New funding supports research into drug-induced brain toxicity

New funding supports research into drug-induced brain toxicity

Important FDA-approved drugs to treat HIV and cancer can save lives, but they come with their own risks. Some clinically used drugs are known to cause neurological side effects in up to half of patients. These side effects range from confusion and memory problems to permanent nerve damage. Kamal Seneviratne, assistant professor of chemistry and biochemistry, has been studying how these drugs damage the brain to reduce their negative effects.

Last year, Seneviratne's lab published the first study revealing disruptions in brain lipid metabolism in response to the HIV drug efavirenz. This study began to showHowThe drug imbalances the lipid chemistry of the brain in certain regions.

Now the Maryland Stem Cell Research Fund (MSCRF) has awarded Seneviratne a $350,000 grant to continue this promising work. He and his students will study how drugs currently in use, such as efavirenz, dolutegravir (another HIV drug) and a common chemotherapy drug (oxaliplatin), can damage brain cells over time.

Nav Phulara, a graduate student in Seneviratne's lab, was first author of the paper published in 2024 and will continue to play a leading role in upcoming research, along with other graduate and undergraduate students at UMBC.

From 'what' to 'how'

The research supported by the new grant leverages Seneviratne's collaboration with Johns Hopkins University neurologist Jinchong Xu, who works with human nerve cells. The research team will conduct their experiments in miniature human “brain organoids” – collections of human brain cells grown in the laboratory from stem cells. Organoids mimic the physiology of a human brain much better than animal models.

"Animal studies are useful, but there are significant limitations due to species differences. It is extremely difficult to obtain human brain tissue," says Seneviratne. "That's why our collaboration with Dr. Xu was a turning point. With the organs, we will finally see how these drugs work in the human brain."

A high-resolution approach that Seneviratne's lab used for their study published in 2024 visualizes molecules directly in intact tissue, while other methods require chopping the samples. The technique, a type of mass spectrometry imaging (MSI) known as MALDI MSI, allows researchers to determine not only how much of different types of molecules is present in the brain, but also exactly where.

Seneviratne and his collaborators will use 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 in brain organoids and how they disrupt the balance of lipids in the brain. Lipids are crucial for the communication and survival of brain cells, which is why their impairment can lead to brain cell death and, in the long term, contribute to neurodegenerative diseases.

“We want to understand the ‘how’ behind the damage,” says Seneviratne. “If we can pinpoint the precise molecular warning signals, clinicians and pharmaceutical companies could one day test new drugs early in their development to avoid these risks.”

A holistic approach

The team's approach is intentionally holistic, going beyond lipids to other metabolites and key proteins. For example, the 2024 study found that efavirenz disrupts levels of ceramides, a class of lipids. Ceramide synthases are key proteins that produce structurally diverse ceramides. In their upcoming work, the researchers will track changes in the expression of ceramide synthases in 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 by a single technique. We will use the tools - imaging, proteomics, molecular biology, biochemical analyzes - that best help us answer these questions."

Kamal Seneviratne, assistant professor of chemistry and biochemistry

By combining high-resolution MALDI MSI and proteomics with human brain organoids containing the full neighborhood of neurons, the project provides a highly relevant picture of drug-induced damage and helps bridge the gap between scientific discoveries and patient outcomes.

The grant also opens a path for future impact. Part of the MSCRF's goal is to promote technology transfer. This means discoveries could ultimately lead to a start-up company and new tools for the pharmaceutical industry.

“This support allows us to turn promising science into something that can really help people,” says Seneviratne. “Ultimately, we hope to provide clinicians with better ways to protect the brain during the treatment of fatal diseases.”

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