Polyglutamine‐Expanded Ataxin‐3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood

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...

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Published in:Movement disorders 2021-11, Vol.36 (11), p.2675-2681
Main Authors: Hübener‐Schmid, Jeannette, Kuhlbrodt, Kirsten, Peladan, Julien, Faber, Jennifer, Santana, Magda M., Hengel, Holger, Jacobi, Heike, Reetz, Kathrin, Garcia‐Moreno, Hector, Raposo, Mafalda, Gaalen, Judith, Infante, Jon, Steiner, Katharina M., Vries, Jeroen, Verbeek, Marcel M., Giunti, Paola, Pereira de Almeida, Luis, Lima, Manuela, Warrenburg, Bart, Schöls, Ludger, Klockgether, Thomas, Synofzik, Matthis, Riess, Olaf
Format: Article
Language:English
Subjects:
Ataxia
Ataxin
Ataxin-3 - genetics
ataxin‐3
Machado‐Joseph disease
spinocerebellar ataxia type 3
singulex technology
target engagement biomarker
Biomaterials
Cerebrospinal fluid
Clinical trials
Cross-Sectional Studies
Humans
Immunoassay
Machado-Joseph disease
Machado-Joseph Disease - drug therapy
Machado-Joseph Disease - genetics
Movement disorders
Neurodegenerative Diseases
Peptides
Peripheral blood
Pharmacodynamics
Polyglutamine
Statistical analysis
Toxicity
Trinucleotide repeat diseases
Trinucleotide repeats
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Summary: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
ISSN:0885-3185
1531-8257
DOI:10.1002/mds.28749