Zebrafish Lysosomal Storage Disease Models

Lysosomal storage diseases (LSDs) are metabolic disorders caused by mutations in lysosomal proteins that lead to lysosomal dysfunction. Loss-of-function mutations in lysosomal proteins disrupt lysosomal catabolism, triggering progressive accumulation of substrate substances and multi-organ pathology. While some enzyme replacement therapies and small molecule drugs have been approved as LSD therapies, most currently known LSDs lack treatment options.

Zebrafish is an attractive model organism for studying genetic diseases, with highly evolved genes and proteins, ease of maintenance and simple genetic and pharmacological manipulations compared to humans. While mammalian and cell-based models have made significant contributions to understanding the etiology of LSD, studies using the zebrafish, a vertebrate with striking resemblance to mammalian systems, as a model for LSD are increasing biology, while also possessing unique advantages such as optical transparency and adaptability for high-throughput screening. Additionally, recent advances in gene editing methods, such as CRISPR-Cas9, have improved the specificity and speed of target model generation and may lead to further improvements in the availability of zebrafish LSD models.

Fig. 1 Accumulation of lysosomal vesicle clusters at the posterior part of the tectum in bloc1s1 mutant zebrafish.

Our Zebrafish Lysosomal Storage Disease Models

Our zebrafish model can be classified into eight disease classes, including sphingolipidosis, mucolipidosis, neuronal ceroid lipofuscinosis, integral membrane protein disease, glycogen storage disease, glycoproteinosis , mucopolysaccharidosis and lysosome-related organelle diseases. We use homology-directed repair to pinpoint point mutations associated with zebrafish disease, stop codon boxes, LoxP sites, epitope markers or reporter proteins, providing more nuanced phenotypic modeling.

Given the current lack of treatment options for most LSDs, there is an urgent need for drug discovery. Each pair of our zebrafish can produce over a hundred embryos per week, so thousands of embryos can be obtained at once for chemical screening. Our existing zebrafish LSD models exhibit screenable phenotypes such as craniofacial defects, microphthalmia, and behavioral changes. Alternatively, we can label different neuronal features by transgenic lines or antibody staining, and then perform imaging-based screens on zebrafish LSD models to identify modulators of neuronal processes such as axon tracing, myelination, Microglia activation and calcium signaling.

Our Advantages

• Rapid identification of small molecules with potential to mitigate myelin loss
• High-throughput imaging of myelinating oligodendrocytes in transgenic zebrafish larvae
• Allows visualization of vasculature during early development
• Targeted gene editing with fine-tuned control of mutations of interest for more accurate disease modeling

Creative Biogene aims to screen potential therapeutics for lysosomal storage diseases through zebrafish models, providing valuable insights into the pathogenesis of a range of zebrafish lysosomal storage diseases. Please contact us to learn more about our services.

References

1. Zhang T, Peterson RT. Modeling Lysosomal Storage Diseases in the Zebrafish. Front Mol Biosci. 2020, 7:82.
2. Cornet C, et al. Combining Zebrafish and CRISPR/Cas9: Toward a More Efficient Drug Discovery Pipeline. Front Pharmacol. 2018, 9:703.
3. Seth A, et al. The emerging use of zebrafish to model metabolic disease. Dis Model Mech. 2013,6(5):1080-1088.
4. Chen T, et al. Development of the Swimbladder Surfactant System and Biogenesis of Lysosome-Related Organelles Is Regulated by BLOS1 in Zebrafish. Genetics. 2018, 208(3):1131-1146.

For research use only. Not intended for any clinical use.