Poster presented at ISSCR 2023 by Seungmi Ryu. The poster is entitled: ESTABLISHING A NEW HUMAN IPSC-DERIVED CEREBELLAR ORGANOID MODEL FOR FRIEDREICH’S ATAXIA.
Authors (underlined, presenting): Seungmi Ryu, Hyenjong Hong, Yogita Jethmalani, Vukasin Jovanovic, Anton Simeonov, Carlos Tristan, and Ilyas Singeç
Friedreich’s ataxia (FRDA), an inherited neurodegenerative disorder, is the most common form of hereditary ataxia in the United States affecting about 1 in every 50,000 people with no cure or effective treatment. It is caused by a GAA repeat expansion mutation in the mitochondrial FXN gene and leads to degenerative changes in the cerebellum, a brain region that controls movement and motor coordination. Most of our current understanding of the human cerebellum is derived from postmortem tissue and animal models. Over the past decade, human induced pluripotent stem cells (iPSCs) have emerged as a powerful platform for disease modeling. Here, we developed a novel 60-day organoid differentiation strategy that recapitulates the hallmarks of human cerebellar development. We confirmed the generation of two primordial regions, the rhombic lip and cerebellar plate ventricular zone, from iPSC lines derived from healthy individuals and FRDA patients. Molecular and cellular analyses revealed that these specified regions can give rise to the main neuronal cell types of the cerebellum, such as granule cells, interneurons, Purkinje cells, and Bergmann glia-like cells that guide migratory neuroblasts to their destination. In comparison to healthy controls, FRDA cerebellar organoids showed disease-specific signatures, such as reduction of the mitochondrial enzyme ACO2 and increased apoptosis. Further analyses indicated abnormal mitochondrial morphology and elevated reactive oxygen species in FRDA cerebellar organoids. Notably, cerebellar organoids with long GAA repeats, which correlate with clinical disease severity, also showed a higher degree of mitochondrial abnormality in vitro. Currently, drug testing, CRISPR-based gene correction, and AAV-mediated gene delivery are underway to test therapeutic options for FRDA. In summary, the newly established cerebellar organoid model provides new opportunities to investigate the fundamental pathophysiology of FRDA in vitro and develop innovative therapies.