Brain Organoids Help Reveal Antiviral Drug’s Promise in Parkinson’s Disease

September 4, 2024

The antiviral drug tilorone may do more than just fight respiratory infections — it might also help halt neural degeneration in Parkinson’s disease (PD).

In a new study, NCATS scientists and their NIH colleagues tested tilorone’s effects in models of the brain cells involved in PD. The 3-D models, called organoids, can help scientists better predict which promising drugs, like tilorone, will work in people.

“By establishing tilorone as a potential therapeutic agent, this study underscores the utility of 3-D midbrain organoids as a powerful tool for preclinical evaluation,” said Qi Zhang, Ph.D., the study’s lead author and a researcher in NCATS’ Division of Preclinical Innovation.

The study by researchers at NCATS, the National Cancer Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) appeared in the Journal of Translational Medicine.

Parkinson’s disease is a debilitating neurodegenerative disorder that affects the substantia nigra. The substantia nigra is the region of the brain that controls movement. Many of the PD-damaged cells in this region contain clumps of a misfolded protein, alpha-synuclein (alpha-syn), that normally helps nerve cells communicate with each other. The faulty protein’s role in the PD process makes it a potential therapeutic target.

Organoids Deliver a Better Brain Model

The lack of effective methods for drug screening has been a major obstacle in developing treatments to slow or stop PD. The new brain-tissue organoids offer hope for a more precise model to study disease and speed drug discovery and development.

“Organoids offer a highly accurate model for PD research and enable deeper insights into the causes of the disease,” explained Yihong Ye, Ph.D., a senior investigator at NIDDK and one of the study’s corresponding authors. “By replicating key aspects of human brain biology, organoids allow us to explore disease progression and potential treatments in a way that traditional models simply cannot achieve.”

The NIH research teams built organoids from human induced pluripotent stem cells. The organoids mimic many of the substantia nigra’s cellular structures and functions. The scientists then exposed the organoids to preformed strands of the misfolded alpha-syn protein. The strands triggered PD-like pathology in the organoids, creating a robust platform for testing potential treatments.

Organoids Highlight Tilorone’s Promise

The researchers chose to test tilorone after it showed promise in preventing strands of misfolded alpha-syn from entering cells. The antiviral is not approved for use in the United States, but it is used in other countries to treat a range of illnesses, including hepatitis, influenza and other respiratory infections.

The earlier research that revealed tilorone’s potential involved simpler 2-D cell models. When the research team tested tilorone in their more complex 3-D organoids, they found it may have even more neuroprotective effects.

Tilorone significantly slowed cells’ uptake of alpha-syn strands in human organoids. The drug also reduced levels of phosphorylated alpha-syn, a biomarker linked with PD progression.

Tilorone treatment also reversed the alpha-syn strands’ damaging effects on cells’ mitochondria and on how cells process lipids. As a result, the drug reduced cell death triggered by exposure to the strands. The researchers also found that tilorone reduced neuroinflammation markers within the organoids. All of tilorone’s therapeutic effects happened at drug concentrations safe for brain cells in vitro.

“Organoids offer an efficient platform for preclinical drug development,” said Wei Zheng, M.D., Ph.D., one of the study’s corresponding authors and a group leader in NCATS’ Therapeutic Development Branch. “This research could significantly reduce the time and cost of bringing new treatments to people worldwide.”