the pharmaceutical industry.
“This support lets us turn promising science into something that can genuinely help people,” Seneviratne says. “Ultimately, we hope to give clinicians better ways to protect the brain while treating deadly diseases."