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Published on: June 14, 2018
Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study
Rita Pepponi1, Roberta De Simone1, Chiara De Nuccio2
1National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Abstract:
Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC.
Insights
Targeting adenosine levels shows promise for treating Niemann-Pick type C disease (NPC). Dipyridamole, by increasing adenosine, reduced cholesterol buildup and improved mitochondrial function in NPC patient cells.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Niemann-Pick type C disease (NPC) is a rare lysosomal lipid storage disorder impacting organs and the central nervous system.
- Current therapeutic options for NPC are limited, necessitating novel treatment strategies.
- Reduced brain adenosine levels are observed in NPC animal models, suggesting a potential therapeutic target.
Purpose of the Study:
- To investigate the potential of increasing adenosine levels as a therapeutic approach for Niemann-Pick type C disease.
- To evaluate the efficacy of dipyridamole, an ENT1 inhibitor, in ameliorating NPC cellular phenotypes.
Main Methods:
- Fibroblasts from NPC1 patients were treated with dipyridamole, a known inhibitor of the equilibrative nucleoside transporter 1 (ENT1).
- Assessed the impact of dipyridamole on cellular cholesterol accumulation and mitochondrial function.
- Investigated the role of adenosine A2A receptor (A2AR) activation in mediating the observed effects.
Main Results:
- Dipyridamole treatment significantly reduced cholesterol accumulation in NPC1 patient fibroblasts.
- Dipyridamole rescued mitochondrial deficits observed in NPC patient cells.
- The therapeutic effects were linked to increased extracellular adenosine levels due to ENT1 inhibition, leading to adenosine A2A receptor activation.
Conclusions:
- Targeting adenosine tone represents a viable therapeutic strategy for Niemann-Pick type C disease.
- Dipyridamole demonstrates potential as a therapeutic agent for NPC by modulating adenosine signaling.
- These findings provide proof of concept for developing adenosine-based therapies for NPC.
