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Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype
Chiara Soldati1, Irene Lopez-Fabuel2,3,4, Luca G Wanderlingh1
1Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
Abstract:
Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent-conjugated bacterial toxins to label Gb3 to develop a cell-based high content imaging (HCI) screening assay for the repurposing of FDA-approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient-derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.
Insights
Tamoxifen reduces globotriaosylceramide (Gb3) accumulation in Batten disease models. This finding suggests tamoxifen may be a potential therapeutic for Batten disease (BD), a group of lysosomal storage disorders.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Batten diseases (BDs) are fatal neurodegenerative lysosomal storage disorders.
- Key features include seizures, vision loss, and progressive cognitive and motor decline.
- Elevated globotriaosylceramide (Gb3) is implicated in CLN3 and CLN7 subtypes of BD.
Purpose of the Study:
- To identify FDA-approved compounds for repurposing to treat Batten diseases.
- To investigate the therapeutic potential of tamoxifen in cellular and murine models of BD.
Main Methods:
- Developed a high-content imaging (HCI) screening assay using fluorescent Gb3 labeling.
- Tested FDA-approved compounds for their ability to reduce Gb3 accumulation in BD cells.
- Utilized patient-derived induced pluripotent stem cells (iPSCs) and a CLN7 mouse model.
Main Results:
- Tamoxifen significantly reduced lysosomal Gb3 accumulation in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs).
- Tamoxifen's mechanism involves activating transcription factor EB (TFEB), enhancing lysosomal and autophagy pathways.
- In vivo, tamoxifen decreased Gb3 and SCMAS levels, reduced neuroinflammation, and improved motor function in CLN7 mice.
Conclusions:
- Tamoxifen demonstrates therapeutic potential for specific Batten disease subtypes by targeting Gb3 accumulation.
- The TFEB pathway activation highlights a novel therapeutic strategy for lysosomal storage disorders.
- Further investigation into tamoxifen as a BD treatment is warranted.
