Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.
ataxin-3; Machado-Joseph disease; spinocerebellar ataxia type 3; singulex technology; target engagement biomarker
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
27
06
2021
received:
14
04
2021
accepted:
21
07
2021
pubmed:
17
8
2021
medline:
17
3
2022
entrez:
16
8
2021
Statut:
ppublish
Résumé
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. We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. 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. 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.
Sections du résumé
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.
Substances chimiques
Peptides
0
polyglutamine
26700-71-0
Ataxin-3
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2675-2681Subventions
Organisme : Medical Research Council
ID : MR/N028767/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Références
Klockgether T, Mariotti C, Paulson HL. Spinocerebellar Ataxia. Nat Rev Dis Primers 2019;5:24.
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.
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.
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.
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.
Hwang J, Banerjee M, Venable AS, et al. Quantitation of low abundant soluble biomarkers using high sensitivity single molecule counting technology. Methods 2019;158:69-76.
Ko J, Ou S, Patterson PH. New anti-huntingtin monoclonal antibodies: implications for huntingtin conformation and its binding proteins. Brain Res Bull 2001;56:319-329.
Jiao S, Wang P, Chen Z, et al. Age is an important independent modifier of SCA3 phenotype severity. Neurosci Lett 2021;741:135510.
Leotti VB, de Vries JJ, Oliveira CM, et al. CAG repeat size influences the progression rate of Spinocerebellar ataxia type 3. Ann Neurol 2021;89:66-73.
Meeter LHH, Gendron TF, Sias AC, et al. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers. Ann Clin Transl Neurol 2018;5(5):583-597.