A team led by Professor Tsung-Hsien Chang at the National Defense Medical Center has successfully cultured human 3D brain organoids using induced pluripotent stem cells (iPSCs). This innovative platform holds great promise for the development of drugs against viral encephalitis, potentially accelerating the drug discovery process.
Viral Meningitis: Unclear Pathogenesis and Limited Drug Development
Viral meningitis is a serious disease that affects the central nervous system, potentially leading to brain dysfunction or even death. However, the pathogenesis of this disease remains poorly understood, and effective treatments are lacking. Current drug development relies mainly on 2D cell cultures and mouse models, but these models do not accurately reflect human physiology, leading to low success rates and high costs in drug development. Additionally, some viruses, such as Parechovirus (PeV-A3), do not effectively infect experimental animals, highlighting the urgent need for a drug development platform that closely mimics human physiology.
3D Organoids Accurately Simulate the Brain and Accelerate Drug Development
To address these challenges, the team cultured iPSCs into embryoid bodies, which were then induced to differentiate into neural spheroids. Finally, these were grown in a specialized medium to develop 3D organoids with brain-like structures and functions. These organoids contain various cell types, including neurons and neural progenitor cells, and exhibit a tissue structure similar to the human brain. This allows for a more accurate simulation of viral infections in the human body, providing a more predictive platform for drug development.
Using this platform, the team successfully demonstrated that PeV-A3 can infect human brain organoids, causing organoid shrinkage and neuronal damage. They also confirmed that interferon effectively inhibits the infection, proving the feasibility of using this platform for anti-viral drug screening. Additionally, by employing single-cell RNA sequencing, they analyzed gene expression changes in different cell populations before and after infection. They discovered that certain cell groups are more susceptible to PeV-A3, which could help elucidate the cellular and molecular mechanisms of viral infections and guide the development of more targeted therapies.
Beyond Animal Experiments: Organoid Models Lead the Way in Precision Medicine
Professor Tsung-Hsien Chang stated that, compared to traditional animal experiments, human organoid models are not only closer to human physiology but also offer advantages such as lower costs, higher efficiency, and alignment with the 3R principles of animal experimentation. Moreover, this platform is not limited to the PeV-A3 virus. The team has also successfully applied it to the Omicron BA.1 variant, finding significant changes in genes related to brain diseases, neurodegeneration, and inflammation after the variant infected the organoids. This further confirms the platform's potential for application in other viral encephalitis cases and emerging infectious diseases such as COVID-19. In the future, this platform could accelerate drug development, providing more effective treatments for patients with viral encephalitis and neurodegenerative diseases.
Resource (mandarin): 幹細胞化身大腦！3D類器官打造抗病毒性腦炎藥物研發平台
