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

doi:10.1002/mds.28749

. 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 Kuhlbrodt³, Julien Peladan³, Jennifer Faber^{4

5}, Magda M Santana^{6

7

8}, Holger Hengel^{9

10}, Heike Jacobi¹¹, Kathrin Reetz^{12

13}, Hector Garcia-Moreno^{14

15}, Mafalda Raposo¹⁶, Judith van Gaalen¹⁷, Jon Infante¹⁸, Katharina M Steiner¹⁹, Jeroen de Vries²⁰, Marcel M Verbeek^{17

21}, Paola Giunti^{14

15}, Luis Pereira de Almeida^{6

7

22}, Manuela Lima¹⁶, Bart van de Warrenburg¹⁷, 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}

Affiliations

¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
² Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
³ Evotec SE, Hamburg, Germany.
⁴ DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.
⁵ Department of Neurology, University Hospital Bonn, Bonn, Germany.
⁶ Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
⁷ Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
⁸ IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
⁹ Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁰ German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹¹ Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
¹² Department of Neurology, RWTH Aachen University, Aachen, Germany.
¹³ JARA-Brain Institute Molecular Neuroscience and Neuroimaging, Jülich, Germany.
¹⁴ Department of Clinical and Movement Neuroscience, Ataxia Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹⁵ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁶ Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal & Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
¹⁷ Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
¹⁸ Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria (UC), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
¹⁹ Department of Neurology, Center for Translational Neuro- and Behavioral Sciences, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.
²⁰ Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²¹ Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
²² Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.

PMID: 34397117
DOI: 10.1002/mds.28749

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.

. 2021 Nov;36(11):2675-2681.

doi: 10.1002/mds.28749. Epub 2021 Aug 16.

Authors

Affiliations

¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
² Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
³ Evotec SE, Hamburg, Germany.
⁴ DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.
⁵ Department of Neurology, University Hospital Bonn, Bonn, Germany.
⁶ Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
⁷ Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
⁸ IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
⁹ Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁰ German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹¹ Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
¹² Department of Neurology, RWTH Aachen University, Aachen, Germany.
¹³ JARA-Brain Institute Molecular Neuroscience and Neuroimaging, Jülich, Germany.
¹⁴ Department of Clinical and Movement Neuroscience, Ataxia Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹⁵ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁶ Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal & Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
¹⁷ Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
¹⁸ Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria (UC), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
¹⁹ Department of Neurology, Center for Translational Neuro- and Behavioral Sciences, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.
²⁰ Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²¹ Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
²² Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.

PMID: 34397117
DOI: 10.1002/mds.28749

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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Comment in

Comment on: Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.
Hanna Al-Shaikh R, Jansen-West KR, Petrucelli L, Wszolek ZK, Prudencio M. Hanna Al-Shaikh R, et al. Mov Disord. 2022 May;37(5):1120-1121. doi: 10.1002/mds.29008. Mov Disord. 2022. PMID: 35587620 No abstract available.
Reply to: "Comment on: Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood".
Hübener-Schmid J, Kuhlbrodt K, Peladan J; European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) Study Group; Rieß O. Hübener-Schmid J, et al. Mov Disord. 2022 May;37(5):1121-1122. doi: 10.1002/mds.29003. Mov Disord. 2022. PMID: 35587632 No abstract available.

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References

1. Klockgether T, Mariotti C, Paulson HL. Spinocerebellar Ataxia. Nat Rev Dis Primers 2019;5:24.
1. Prudencio M, Garcia-Moreno H, Jansen-West KR, et al. Towards allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3. Sci Transl Med 2020;12:eabb7086.
1. Gonsior K, Kaucher AG, Pelz P, et al. PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study. J Neurol 2021;268:1304-1315.
1. Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet 2014;51:479-486.
1. Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006;66:1717-1720.

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[1] Klockgether T, Mariotti C, Paulson HL. Spinocerebellar Ataxia. Nat Rev Dis Primers 2019;5:24.

[2] Klockgether T, Mariotti C, Paulson HL. Spinocerebellar Ataxia. Nat Rev Dis Primers 2019;5:24.

[3] Prudencio M, Garcia-Moreno H, Jansen-West KR, et al. Towards allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3. Sci Transl Med 2020;12:eabb7086.

[4] Prudencio M, Garcia-Moreno H, Jansen-West KR, et al. Towards allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3. Sci Transl Med 2020;12:eabb7086.

[5] Gonsior K, Kaucher AG, Pelz P, et al. PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study. J Neurol 2021;268:1304-1315.

[6] Gonsior K, Kaucher AG, Pelz P, et al. PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study. J Neurol 2021;268:1304-1315.

[7] Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet 2014;51:479-486.

[8] Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet 2014;51:479-486.

[9] Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006;66:1717-1720.

[10] Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006;66:1717-1720.

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

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

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