Xiaolin Lin, Ingrid Åmelem, Jørn-Ove Schølberg, Synnøve Algrøy Fjeldstad, Wannan Tang, Borghild Hvesser Farsund, María Cámara-Quílez, Niklas Nonboe Andersen, Aleksandr Ianovski, Vidar Langseth Saasen, Jing Ye, Mirta Mittelstedt Leal de Sousa, Magnar Bjørås
Juvenile neuronal ceroid lipofuscinosis (JNCL), caused by mutations in the CLN3 gene, is a severe neurodegenerative disorder with limited treatment options. To address this challenge, we have established a suite of patient-derived organoid models that recapitulate key tissues affected in JNCL, including retinal, brain, and neuromuscular junction systems. These models faithfully reproduce hallmark pathological features of the disease and serve as robust platforms for preclinical evaluation of therapeutic strategies. We are currently assessing adeno-associated virus (AAV)-based gene therapies in these organoids. Preliminary findings reveal promising transduction efficiencies and therapeutic responses, with distinct differences in efficacy depending on AAV serotype and construct design—highlighting the need for model-specific optimization. Concurrently, we are utilizing these organoid systems for high-throughput screening of small molecules, including Miglustat and its derivatives, which show potential in rescuing disease-related cellular pathology and may offer complementary or alternative treatment avenues. In the near future, we aim to explore the potential of these patient-derived organoids as high-quality, clinical-grade sources of cells for use in cell therapy. This future direction could open new possibilities for regenerative approaches and personalized treatment strategies in CLN3 disease. Together, these patient-derived organoid models represent a powerful translational bridge from bench to patient care, enabling mechanistic insights, therapeutic discovery, and the development of innovative interventions for JNCL. Our ongoing work aims to refine these platforms and expand their utility in accelerating the development of effective treatments for JNCL.