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. 2021 Nov;36(11):2675-2681.
doi: 10.1002/mds.28749. Epub 2021 Aug 16.

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

Jeannette Hübener-Schmid  1   2 , Kirsten Kuhlbrodt  3 , Julien Peladan  3 , Jennifer Faber  4   5 , Magda M Santana  6   7   8 , Holger Hengel  9   10 , Heike Jacobi  11 , Kathrin Reetz  12   13 , Hector Garcia-Moreno  14   15 , Mafalda Raposo  16 , Judith van Gaalen  17 , Jon Infante  18 , Katharina M Steiner  19 , Jeroen de Vries  20 , Marcel M Verbeek  17   21 , Paola Giunti  14   15 , Luis Pereira de Almeida  6   7   22 , Manuela Lima  16 , Bart van de Warrenburg  17 , Ludger Schöls  9   10 , Thomas Klockgether  4   5 , Matthis Synofzik  9   10 ; European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI) Study Group; Olaf Riess  1   2
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Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood

Jeannette Hübener-Schmid et al. Mov Disord. 2021 Nov.

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.

Keywords: ataxin-3; Machado-Joseph disease; spinocerebellar ataxia type 3; singulex technology; target engagement biomarker.

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References

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