Acid ceramidase inhibition as a mechanism to treat lysosomal disorders

Davies, Mari; Riseley, Ross; Jones, Dyfyr H.; Waller-Evans, Helen

doi:10.1016/j.ymgme.2022.107069

Molecular Genetics and Metabolism

2023

DOI: 10.1016/j.ymgme.2022.107069

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Acid ceramidase inhibition as a mechanism to treat lysosomal disorders

Mari Davies¹,

Ross Riseley²,

Dyfyr H. Jones³

et al.

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2024

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Inhibition of acid ceramidase as a therapeutic strategy for Niemann-Pick C disease

Haynes,

Ward,

Jones

et al. 2024

Preprint

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Lysosomal storage disorders (LSDs) are a group of individually rare diseases that as a group constitute the most common forms of childhood neurodegeneration. These life limiting and life shortening diseases have the largest economic burden per patient of any rare disease with the majority being orphan diseases with no disease modifying therapy. Whilst there is significant development in the area of gene therapies for LSDs, these can only be used to treat individual diseases, are expensive, and in recent times many companies have abandoned their gene therapy pipelines. Small molecules on the other hand can be developed to target common mechanisms of pathogenesis or common central disease phenotypes providing therapies that can treat multiple diseases. In this study we report acid ceramidase as a novel therapeutic target for treating Niemann-Pick type C (NPC) disease. Using siRNA, and the literature tool compound carmofur, we observed a reduction in lysosomal area and reduced accumulation of the lipids cholesterol and LBPA in an NPC cellular model. These lipids are known to accumulate as secondary storage molecules across many lysosomal diseases, particularly primary sphingolipid storage disorders where lyso-sphingolipids are known to accumulate via the action of acid ceramidase. As acid ceramidase has also been shown to be a therapeutic target for Krabbe disease, our findings indicate that this is a novel target for the potential treatment of multiple LSDs with primary or secondary storage of sphingolipids.

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Inhibition of acid ceramidase as a therapeutic strategy for Niemann-Pick C disease

Haynes,

Ward,

Jones

et al. 2024

Preprint

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Acid ceramidase inhibition as a mechanism to treat lysosomal disorders

Cited by 1 publication

References 0 publications

Inhibition of acid ceramidase as a therapeutic strategy for Niemann-Pick C disease

Inhibition of acid ceramidase as a therapeutic strategy for Niemann-Pick C disease

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