Polyglutamine‐Expanded Ataxin‐3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood. Issue 11 (16th August 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Movement disorders. Volume 36:Issue 11(2021)
• Page Start: 2675
• Page End: 2681
• Publication Date: 2021-08-16
• Subjects: ataxin‐3; Machado‐Joseph disease; spinocerebellar ataxia type 3; singulex technology; target engagement biomarker; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.28749
• Languages: English
• ISSNs: 0885-3185

Abstract

Abstract: Background: 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. Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ‐expanded ataxin‐3 in plasma and cerebrospinal fluid (CSF). Methods: Using the novel single molecule counting ataxin‐3 immunoassay, we analyzed cross‐sectional and longitudinal patient biomaterials. Results: 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. Conclusions: 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