Hübener-Schmid Jeannette, Kuhlbrodt Kirsten, Peladan Julien, Faber Jennifer, Santana Magda M, Hengel Holger, Jacobi Heike, Reetz Kathrin, Garcia-Moreno Hector, Raposo Mafalda, van Gaalen Judith, Infante Jon, Steiner Katharina M, de Vries Jeroen, Verbeek Marcel M, Giunti Paola, Pereira de Almeida Luis, Lima Manuela, van de Warrenburg Bart, Schöls Ludger, Klockgether Thomas, Synofzik Matthis, Riess Olaf
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
Mov Disord. 2021 Nov;36(11):2675-2681. doi: 10.1002/mds.28749. Epub 2021 Aug 16.
Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers.
We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF).
Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials.
Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases.
The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
3型脊髓小脑共济失调是一种罕见的神经退行性疾病，由ataxin-3基因中的CAG重复序列扩增引起。尽管目前尚无治愈性疗法，但降低聚谷氨酰胺（polyQ）毒性的临床前基因沉默方法显示出有前景的结果。鉴于即将开展的临床试验，定量且易于获取的分子标志物作为药效学标志物，尤其是作为靶点结合标志物至关重要。
我们旨在开发一种超灵敏免疫测定法，以特异性测量血浆和脑脊液（CSF）中polyQ扩增的ataxin-3。
使用新型单分子计数ataxin-3免疫测定法，我们分析了患者的横断面和纵向生物材料。
统计分析揭示了与临床参数的相关性以及在从共济失调前期向共济失调期转变过程中polyQ扩增的ataxin-3的稳定性。
这种新型免疫测定法能够定量血浆和CSF中polyQ扩增的ataxin-3，而血浆中ataxin-3水平与疾病严重程度相关。纵向分析表明，polyQ扩增的ataxin-3在短时间内具有高度稳定性。© 2021作者。由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版的《运动障碍》。
