针对弗里德赖希共济失调治疗的基于基因的方法。
Gene-based approaches toward Friedreich ataxia therapeutics.
作者信息
Hebert M D, Whittom A A
机构信息
Department of Biochemistry, 2500 North State Street, The University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
出版信息
Cell Mol Life Sci. 2007 Dec;64(23):3034-43. doi: 10.1007/s00018-007-7293-6.
Friedreich ataxia is an autosomal recessive trinucleotide-repeat disease caused by expanded GAA repeats in the first intron of the FRDA gene. These GAA repeats are suspected to form unusual non-B DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. GAA repeats also induce heterochromatin formation and silencing of the frataxin gene locus. Frataxin plays a crucial role in iron metabolism and detoxification and interacts with electron transport chain proteins. There is no effective therapy for Friedreich ataxia, but antioxidant therapy has shown promise and is currently in clinical trials. In this review we focus on the mechanisms by which expanded GAA repeats reduce transcription and discuss how these findings have lead to gene-based approaches that may be effective in treating Friedreich ataxia.
弗里德赖希共济失调是一种常染色体隐性三核苷酸重复疾病，由FRDA基因第一内含子中GAA重复序列扩增所致。这些GAA重复序列被怀疑形成异常的非B型DNA构象，从而降低转录水平，并随后减少编码蛋白——铁调素的含量。GAA重复序列还会诱导异染色质形成，使铁调素基因位点沉默。铁调素在铁代谢和解毒过程中起关键作用，并与电子传递链蛋白相互作用。目前尚无治疗弗里德赖希共济失调的有效疗法，但抗氧化疗法已显示出前景，目前正处于临床试验阶段。在本综述中，我们重点关注GAA重复序列扩增降低转录的机制，并讨论这些发现如何促成了可能有效治疗弗里德赖希共济失调的基于基因的方法。
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