Oxidation Biology Unit, Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Melbourne, VIC, 3052, Australia.
Department of Psychiatry and the Biological Psychiatry Laboratory, Hadassah Hebrew University Medical Center, Jerusalem, 91120, Israel.
Biometals. 2020 Jun;33(2-3):87-95. doi: 10.1007/s10534-020-00233-5. Epub 2020 Feb 25.
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.
尼曼-匹克病 C 型（NP-C）是一种致命的溶酶体贮积病，伴有进行性神经退行性变。除了特征性的胆固醇和脂质过载表型外，我们之前还发现，金属稳态失衡也是一种病理特征。NP-C 的 Npc1 小鼠模型中大脑铁含量增加可能潜在导致神经退行性变，类似于阿尔茨海默病和帕金森病等神经退行性疾病。地拉罗司（DFP）是一种穿透血脑屏障的铁螯合剂，在帕金森病临床试验中已证明对预防神经恶化有效。因此，我们假设针对脑铁过载的 DFP 治疗可能对 NP-C 具有治疗益处。Npc1 小鼠被分配到四个实验组：（1） 无症状前（P15）+75mg/kg DFP；（2） 无症状前（P15）+150mg/kg DFP；（3） 有症状（P49）+75mg/kg DFP；（4） 有症状（P49）+150mg/kg DFP。我们的研究发现，在 Npc1 小鼠中，DFP 治疗并没有改善预期的疾病轨迹和中位寿命。此外，早期治疗和更高剂量的 DFP 导致体重下降和共济失调的发生。我们的研究结果表明，尽管大脑铁含量增加，Npc1 小鼠仍容易受到药物性铁耗竭的影响，尤其是在生命早期。因此，根据目前的模型，铁螯合疗法不是 NP-C 的合适治疗选择。
