Some drugs used to treat HIV and cancer, while effective, are known to cause neurological side effects in a significant number of patients. These side effects can include confusion, memory issues, and even permanent nerve damage. Kamal Seneviratne, an assistant professor of chemistry and biochemistry, has been investigating how these drugs impact the brain in hopes of reducing their harmful effects.
Seneviratne's lab previously published research showing that the HIV drug efavirenz disrupts lipid metabolism in specific regions of the brain. This work was among the first to highlight how such drugs can upset the balance of lipids—molecules essential for healthy brain function.
The Maryland Stem Cell Research Fund (MSCRF) has now awarded Seneviratne a $350,000 grant to further this research. The team will study not only efavirenz but also dolutegravir (another HIV medication) and oxaliplatin, a chemotherapy agent. Their focus is on understanding how these drugs may damage brain cells over time.
Nav Phulara, a Ph.D. candidate who led the earlier study, will continue to play a key role in the new research alongside other students from UMBC.
A collaboration with neurologist Jinchong Xu at Johns Hopkins University allows the team to use human neural cells grown into "brain organoids"—clusters of human brain cells developed from stem cells. According to Seneviratne: "Animal studies are useful, but there are major limitations due to species differences. It is extremely difficult to obtain human brain tissues," he 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."
The researchers use mass spectrometry imaging (MALDI MSI), which enables them to visualize molecules directly within intact tissues and pinpoint where various molecules accumulate in the brain organoids. They combine this approach with proteomics—the comprehensive study of proteins—to track both drug distribution and disruptions in lipid balance caused by these medications.
Seneviratne explains: "We want to understand the 'how' behind the damage," he says. "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."
Their approach extends beyond lipids; they also examine metabolites and proteins affected by drug exposure. For example, previous findings showed that efavirenz alters levels of ceramides—a type of lipid—and impacts ceramide synthases, which are enzymes involved in producing ceramides. The upcoming research will monitor changes in ceramide synthase expression across different cell types within organoids.
By integrating advanced imaging techniques with proteomics and using human-derived organoids that closely mimic real brain tissue, Seneviratne’s project aims to provide insights that could lead directly to better patient outcomes.
The MSCRF grant may also foster future commercial applications by supporting technology transfer efforts intended to move discoveries from academic labs into industry settings.
"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."
