Spinocerebellar ataxias: prospects and challenges for therapy development.
Spinocerebellar ataxias: prospects and challenges for therapy development.
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脊椎小脑共济失调：治疗开发的前景和挑战。
DOI：
10.1038/s41582-018-0051-6
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Paulson HL
中科院分区：
文献类型：
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作者：
Ashizawa T;Öz G;Paulson HL
脊髓小脑共济失调（SCA）包括40多种常染色体显性遗传神经退行性疾病，主要表现为进行性共济失调。在过去的几年里，对SCA的致病机制的研究已经导致了有希望的治疗策略的发展，特别是对于由多聚谷氨酰胺编码CAG重复序列引起的SCA。靶向致病级联中的第一步的基于核苷酸的基因沉默方法不仅对于多聚谷氨酰胺SCA而且对于由毒性突变蛋白或RNA引起的许多其他SCA都是一种有前途的方法。对于这些和其他新兴的治疗策略，需要良好的协调准备，以进行富有成效的临床试验。为了实现这一目标，来自美国和欧洲的研究人员正在合作，分享来自各自SCA队列的数据。增加对SCA自然史的了解，包括疾病的预表现和早期症状阶段，将改善疾病改善药物临床试验成功的前景。此外，研究人员正在寻找经验证的临床结局指标，以证明对SCA人群变化的反应性。研究结果表明，MRI和磁共振波谱生物标志物将提供疾病活动和进展的客观生物学读数，但需要更多的工作来建立疾病特异性生物标志物，以跟踪治疗试验中的靶点参与。总之，这些努力表明，开发一种或多种SCA的成功疗法并不遥远。
The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away.
DOI：
10.1016/j.jocn.2014.08.006
发表时间：
2015-01
期刊：
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
影响因子：
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作者：
Rozenfeld MN;Nemeth AJ;Walker MT;Mohan P;Wang X;Parrish TB;Opal P
通讯作者：
Opal P