铁螯合剂治疗脑铁蓄积性神经变性的基因靶点和应用

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Neharika Marupudi,  and , May P. Xiong*, 
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引用次数: 0

摘要

脑铁积聚性神经变性(NBIA)是一组神经变性疾病,通常由单基因突变引起,导致肌张力障碍、反射亢进等运动失调症状。脑铁积聚可通过核磁共振成像诊断,并被假定为氧化应激的原因,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(PKAN)、PLA2G6相关神经变性(PLAN)、线粒体膜蛋白相关神经变性(MKAN)和β-螺旋桨蛋白相关神经变性(BPAN)。目前还没有治疗这些疾病的方法,但铁螯合剂已被证明具有治疗 NBIA 的潜力。本综述研究了三种螯合剂:去铁胺(DFO)、去铁胺(DFS)和去铁酮(DFP)。去铁胺已被用于治疗阿尔茨海默病(AD)和帕金森病(PD)等神经退行性疾病;然而,这些研究以及 PKAN 研究中与剂量相关的毒性表明,该药物在应用于 NBIA 病例之前仍需进一步开发。除目前临床使用的铁螯合疗法外,其他铁螯合疗法尚未进入临床研究阶段,但它们可能具有目前的螯合剂无法进入大脑的特性。鼻内制剂是螯合疗法的一种有吸引力的研究剂型,因为这种给药方法可以绕过血脑屏障,进入中枢神经系统。基因疗法不同于铁螯合疗法,因为它是对疾病的因果治疗,而铁螯合剂只针对 NBIA 的疾病进展。由于 NBIA 疾病的病理生理学尚不清楚,未来的行动方案应侧重于病因治疗;然而,铁螯合疗法是目前最佳的行动方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation

Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation

Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation

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.

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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
发文量
0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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