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Central Nervous System Therapeutic Targets in Friedreich Ataxia
Human Gene Therapy ( IF 4.2 ) Pub Date : 2020-12-16 , DOI: 10.1089/hum.2020.264
Ian H Harding 1, 2 , David R Lynch 3 , Arnulf H Koeppen 4 , Massimo Pandolfo 5
Affiliation  

Friedreich ataxia (FRDA) is an autosomal recessive inherited multisystem disease, characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery in FRDA, including progress toward novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. In this work, we have re-examined the neuropathology of FRDA, recognizing new issues superimposed on classical findings, and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different time points. As most major targets of long-term therapy are in the CNS, this review uses multiple tools for evaluation of the importance of specific CNS locations as targets. In addition to clinical observations, the conceptualizations in this study include physiological, pathological, and imaging approaches, and animal models. We believe that this review, through analysis of a more complete set of data derived from multiple techniques, provides a comprehensive summary of therapeutic targets in FRDA.

中文翻译:

弗里德赖希共济失调的中枢神经系统治疗靶点

弗里德赖希共济失调 (FRDA) 是一种常染色体隐性遗传的多系统疾病,其特点是神经元系统的脆弱性存在显着差异。一般来说,本体感觉系统似乎较早受到影响,而在疾病后期,小脑齿状核和一定程度上的皮质脊髓束退化。在当前扩大 FRDA 治疗发现的时代,包括新基因疗法的进展,有必要更深入、更具体地考虑神经系统中的潜在治疗目标。在这项工作中,我们重新检查了 FRDA 的神经病理学,认识到叠加在经典发现上的新问题,并剖析了该疾病的外周神经系统 (PNS) 和中枢神经系统 (CNS) 方面以及受影响的细胞类型。需要了解神经病理变化的时间过程,以确定可改变的疾病进展区域以及可以在不同时间点定位的 CNS 和 PNS 位置。由于长期治疗的大多数主要目标位于中枢神经系统,因此本综述使用多种工具来评估特定中枢神经系统位置作为目标的重要性。除了临床观察外,本研究的概念还包括生理、病理和成像方法以及动物模型。我们认为,本综述通过对来自多种技术的更完整数据集的分析,对 FRDA 中的治疗靶点进行了全面总结。
更新日期:2020-12-18
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