Open Access

Jeannette Hübener‐SchmidORCiD, Kirsten Kuhlbrodt, Julien Peladan, Jennifer Faber, Magda M. Santana, Holger HengelORCiD, Heike Jacobi, Kathrin ReetzORCiD, Hector Garcia‐Moreno, Mafalda RaposoORCiD, Judith van Gaalen, Jon InfanteORCiD, Katharina M. Steiner, Jeroen de Vries, Marcel M. Verbeek, Paola Giunti, Luis Pereira de AlmeidaORCiD, Manuela Lima, Bart van de Warrenburg, Ludger Schöls, Thomas Klockgether, Matthis Synofzik, Olaf Riess

• 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