Marupudi Neharika, Xiong May P
Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602-2352, United States.
ACS Bio Med Chem Au. 2024 Mar 11;4(3):119-130. doi: 10.1021/acsbiomedchemau.3c00066. eCollection 2024 Jun 19.
Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative diseases that are typically caused by a monogenetic mutation, leading to development of disordered movement symptoms such as dystonia, hyperreflexia, etc. Brain iron accumulation can be diagnosed through MRI imaging and is hypothesized to be the cause of oxidative stress, leading to the degeneration of brain tissue. There are four main types of NBIA: pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MKAN), and beta-propeller protein-associated neurodegeneration (BPAN). There are no causative therapies for these diseases, but iron chelators have been shown to have potential toward treating NBIA. Three chelators are investigated in this Review: deferoxamine (DFO), desferasirox (DFS), and deferiprone (DFP). DFO has been investigated to treat neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD); however, dose-related toxicity in these studies, as well as in PKAN studies, have shown that the drug still requires more development before it can be applied toward NBIA cases. Iron chelation therapies other than the ones currently in clinical use have not yet reached clinical studies, but they may possess characteristics that would allow them to access the brain in ways that current chelators cannot. Intranasal formulations are an attractive dosage form to study for chelation therapy, as this method of delivery can bypass the blood-brain barrier and access the CNS. Gene therapy differs from iron chelation therapy as it is a causal treatment of the disease, whereas iron chelators only target the disease progression of NBIA. Because the pathophysiology of NBIA diseases is still unclear, future courses of action should be focused on causative treatment; however, iron chelation therapy is the current best course of action.
脑铁沉积神经变性病（NBIA）是一组神经退行性疾病，通常由单基因突引起，导致诸如肌张力障碍、反射亢进等运动症状紊乱。脑铁沉积可通过磁共振成像（MRI）诊断，据推测是氧化应激的原因，导致脑组织变性。NBIA主要有四种类型：泛酸激酶相关神经变性病（PKAN）、磷脂酶A2G6相关神经变性病（PLAN）、线粒体膜蛋白相关神经变性病（MKAN）和β-螺旋桨蛋白相关神经变性病（BPAN）。这些疾病尚无病因性治疗方法，但铁螯合剂已显示出治疗NBIA的潜力。本综述研究了三种螯合剂：去铁胺（DFO）、地拉罗司（DFS）和去铁酮（DFP）。DFO已被研究用于治疗诸如阿尔茨海默病（AD）和帕金森病（PD）等神经退行性疾病；然而，这些研究以及PKAN研究中的剂量相关毒性表明，该药物在应用于NBIA病例之前仍需进一步研发。目前临床使用之外的铁螯合疗法尚未进入临床研究，但它们可能具有目前螯合剂无法实现的进入大脑的特性。鼻内制剂是一种有吸引力的螯合疗法剂型，因为这种给药方法可以绕过血脑屏障并进入中枢神经系统（CNS）。基因治疗与铁螯合疗法不同，因为它是对疾病的病因性治疗，而铁螯合剂仅针对NBIA的疾病进展。由于NBIA疾病的病理生理学仍不清楚，未来的行动方案应侧重于病因性治疗；然而，铁螯合疗法是目前最佳的行动方案。
