Niemann-Pick Disease Type C (NP-C) is a fatal lysosomal storage disorder with progressive neurodegeneration. In addition to the characteristic cholesterol and lipid overload phenotype, we previously found that altered metal homeostasis is also a pathological feature. Increased brain iron in the Npc1−/− mouse model of NP-C may potentially contribute to neurodegeneration, similar to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Deferiprone (DFP) is a brain penetrating iron chelator that has demonstrated effectiveness in preventing neurological deterioration in Parkinson’s disease clinical trials. Therefore, we hypothesized that DFP treatment, targeting brain iron overload, may have therapeutic benefits for NP-C. Npc1−/− mice were assigned to four experimental groups: (1) pre-symptomatic (P15) + 75 mg/kg DFP; (2) pre-symptomatic (P15) + 150 mg/kg DFP; (3) symptomatic (P49) + 75 mg/kg DFP; (4) symptomatic (P49) + 150 mg/kg DFP. Our study found that in Npc1−/− mice, DFP treatment did not offer any improvement over the expected disease trajectory and median lifespan. Moreover, earlier treatment and higher dose of DFP resulted in adverse effects on body weight and onset of ataxia. The outcome of our study indicated that, despite increased brain iron, Npc1−/− mice were vulnerable to pharmacological iron depletion, especially in early life. Therefore, based on the current model, iron chelation therapy is not a suitable treatment option for NP-C.
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The authors wish to thank Dr. Ibrahima Diouf for statistical advice. This work was supported by research grants from the Australian NPC Disease Foundation, Inc. to Y.H.H. and A.I.B.; the Australia-Israel Medical Research Foundation (AUSiMED) to A.L. and A.I.B.; Victoria Israel Science Innovation and Technology Scheme Grants for Feasibility and Proof of Concept Projects to A.L. and A.I.B.; Cooperative Research Centre for Mental Health to A.I.B. The Florey Institute of Neuroscience and Mental Health acknowledges the strong support of the Victorian Government and in particular funding from the Operational Infrastructure Support Grant.
This work was supported by research grants from the Australian NPC Disease Foundation, Inc.; the Australia-Israel Medical Research Foundation (AUSiMED); Victoria Israel Science Innovation and Technology Scheme Grants for Feasibility and Proof of Concept Projects; Cooperative Research Centre for Mental Health; and the Victorian Government Operational Infrastructure Support Grant
Conflict of interest
A.I.B. is a shareholder of Prana Biotechnology Ltd, Cogstate Ltd, Brighton Biotech LLC, Grunbiotics Pty Ltd, Eucalyptus Pty Ltd, and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in Collaborative Medicinal Development LLC.
Animal experimental procedures were approved by the Florey Animal Ethics Committee (AEC# 17–042).
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Hung, Y.H., Lotan, A., Yeshurun, S. et al. Iron chelation by deferiprone does not rescue the Niemann-Pick Disease Type C1 mouse model. Biometals 33, 87–95 (2020). https://doi.org/10.1007/s10534-020-00233-5
- Niemann-Pick Disease Type C
- Npc1 mouse model