Oral Presentation International Congress on Neuronal Ceroid Lipofuscinoses 2025

Investigating drug repurposing in childhood dementia using patient-derived cell models (125891)

Elina Casoli 1 2 , Anthony R. White 2 , Lotta E. Oikari 2
  1. University Toulouse, Science and Engineering, Toulouse, Haute Garonne, France
  2. Cellular and Molecular Neurodegeneration, QIMR Berghofer, Brisbane, QLD, Australia

Childhood dementia, characterized by a progressive deterioration of neurocognitive functions during childhood, affects approximately 1 in 2,900 children with a median life expectancy of 10 years. This condition can be caused by more than 140 genetic disorders, including lysosomal storage diseases like neuronal ceroid lipofuscinoses (NCL), also known as Batten disease. Batten disease is caused by mutations in the CLN gene, resulting in the toxic accumulation of lipofuscin in neurons. Currently, no curative treatments exist for this condition. In this study, we aimed to investigate drug repurposing as a potential treatment for childhood dementia using patient-derived cell models. Potential therapeutic candidate drugs were first identified via a computational analysis. To assess the efficacy of potential therapeutic treatments, the safe concentrations of therapeutic drugs were first evaluated using ReN cells (an immortalised human neural progenitor cell line) as a preliminary model. ReN cells were spontaneously differentiated into mixed cultures of neurons and astrocytes, after which a dose response of the drugs of interest was performed to identify non-toxic concentrations. After this CLN3 Batten disease induced pluripotent stem cell (iPSC)-derived brain cell cultures were established as a disease-specific cell model. CLN3 brain cells showed an altered expression of lysosomal markers when compared to ReN-derived cultures, demonstrating a disease phenotype. Following characterisation of CLN3 brain cell cultures, the cells were treated with safe concentrations candidate drugs to identify therapeutic effects on lysosome health and lipofuscin accumulation.  

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